CA2226963A1 - Crystalline zap family proteins - Google Patents

Abstract

The invention relates to human ZAP-70, and in particular, to the region of ZAP70 containing the tandem Src homology-2 ("SH2") domains, to crystalline forms thereof, liganded or unliganded, which are particularly useful for the determination of the three-dimensional structure of the protein. The threedimensional structure of the tandem SH2 region of ZAP provides information useful for the design of pharmaceutical compositions which inhibit the biological function of ZAP and other members of the ZAP family of SH2 domaincontaining proteins, particularly those biological functions mediated by molecular interactions involving one or both SH2 domains.

Description

- DEN~ANDES OU ~3REVFrS VOLUMINEVX

LA PRÉSEI\ITE PARTIE DE CETTE DEMANDE OU CE BREYET
COMPREND PLUS D'U~ TOME.

CECl E~ST LE ~C3~E / DE ~

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THAN ON~ VOLUME

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NO~E: For addltiona1 wf~mes-please c~3ntac~~the C:anad;an Patent aff~ca .

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Crystalline ZAP Family Proteins Copyright Notice A portion of the ~licclosllre of this patent document contains material which is subject to copyright prule~;lion. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or patent riicclQs~lre~ as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever.

Field of the Invention The invention relates to human ZAP-70, and in particular, to the region of ZAP-70 containing the tandem Src homology-2 ("SH2") domains, to crystalline forms thereof, liganded or 1~ unliganded, which are particularly useful for the determination of the three-dimensional structure of the protein. The three dimensional structure of the tandem SH2 region of ZAP
provides i~ ,r".dlion useful for the design of pharmqceuti~AI cor"posilions which inhibit the biologicql function of ZAP and other proteins of the ZAP family, particularly those biological functions mediated by molecular interactions involving one or both SH2 dor.,~i"s.
Background Safe and effective immunosu~plessive agents are required for the treatment of patients suffering from autoimmune disorders and for recipients of transplanLed organs or tissues. For 2~ instance, in the absence of an effective immunosu~ s:,ive agent, patients often reject a transplanted organ, sometimes with fatal consequences. The immunosuppressive agent must block the immune response, but must also be sufficiently well tolerated by the body to permit chronic applicdL,on. For instance, one compound with immunosu~p,~ssive activity, FK506, has been used to prevent rejection of lldnsplallLt:d livers. I l~ ever, severe kidney toxicity has been 30 observed in palie.~l receiving FK506, in some cases requiring kidney transplant following the liver transplant.

Research aimed at discovering new immunosuppressive agents has been hampered by the lack of information about precise ~ sc~lqr mecl.al.;_.,.s of the immune response. As a result, random 3~ screening of compounds has accounted for a substantial share of ,t,sea~:l. efforts aimed at identifying new immunosuppressive drugs. More recently, "structure-based" approaches to drug design have been dll~"-,uled. For example, compounds de:~iylled to bind to the protein FKBP, one of the cellular targets of FK~06, were synthesized as car ~' immunosu~upl~ssive agents.
Those efforts were unfortunately doomed by the lack of unde~:,ldnd,.,g of the actual molec~ r .

SUBSTITUTE ~}~EE~ ~RULE 26) W O 97/08300 PCT~US96/13918 ~l~echao;;"" of immunosu~,,u,~ssion mediated by FK506. It is now known that FK~;06 binds in a complex with two proteins, FKBP and calcineurin. FKCi06s immunosuppressive effects are due to the illl-9' ~:ion of calcineurin in T cells. However, since calcineurin is present and i""oo.l~"l in other cells, FK506 affects other cells and tissues leading to undesired effects.
c;
Meanwhile independent efforts have led to the identification of a protein tyrosine kinase, ZAP-70, as a critical mediator of the immune response. Blocking the biclogical function of ZAP-70 will lead to immunosuppression. Unfortunately until now three-dimensional structural details of ZAP-70 have been co"- ~ r'y u-ll~lloJL.,. In the absence of three-.li.-.ensional 10 structural details for that protein, des;y.,i.,g i,-l ~: ,rs- based on that structure would have been ;IIIIJOS-' e. We have now obtained crystals of a critical region of ZAP-70 containing its tandem SH2 dGr"a;":;, with and without bound ligands of various types. and have del~ ,ed its three dimensional structure. With this i"r.~lllldlion it is now possible for the first time to rationally design i--hiL;tol~ of ZAP-70 which can function as immunosu~J-essive agents e.g. compounds 15 which inhibit molecular interactions involving one or both of the ZAP-70 SH2 domains.
Although the three-dimensional structures for several individual SH2 domains of other proteins are known no one has heretofore reported determining the three-dimensional structure of a tandem SH2 region. And, as we discuss below the three-di-"el-sic nal coordinates of previously known SH2 domains would have been insufficient to solve the structure of the 2 0 ZAP-70 tandem SH2 region.

Summary of the Invention This invention concerns the region of human ZAP-70 :,pan"i"g its two SH2 domains. We refer to 2 5 that region as the ZAP tandem SH2 region" or simply ZAP-NC since the region contains both the more N-terminal SH2 domain and the more C-terminal SH2 domain of human ZAP-70 (see FIG. 4). The invention begins with obl..i.-;"g crystals of human ZAP-NC, cor"~ ~ed or u"cor" lexed with various iigands of sufficient quality to determine the three ii."ensional (tertiary) structure of the protein by X-ray diffraction methods.
In considering our work, it should be appreciated that ol,l~;, ,g protein crystals in any case is a somewhat ullpr~ic 'le art, especially in cases in which the practitioner lacks the çluidance of prior successes in preparing and/or crystalizing any closely related proteins. Obtaining our first crystals of ZAP-NC was therefore itself an unexpected result. In addition, our 3~ dete""i"alioll of the three-dimensional structure of ZAP-NC represents the first solution of a three-~ ~-ensional structure for a tandem SH2 region from any protein and revealed an unpredicted array of surface features which contained truly surprising structural aspects. Our results are useful in a number of Applic~liolls.

SUBSTITUTE S~tE~ ~RULE 26~

WO 97/08300 PCTrUS96/13918 For example, the knowledge obtained concerning ZAP-NC can be used to model the tertiary structure of reiated proteins. For instance the structure of renin has been ~"odrlEd using the tertiary structure of endull,iapepsin as a starting point for the derivation. Model building of cercarial el~st~-se and tophozc ile cysteine protease were each built from known serine and 5 cysteine proteases that have less than 35% sequence identity. The resultant models were used to design i"hi.,i~or:j in the low micromolar range. (Proc. Natl. Acad. Sci. 1993, 90, 3583).
~ Furthermore, alternative methods of tertiary structure determination that do not rely on X-ray diffraction techniques and thus do not require cryst~ tion of the protein such as NMR
techniques, are simplified if a model of the structure is available for refinement using the 1 0 additional data gathered by the alternative technique. Thus, knowledge of the tertiary structure of the ZAP tandem SH2 region provides a significant window to the structure of the other ZAP
family members, including for example SYK.

Knowledge of the three-dimensional structure of a tandem SH2 region such as ZAP-NC provides 15 a means for investigating the mechanism of action of the protein and tools for identifying inh;LiLo,:, of its function. For exampie, SH2 domains are known to be involved in intramolecular and intermolecular interactions usually protein-protein interactions which are critical for biological activity of the SH2-bearing protein. Knowledge of the three-P ,.en~ional structure of the tandem SH2 region allows one to design ~---le ~les capable of binding thereto, including molecules which are thereby capable of illl,;bilillg the interaction of the tandem SH2 region with its natural ligand(s).

Acco~ ii.,uly, one object of this invention is to provide a composition colllpliailly a protein in crystalline form having a peptide sequence derived or selected from that of a protein of the ZAP
family. The protein will comprise at least one and preferably two SH2 domains e.g. a protein containing the tandem SH2 region of ZAP-70, SYK or other related tandem SH2 conl~i-,i"g protein. In the case of ZAP-70, the protein may comprise a peptide sequence spanning at least amino acid residues 3-279. Such a crystalline co""~osilion may contain one or more heavy atoms, e.g., one or more lead mercury, gold and/or selenium atoms for instance. Such a heavy atom derivative may be obtained for example, by ekuressi"g a gene encoding the protein under condilions permitting the incorporation of one or more heavy atom labels (e.g. as in the incorporation of selenomethionine), reacting the protein with a reagent capable of linking a heavy atom to the protein (e.g. trimethyl lead acetate) or soaking a substance conl~i"i"g a heavy atom into the crystais.
~ The protein may be in the form of a complex with one or more ligand molecules "ligand" being used in the broadest sense, referring to any substance capable of observable binding to the protein. The peptide sequence of naturally occuring ligands ("ITAMs", see below) for a number of SH2 domains is known and consensus sequence i,.lu""alion on peptide ligands for SH2 SUBS~tTUTE ~}~FE~ ~RULE 26) W O g7/08300 PCT~US96/}3918 dGn,ai"s has been r~iccussed in the scientific literature. In the case of ZAP-70, peptide ligands of 15-1g residues derived in sequence from naturally occuring ligands for ZAP-70 or other SH2 donnains may be used. Those ligands typically contain one or two phosphorylated tyrosine residues. Alternatively, one or both of such phosphorylated tyrosine moieties may be replaced 5 by phospl,ol~/rosine mimetic reagents, numerous e~d~ S of which are known in the art.

Illustrative crystalline compositions of this invention having various physicochemical characteristics are tiicclr75ed infra. Preferred crystalline cor"posilions of this invention are cAr~hle of diffracting x-rays to a resolution of better than about 3.~ A, and more preferably to 1 0 a resolution of 2.6 A or better, and even more ,l~reierably to a resolution of 2.2 A or better, and are useful for determining the three-dimensional structure of the material. (The smaller the number of angstroms, the better the resolution.) Crystalline co",posilions of this invention specifically include those in which the crystals 15 comprise ZAP-family proteins characterized by the structural coordinates set forth in any of the acco""~anying Appendices or characterized by coo,d ,dles having a root mean square devidlion Lhere~,~"", with respect to backbone atoms of amino acids listed in the Appendices, of 1.5 A or less.

2 0 Structural coordindL~s of a crystalline cor"posilion of this invention may be stored in a machine-readable form on a machine-ref31' ' "~ storage medium, e.g. a computer hard drive, diskette, DAT tape, etc., for display as a three-di-"el-sional shape or for other uses involving computer-~ssistPd manipulation of, or computation based on, the structural coo,di"~les or the three-dimensional structures they define. For example, data defining the three dimensional 2 5 structure of a protein of the ZAP family, or portions or structurally similar homologues of such proteins, may be stored in a machine-readable storage medium, and may be displayed as a graphical three-dimensional representation of the protein structure, typically using a computer capable of reading the data from said storage medium and p~uy~dm~ed with instructions for creating the representation from such data. This invention thus encompasses a 3 0 machine, such as a computer, having a memory which collldills data representing the structural cool~indles of a crystalline composition of this invention, e.g. the coordinates set forth in our Appendices, together with additional optional data and instructions for manipulating such data.
Such data may be used for a variety of purposes, such as the elucld~tion of other related structures and drug discovery.
For example, a first set of such machine ,~adable data may be co" ~ led with a second set of machine-re~d~hlE data using a machine programmed with instructions for using the first data set and the second data set to determine at least a portion of the coo,d;..dLes cc",~3ponding to the second set of machine-readable data. For i,.sldnce, the first set of data may cG",pri-,e a Fourier SUBSTITUTE ~}E~ ~RULE 2~i~

W O 97/08300 PCT~US96/13918 I,dn:,~Gr." of at ieast a portion of the coor~li.,ales for ZAP or SYK proteins set forth in the Appendices hereto, whiie the second data set may comprise X-ray ~itr,d-,lion data of a ~. -'9 ~'~
or molecu' r complex.

5 More specifically, one of the objects of this invention is to provide three-dimensional structural information on new complexes of ZAP family members with various ligands, as weil ~ as structural i,,ru,.. alion on other tandem SH2 regions, previously unsolved individual SH2 domains, new ZAP family members and muteins or other variants of any of the foregoing. To that end, we provide for the use of the structural coordi.,dles of a crystalline co--.posiiion of this 10 invention, or portions thereof, to solve, e.g. by molecular replacement, the three dimensional structure of a crystalline form of such a protein or protein:ligand complex, typically involving a protein containing at least one SH2 domain. Doing so involves obtaining x-ray diffraction data for crystals of the protein or protein:ligand co-complex for which one wishes to determine the three dimensional structure. Then, one determines the three-dimensional structure of that 15 protein or complex by analyzing the x-ray diffraction data using molecular replacement techniques with reference to the previous structural coordinates. As described in US Patent No.
5,353,236, for instance, molec~ r replacement uses a molecule having a known structure as a starting point to model the structure of an u..k..c,.." crystalline sample. This technique is based on the principle that two molecules which have similar structures, orientations and positions 20 in the unit cell diffract similarly. Molecular replacement involves posi~ior,i,.g the known structure in the unit cell in the same location and orientation as the unh--~.r.-l structure. Once positioned, the atoms of the known structure in the unit cell are used to CAICIII~te the structure factors that would result from a hypothetical diffraction experiment. This involves rotating the known structure in the six dimensions (three angular and three spatial dimensions~ until 2 5 alignment of the known structure with the experimental data is achieved. This approximate structure can be fine-tuned to yield a more accurate and often higher resolution structure using various refinement techniques. For instance, the resultant model for the structure defined by the experimental data may be s~lhjectf3d to rigid body refinement in which the model is s-~hJect~d to limited additional rotation in the six .~i...ensions yielding positioning shifts of under about 30 5%. The refined model may then be further refined using other known r~ri.,er"e"l methods.

For example, one may use molecular replacement to exploit a set of coordinates such as set forth in Appendix 1, Appendix ll or Appendix lll to determine the structure of a crystalline co-complex of ZAP-NC, or a portion thereof, with a ligand other than the ~1 peptide. Likewise one 35 may use that same approach to del~r.,.i.,e the three dimensional structure of a co-complex of SYK-NC, or a portion thereof, with a ligand therefor.

Another obJect of the invention is to provide a method for deLe." .i.,g the three-di..,ensional structure of a protein conldill ,9 at least one SH2 domain, or a co-co,. ,1 ~ of the protein with a SUBSTITUTE ~ RULE 26) W O 97/08300 PCT~US96/13918 ligand therefor, using homology ",od-" ,g tecl.~ es and structural coon' lal3s tor a cGIll~osilion of this invention. Homology modeiing invo~ves constructing a model of an u l.hl,o..,l structure using structural coordinates of one or more related proteins, protein domains and/or subdomains. I l~ lc~,~r modeling may be conducted by fitting collllllon or hol~ us portions of the protein or peptide whose three dim~nsional structure is to be solved to the three ,li",ensional structure of homologous structural elements. Homology modeling can include rebuilding part or all of a three di",ensional structure with replacement of amino acids (or other co~"poner,l~) by those of the related structure to be soived. For ~alll,~ E, using the structural coor.Ji,l~L~s of ZAP-NC colllpl~,~ed with the ~1 peptide, one may determine the three dil.,ensional structure of SYK-NC or a portion thereof, using homology ",odeli"g. A set of cooldillales defining the three dimensil",al structure of SYK-C c01" ' ed with the peptide Thr-pTyr-Glu-Thr-Leu which were obtained from evaluation of NMR data are set forth in Appendix IV. Those coon li ,ales may be stored, displayed, [lldrl', ~ t~d and otherwise used in like fashion as the ZAP-NC coordinates of Appendices I - Ill.

Thus, crystalline coi,,,uosilions of this invention provide a starting material for use in solving the three-dimensional structure of other members of the ZAP-70 family of proteins, notably SYK, as well as newly discovered proteins co~ il ,9 at least one SH2 domain and linking polypeptide (i.e., non-SH2 polypeptide) where the linking polypeptide has at least about 2~%
peptide sequence similarity, or pref~rdbly Identity, to a portion (preferably at least six amino acids) of the ZAP-NC or SYK-NC inter-SH2 linking domain. Sequence similarity may be determined using any conventional sil"ilariLy matrix. See e.g. Dayhoff, M.O.; Schwartz, R.M.;
Orcutt, B.C., Atfas of Protein Sequence and Structure 1979, ~, Suppl. 3,345; Greer, J., J.
Mol. Biol. 1981, 1~3, 1027; and Gonnet, G.H., Cohen, M.A., Benner, S.A. Science t992, 2~6, 2 5 1443. Proteins conLdi- .g at least one SH2 domain together with non-SH2 domain peptide sequence homologous to the interdomain linker of ZAP or SYK, i.e. containing at least 25%
peptide sequence identity or similarity as described above, are considered ZAP family members for the purpose of this riiCClOsure.

3 0 By way of further example, the structure defined by the machine readable data may be corrrut~tionally evaluated for its ability to associale with various chemical entities. The term "chemical entity", as used herein, refers to chemical compounds, coi..plexes of at least two ~;i,e.. ' compounds, and t.~y,ne"L, of such compounds or co,l,, I - ~~

35 For i.~ nce, a first set of machine-readable data defining the 3-D structure of a ZAP-family protein, or a portion or co-co--,pisx thereof, is combined with a second set of machine-readable data d~til "~ the structure of a chemical entity or moiety of interest using a machine pro~.~",.led with instructions for evaluating the ability of the chemicai entity or moiety to ~-cso~ le with the ZAP-family protein or portion or complex thereof and/or the location and/or SVBSTITUTE S~t E~ (RU~ E 2~;~

W O 97/08300 PCTrUS96/13918 orientation of such ~csoci~tion. Such ",ell,ods provide insight into the location, orientation and ener~etics of ACso~iQtion of the ZAP family protein with such chemical entities.
Chemical entities that are capable of associating with the ZAP family member may inhibit its interaction with naturally occurring iigands for the protein and may inhibit biological functions mediated by such interaction. In the case of ZAP-70, such L-~lcg;cal functions include activation of T cells during an immune response. Such chemical entities are potential drug can " ' 1 () The protein structure encoded by the data may be displayed in a g,~p~ -- format per",illi"g visual inspection of the structure, as well as visual inspection of the structures association with chemical entities. Alternatively, more quantitative or computational methods may be used.
For example, one method of this invention for evaluating the ability of a che--. entity to ~soci tP with any of the rro ec~'es or molecular complexes set forth herein comprises the steps 15 of: a) employing computational means to perform a fitting operation between the chemical entity and a binding pocket or other surface feature of the molecule or molecular complex; and b) analyzing the results of said fitting operation to quantify the association between the cl)e,.,ical entity and the binding pocket.

2 0 This invention further provides for the use of the structural coordinates of a crystalline composition of this invention, or portions thereof, to identify reactive amino acids, such as cysteine residues, within the three-dimensional structure, pr~erably within or adjacent to a ligand binding site; to generate and visualize a l"~.ec ~ r surface, such as a water-~cess:'-lc surface or a surface cor-p~i~i,-g the space-filling van der Waals surface of all atoms; to 2 5 C~lClll~tf? and visualize the size and shape of surface features of the protein or complex, e.g., ligand binding pockets; to locate potential H-bond donors and accel.lu-s within the three-di".ensional structure, preferably within or adjacent to a ligand binding site; to calculate regions of hydrophobicity and hydrophilicity within the three-cli" .ensional structure, preferably within or adjacent to a ligand binding site; and to c~lc~ tp~ and visualize regions on 3 0 or adjacent to the protein surface of favorable interaction energies with respect to selected functional groups of interest te.g. amino, hydroxyl, carboxyi, methylene, alkyl, alkenyl, aromatic carbon, aromatic rings, heteroaromatic rings, s~hstitllted and uncllhstituted phosphates, sllhstitlltpd and unsllhstitutp-d pl~ospl~onales, sl~hstit~lt~d and unc hstit ted fluoro and difluorophosphonates; etc.). One may use the foregoing applua-;hes for characterizing the 3 5 protein and its interactions with moieties of potential ligands to design or select compounds capable of specific covalent attachment to reactive amino acids (e.g., cysteine) and to design or select compounds of cû.--pl~..-entary characteristics (e.g., size, shape, charge, hydrophobicity/hydrophilicity, ability to participate in hydrogen bonding, etc.~ to surface features of the protein, a set of which may be preselected Using the structural coG--J;,-ales, one .

CUBST~TUTE ~tE~ tRULE 26 W O 97/0~300 PCT~US96/13918 may also predict or c~31c~ t~ the orierlldlion, binding COI1YI~III or relative affinity of a given ligand to the protein in the cc,~ xed state, and use that information to design or select compounds of improved affinity.

5 in such cases, the structural coordinates of the ZAP family protein, or portion or complex thereof, are entered in machine readable form into a machine proy-d",-"ed with instructions for carrying out the desired operation and co"lai" ,g any necessary addilional data, e.g. data defining structural and/or functional characteristics of a potential ligand or moiety thereof, defining molecular chara-;letislics of the various amino acids, etc.

One method of this invention provides for selecting from a dat~h~ce of chemical structures a compound capable of binding to a ZAP family protein. The method starts with structural coor~li"ales of a crystalline co~"~,osilion of the invention, e.g., coordinates defining the three dimensional structure of a ZAP family protein or a portion thereof. Points ~sori~ted with that 15 three dimensional structure are characterized with respect to the favorability of interactions with one or more functional groups. A database of chemical structures is then searched for carldil~te compounds conldil ~ ~y one or more functional groups disposed for favorable interaction with the protein based on the prior characterization. Compounds having structures which best fit the points of favorable interaction with the three dimensional structure are thus 2 0 identified.

It is often plt:rl:"ed, although not required, that such searching be conducted with the aid of a computer. In that case a first set of machine~ data defining the 3D structure of a ZAP-family protein, or a portion or protein-ligand complex thereof, is combined with a second set of 2 5 machine readable data defining one or more moieties or functional groups of interest, using a machine programmed with instructions for identifying preferred locations for favorable interaction between the functional group(s) and atoms of the protein. A third set of data, i.e.
data defining the location(s) of favorable interaction between protein and functional group(s) is so generated. That third set of data is then co",': ,ed with a fourth set of data defining the 3D
3 0 structures of one or more chemical entities using a machine programmed with instructions for identifying chemical entities conlai"l ,g functional groups so disposed as to best fit the locations of their respective favorable interaction with the protein.

Compounds of the structures selected or designed by any of the ~or~s ~ ,g means may be tested 3 5 for their ability to bind to a ZAP family protein, inhibit the binding of a ZAP family protein to a natural or non-natural ligand therefor, and/or inhibit a L;olo~;ç~l function mediated by a ZAP
family member.

SUE~STiTUTE SI~E~ ~RULE 2~;~

CA 02226963 l998-02-l2 This invention also provides pe~,lidon,i",etic methods for designing a compound capable of binding to a ZAP family protein. One such method involves graphically displaying a three-di."ensional representation based on coo..Ji"ates defining the three- ~i",ensional structure of a ZAP family protein or a portion thereof complexed with a ligand. Interactions between portions 5 of a ligand and the protein are characterized in order to identify can moieties for replacement. One or more portions of the ligand which interact with the protein may be replaced with suhstit(lte moieties selected from a knowl~dge base of one or more candidate substitute moieties, and/or r"~ ;ss may be added to the ligand to permit additional interactions with the protein.

The computational approaches and structural insights r~icclosed herein also permit the design or iden~i~icdlion of moiecules with redL~ced capability, or substantial inability, to bind to a ZAP
family protein. To such end, one may app~y the same .llodel;"g and computational methods to the data described herein, but with the opposite goal, i.e., to design or identify compounds which 15 lack substantial binding affinity to one or more ZAP family members. That can be useful in research efforts aimed at discovery of inhibitors of SH2-mediated interactions other than those mediated by a ZAP family member. The goal of such efforts are inhibitors of those other SH2-mediated interactions which lack ZAP-fami~y mediated activities, such as immunosuppression, which in that context, would be u~desiled side effects.
Compounds first identified by any of the methods described herein are also enco""~assed by this invention.

Brief Description of the Drawings FIG. lA Backbone ribbon representation of the overall fold of the complex of ZAP-NC and the ~1 peptide oriented such that the N-terminal SH2 domain is on the left-hand side of the figure, the C-terminal SH2 domain is on the right-hand side of the figure and the inter-SH2 domain region is in the middle, I,oppi.,g toward the bottom of the figure. Secondary structural elements 3 0 are labeled accor Ji"g to the convention for SH2 domains.20 An a-carbon trace of the peptide is included. All elements are labeled in ZAP-N; in ZAP-C, only the central sheet and helices are labeled. Termini of the protein and peptide are denoted by N and ~::. Loop regions are named for the secondary ele.-l~ , which they connect, i.e., the BC loop conl-e-,t~ strands B and C. The N
terminus of the peptide is at the right-hand side of the figure. The peptide consi~l:, of 1 3 5 residues, starting at residue 48 of the mature ~ subunit of the T cell receptor (TCR3.
Phosphotyrosines are at relative positions 4 and 15. D~:~i"ilion of least squares planes fitted to the main chain atoms of each pYXXL motif gene,dles a pair of planes at an angle of 120~. Due to the sldggert:d c~ri~llldLion of the SH2 do.,lail,s, the pYXXL motifs are seuardled by an S -shaped segment of peptide. This sequence cor.~di..s nearly one full turn of an a-helix between residues g SUBSTITUTE S~EE~ (~ULE 2~i~

CA 02226963 l99X-02-12 W O 97/08300 PCT~US96/13918 Asn 8 and ~ Arg 12. Pockets for each pY and pY~3 residue are visible. it is notable that the N-terminal ~1 residues contribute to the enclosure of ~ pTyr 4. The figure was generated with Sybyl ~Tripos~. An electron density map of the region near the interface between the two SH2 domains may be c:~lc~ t~d with 21Fol-lFcl co,~ for data between 15.0 and 1.9 A, 5 contoured at 1.0 s.

FIG. 1 B The BC loop, from ,~ B5 to B C3, of ZAP-N may be superimposed with the co.,t::,pond;..g residues of the Lck SH2:middle T co-~ ~ and the relative position of the BC loops examined when the structures are fitted accolcl;..g to secondary structural ele-.-enl~. Superimposition of 10 the backbone atoms of the loops results in an r.m.s. dcvid~ion of 0.65 A. Similar results are observed with the B~ loop of ZAP-C. In co.. '-- - of pl1ospl~ope~,tides with isolated SH2 do",ai"s the BC loop contributes neariy half of the direct hydrogen bonds to the pho~phdla group. For both SH2 domains of ZAP-NC the BC loop is extended such that several waters are mediating contact between the loop and the pl~osplldl~ group. An t:~lended cunrulllidliùll is also 1 5 observed for unco.,.i~lexed SH2 domains, and has been l~ollt:d in cc".,pl~xes with peptides in which the phosphate group is replaced by a phos~ unale.14 The loop is repositioned via a hinged motion about the residues at ,~ B5 and ,3 C3. The B~:; loop of ZAP-C is more extende-l Z~P-N
experiences hindered motion about BC due to its inl~ld~;liuns with ZAP-C.

2 0 FIG. 2 Sequence ali~ , . .e. -l~ [SEQ ID NOS 21 - 25~ for s~le~ Led SH2 ciu. - -a;, .:,.33 Boxed areas indicate segments used for measuring "full" backbone r.m.s. deviation; unboxed areas are ~Y~ ded from the c~lc~ tion due to the presence of gaps for one or more of the sequences.
Notation below the aliy,...-enl:, indicate structurally conserved regions, and use the previously reported nomenclature;2U these regions were used for the "core" r.m.s. deviation c~lc~ tion.
2 5 Thin lined boxed areas within ZAP-N and ZAP-C indicate the secondary structural elements in ZAP-NC. Src = avian Src; Lck = human p56-Lck; Syp-N = N-terminal SH2 of murine Syp phosphatase (PTP1D); ZAP-N(C) = N- or C- terminal SH2 of human ZAP-70.

FIG. 3 Phosphotyrosine binding sites. The phosphotyrosine residues are oriented in a similar 3 0 fashion in each figure to f~ direct co,,.~ari:,on. a, Selected residues for the ~ pTyr 4 association with ZAP-C. i~irect hydrogen bonds to the pl1os,)l~dl~ group of ~ pTyr 4 are i--d;c-dlad by dashed lines. Cr~ldllog.dphic waters are indicated as spheres; waters labeled 551, 555 and 556 make b-id~i,-y contacts between the phosphdle and the SH2 domain~ water 622 forms a bridge to ~1. b, Selected residues in close Z~-5S~ ion with ~ pTyr 15. As in a dashed lines 3 5 indicate direct hydrogen bonds to the pl1o~ hd~e group. Tyr 238 and Lys 242 from ZAP-C
coll~ t~ the hydrogen-bonding network of the ,ol~o~ dle. Waters are represented as spheres;
ail of them are involved in salt-bridging the phosphotyrosine to the SH2 domains. Several residues that form the pocket have been omitted for clarity. c. The interface between the SH2 domains involves an extensive network of hydrogen bonds. Interactions involving ~ pTyr 15 .
- lû -SUi~ST~TUTE ~t E~ ~RUI E 2~) W O 97/~8300 PCTrUS96/13918 have been described el~ er~ herein. Several hyd,u~ contacts also exist, the most provocative of these is the protrusion of Arg 41 (ZAP-N BC loop) into a small hydluph~,bic de~ ssion formed by Phe 229 (ZAP-C ,B F), Tyr 238 (ZAP-C aB), and the side chain of Thr 227 (ZAP-C EF ioop). Arg 41 also has three hydrogen-bonding cGnl~ to ZAP-C. This is the 5 first of three residues in the BC loop of ZAP-N that form an artificial parallel sheet with strand F in ZAP-C. Only one of the three hydrogen-bonding contacts involves main chain atoms exciusively.

FIG. 4 Schematic view of ZAP-70 bound to the ~1 subunit of the activated T cell receptor. Left:
1 0 Activation of T cells is initiated by ~so~ ;on of the T cell receptor (TCR) with a peptide antigen bound to the ma~or hi_~ocor,,~udliLilily colll,l~lex (MHC) on an antigen-presenting cell.
TCR-MHC association stimulates phosphorylation of T cell receptor subunits on tyrosines within the ITAMs (most likely by the Src family PTKs, Lck or Fyn). ZAP-70 binds to the phospholylated ITAM via its tandem SH2 domains (amino acids 1-259) in an u,ienlalion such 1 5 that the N-SH2 domain binds to the C-proximal pYXXL motif and the C-SH2 domain binds the N-ploxi,.,al pYXX~ motif. Proposed posiliol1s of the other dc"--ai--s of ZAP-70, referred to as interdomain B (amino acids 260-310) and catalytic domain (amino acids 311-620) are illustrated. Two ZAP-70 molecules could bind to the activated TCR CGIllpleX since the ~ subunit is present as a disulfide-linked dimer. Right: Schematic ,~pl~se"ldlion of the complex between 2 0 the SH2 domains of ZAP-70 in complex with the doubly-pho:.~,l-orylated ~1 ITAM. The SH2 domains of ZAP-70 make extensive CollLd-.;t:~ with the ~1 peptide. The primary d~ler"-;"a,.l-~ of binding are the phosphotyrosine and leucine residues of two pYXXL sequences within an ITAM.
The structure reveals a unique binding pocket for the pY of the C-proximal pYXXL motif in the interface between the two SH2 domains. In addition, the crystal structure reveals that 25 interdomain A forms a coiled-coil helical structure. This domain may participate in positioning the two SH2 domains for association with ITAMs, and in comm--,;ct~ g structural changes to interdomain B and/or the kinase domain upon ,~ce~,lor engagement.

FIG. ~i depicts a binding curve of a doubly-pllospllorylated ~ ZAP-NC complex, with 3 0 associated Scatchard plot of the data, as d~l~lll .ed by fluorescence pola,i~alion.

FIG. ~i depicts the ZAP-NC: ~1 complex encased in a gridded box for receptor site ",app:.,g.
Only the backbone of ~AP-NM and the peptide are illustrated. Colors may be i. ldicdled as foilows: red and blue for oxygen and nil.ogel1 atoms, respectively; yellow for carbon atoms of 3 5 the peptide; cyan, orange and green for N-terminal SH2 domain, the inter-SH2 spacer and the C-proximal SH2 domain carbon atoms, respectively. Note that the box encompasses space that is occupied by the peptide, as well as several inl&lracial regions of the SH2 dol"ai"s.

~UBSTITUTE ~a~{F~ ~RULE 2~) WO 97/08300 PCT~US96/139~8 FIG. 7 depicts a representative site contour map of ZAP-NC. FIG. 7A A s~le~ d region of the receptor map for ZAP-NC plus an amino cation probe contoured at -10 kcal/mol. A pocket on the protein surface is i, "- -d by a solvent-:~ccp-cs;~le surface. FIG. 7B The individual amino acids that are in close p~OXi.l.ity to the contour map are shown explicitly. The position of the 5 contour i,.dical~s that strong interactions will be achieved between a hydrogen-bond clGIldlil~y moiety and the main chain carbonyl oxygens of Arg 192, Glu 194, and Thr 197, as well as the side chains of Gln 195 and Tyr 198.

RIG. 8 depicts a computer system.

FIG. 9 depicts storage media of this invention.

Detailed Description of the Invention 15 A. Introduction: The immune response is Inedi~tPd by signailing through the T cell receptor compiex with wllich ZAP-70 is ~ssoci~ted T cell recog"ilion of antigen-presenting cells initiates a c~-cc~rle of i"l,~ luhr proGe-sses that ullillldt~ly result in changes in gene ex,u,essioll, the production of secreted ,~.edidlom, and 20 cellular pruliferalion. 1, 2 This recognition is mediated by the T cell receptor (TCR), which cons;:,L:j of the antigen binding subunits oc and ,~, the CD3 co",plex of ~-~ and 1~-~ heterodimers, and the ~ homodimer. With the ex~-e~lion of aand ~, the i~ ell~l~-r portion of each subunit includes one to three peptide sequences that contain the motif YXX(UI)X(7 g)YXX(UI), where X is variable. 3 Following receptor stimulation, these Immunoreceptor yrosine activation 2 5 motifs. or ITAMs, become phosphorylated on tyrosine residues and in this modified form, provide binding sites for downstream signaling proteins.

The TCR has no intrinsic protein tyrosine kinase (PTK) activity, however members of both the Src family and the SYK/ZAP-70 family of PTKs are i"" "- d in the fullcliol ,g of antigen 3 0 receptors.4 Current evidence indicates that Src family kinases phosphorylate the ITAMs of the TCR. 4 ZAP-70 then associates with the doubly-pllos~ orylated ITAMs of the ~ and CD3 ~ chains through its SH2 domains~ and is itself phosphorylated during early T cell activation. 6 ZAP-70 (~ ~ssoc;~tPd protein) is a 70 KDa protein tyrosine kinase that is ex~u,~::,sed exclusively in T
cells and NK cells.7 ZAP-70 is known to play a critical role in T cell activation. Genetic 3 5 alterations in the ZAP-70 gene that cause loss of ~ s~ion of ZAP-70 in humans prevent antigen activation of CD4+ T cells, inhibit maturation of CD8+ T cells, and lead to severe combined immunodeficiencies. 8, 9 ZAP-70 binding to the TCR is believed to be essential for signal transduction since peptides that biock the ~c50 ~ ion of ZAP-70 with the ~ chain also SU85TITUTE ~ (RULE 2fi) W O 97/08300 PCTfUS96/13918 inhibit T cell signaling events.10 For these reasons, ZAP-70 is an ideal target for the development of novel immunosu~" lessive therapies.

The first 259 residues of ZAP-70 consist of two SH2 domains that are connecled by a 6~
5 residue segment and are followed by a second co,~necLil,g region and a catalytic domain.7 SH2 domains consist of approximately 100 amino acids. Their role in the specific recognition of tyrosine-phosphorylated proteins is integral to a variety of intr2(celllll~r signaling events (recently reviewed in 11, 12 ). Several SH2don,ai--s have been delllon:,l-dled to retain the ability to bind with high affinity to short peptides that contain phosphotyrosine (pY) when 10 expressed as isolated proteins. Selectivity for isolated SH2 domains is dependent upon recognition of residues immediately C-terminal to the phosphorylated tyrosine (pY+nj. The three-dimensional structures of several isolated SH2 domains (both liganded and unliganded),13~ 14 as well as one SH3-SH2com,'a 15 and one SH3-SH2-SH3 protein,l6 have been determined by X-ray crystallography or NMR. In order to bind to the TCR, ZAP
15 requires that both of its SH2 domains are present and functional and that both tyrosines within the ITAM are phosphorylated.17~ 19 B. Structure Determination Despite the pivotal role of ZAP-70 in the immune response, nothing was known of the three-di,.,ensional architecture by which the tandem SH2 region of ZAP-70 engages the ITAMs in the interactions required for its biological activity. X-ray crystallographic techniques could in principle address such issues. However, not~ h:.ldn.li,lg the key biological functions mediated by ZAP-70 and other ZAP family members such as SYK, there have been no reports disclosing 2 5 that suitable crystals had been or could be obtained, let alone reports cl;s-,losi"g any x-ray crystallographic data or other information concerning the three-dimensional structure of any tandem SH2 domain. Even in the event that crystals had been obtained, then-available three-dimensional structural data relating to individual SH2 dor,.ai,.s would not have been useful in solving the tandem structure, at least in part, because it wouldn't have permiKed least squares 30 ,.,i,.i,..i~alion techniques necessary for structure refinement.

Nonetheless, we have succeeded in producing a protein containing the peptide sequence of the region of human ZAP-70 spanning both the more N-terminal SH2 domain, the more C-terminal SH2 domain and the linking region (nZAP-NC"), and have obtained crystals of that protein, 35 cryst~";7~d in unliganded form and in co..,pl~x~s with various ligands. Using such materials, we have solved the three-dimensional structure of ZAP-NC using x-ray diffraction techniques. In view of our successes as ~iisclQsed herein, it can now be said that proteins co,..pris;,lg tandem SH2 domains, especially those of ZAP family members such as ZAP and SYK, can be produced in stable form, purified, and crystallized whether in complexes with a ligand or not, and that their SU~5TITUTE ~tE~ ~RULE 2~;) W O 97/08300 PCTnUS96/13918 three-dimensional structures can be determined, all using ",aLerial:, and ~ lllods such as disclosed herein.

Mat~rials 5 As l~"Lioned elsewhere, ZAP-NC is one of a number of proteins that contain two src-homology 2 (SH2) domains. The presence and boundaries of an SH2 domain in a protein sequence can be identified by using a computer ~ ,-.,e"l prug.d", that idel,lities amino acid sequence ho~
to a known SH2 domain. Generally, the SH2 domain (amino acids between 140-255) of Src are used for such analyses, but SH2 domains from other proteins can be used as well. The aliyllllle 0 method typically used by such pluy~d~s is the Need:e".all-Wunch r' ~ lb See e.g., "A
General Method Arplic-'ls to the Search for Similarities in the Amino Acid Sequence of Two Proteins." Needlman, S.B.; Wunch, C.D. J. Mol. Biol. 1970, 48, 443-453. SH2 domains have been identified in a large and growing number of proteins, some of which contain multiple SH2 domains. For example, tandem SH2 regions are present in human ZAP-70 (Spdnll;~l9 amino acids 1-259), human SYK (spanning amino acids q - z~, PLCy, Pl3K, rasGAP, SH-PTP1, and SH-PTP2.

We expressed ZAP-NC as a glutathione-S-I,dnal~rase (GST) fusion protein. The cDNA encoding residues 1-259 from human ZAP-70 10 was cloned into the pGEX2T e~y~e~;on vector 41 and 20 tr~llslorllled into E coliBLZ1 or E. colf B834. The resulting construct produced a fusion protein of GST-ZAP-NC linked by a polypeptide segment cout~i..ing the sequence -LVPRGS-which comprises a II-n,--.L,in cleavage site. The seleno...~ /l (SeMet) ZAP-NC was produced using the auxotrophic strain of E coli834 42 with the selenomethionine replacing methionine in a defined media. The GST-ZAP-NC fusion protein was isolated using gluta~hione agarose and 25 then cleaved with ll,.u.n' ,. Cleavage yields two polypeptides, the GST and ZAP-NC. The ZAP-NC
polypeptide contains two extra amino acids (Gly-Ser) at the amino terminus from the linker segment of the pGEX2T ex~r~ssion vector. These two extra amino acids were shown to have no functional effect on ZAP-NC binding to peptide ligands. ZAP-NC was sepa-~ted from GST by binding ZAP-NC to a pllosphùlyroslne agarose coiumn and eluting with a salt y,ddit:rL
3 0 Suhsequently, ZAP-NC was further purified on a pheny~ sepharose column. ZAP-NC:peptide ligand complexes were formed by mixing two-fold excess of peptide and purified ZAP-NC, then subjecting the mixture to ch~cl..al~,graphy usiny a superdex 7~; gel flltration column. Fractions col,lFi..;"g the purified ZAP-NC:peptide co,-, I -- were combined and used for sl~hseclll~nt cryst~ tion experiments.

Other ZAP-NC pl~JL~i.ls may also be used, inciuding ZAP-NC proteins truncated at the N-terminus and/or C-terminus to contain just the SH2 homology boundaries. Likewise. the protein may be e,~Lended at the C-terminus to inciude additional amino acids ~,~le,~ding to include additional domains (spacer B) up to the entire ZAP-70 protein (amino acids 1-6Z0).

SU8S i ITUTE ~i {E~ ~RULE ~h~

W O 97/08300 PCTrUS96/13918 Additionally, other tandem SH2 regions, especially from human and non-human ZAP family "le,l.be,~, including proteins such as human SYK, may be prepared and used in an~logol~ fashion to that described herein. It should further be ap~ cia~ed that other e~less;o~ systems may be readily el~ ycd. For j~xLance~ the tandem SH2 protein may be produced in E colf using T7, 5 maltose-binding protein fusion (MBP~, with epitope tags (His6, HA, myc, Flag) included or cleaved off. Baculoviral expression may be used, e.g. using pVL1393 or derivatives, for tandem SH2 protein, fused (or not) to epitope tag or fusion partner such as GST. Conventional IllaL~ridls and uleLllocls for e,.~lession in Illdlllll -" ~, yeast or other cells may also be used.

10 Peptide ligands for co-cry.stA~ tion with ZAP-NC or other tandem SH2 proteins may be prepared using conventional ")elhocls, containing peptide sequences based on naturally occurring ITAM sequences such as ITAM sequences derived from the T cell receptor ~ 2, ~3, ~, ~or ~
subunits or from the ~ or y subunits of the IgE receptor, for example. In most cases such ligands will contain the 15 amino acid minimal ITAM sequence YXXLXXXXXXXYXXL [SEQ ID NO tl and 15 may contain ad~ ional amino acids at either or both the N- and C-termini. The N-terminus may comprise a free amino group or may be modified, e.g. amidated. Likewise, the C-terminus may be a free carboxylate or may be a",iddlad or otherwise ,llocliried. Tyrosines may (each) be phosphorylated (pTyr). Alternatively, difluourophosphonoTyr, phosphonolll~ll,yl phenylalanine, hemi-phosphorylated Tyr, or other pTyr mimetics may be used in place of pTyr.
2 0 The ligand may contain amino acid replacements, i"se,li:3ns or deletions with respect to a naturally occurring ITAM sequence. Furthermore, hybrid peptide-nonpeptide ligands and non-peptide ligands may also be used. Exdrl,, 19~ of such ligands are d ~ in Table 1.

Crystalliza tion 2 5 Cry~t~ ation experiments were conducted using a sparse matrix screening approach, in the case of ZAP-NC crystals. beginning with a Crystal Screen 1 kit (Hampton Research, Riverside, CA). Crystals conlc~i,. I9 SYK-NC were obtained as described below. In the case of ZAP-NC, best results were obtained using protein st~hi ~d in 0.5 M NaCI, followed by removal of salt by dialysis prior to the cryst~ tion experiments. Special handling of that sort was not 3 0 necessary for SYK-NC, but may be useful for other tandem SH2 conldi., ,9 ptc,lei,ls.

For example, crystals of ZAP-NC colll, ~ -d with the doubly-pho~horylated 19meric ~ ITAM
peptide (Ligand 5, Table 1) were grown from polyethylene glycol ~PEG) 4000. The structure was elu~ ted by multiple isomorphous replacement at 1.9 A ,.s~'-ltion. It was not possibte to 35 solve the structure by molecular replacement alone using coo~dil,dLes for previously deL~Illl;.led SH2 domains. This was due to the low sequence identity with other SH2 domains and between the two ZAP dGIIl._;,ls, as well as to the plesence of the 65 residue ill~r.lonlaill region.
The details of cryst~ tion, data collection, multiple isomorphous replacement (MIR), and refinement are described below.

- 1~; -SUBSTITUTE ~ E~ tRULE 26~

WO 97/08300 PCT~US96/13918 Speciflcally, ZAP-NC complexed with doubly-phosphorylated ~1 peptide was concer,l,~l~d to 30 mg/ml in 20mM Tris, pH 8.5, 20C3mM sodium chloride and 20mM ~liLI,: Ihl~itol. The CGlllp'~X
was treated with 4mM trimethyliead acetate (TML). Crystals were obtained by vapor diffusion 5 in hanging drops co,.l~i.. i~,g 13.5 mg/ml co." !~- and lQ% PEG 4000, 50mM sodium citrate, 100mM ammonium acetate, 0.005% sodium azide and 20mM ~itl,i~ itol, pH 6.2, overreservoirs of 20% PEG 4000 and 20mM ~ Jtl,r~itol. The crystals are monoclinic (P21, a=50.1~, b=63.37, c=54.00 A, ~=114.44~) with one molecule per asymmetric unit.

1 0 In other experiments, using similar con-~ilions, we were also able to obtain crystals of ZAP-NC
CGnl, 'eYc~d with doubly-phosphorylated ~1 peptide which were found to contain two mdl~c-l'~s per asymmetric unit. Those crystals are also monoclinic (P21, a=65.17, b=62.00, c=78.67 A, ~ =111.32~).

1 5 As described in detail in Experimental Example lll (A) and (B), crystals were also obtained under similar con~lilions of liganded and unliganded ZAP-NC and SYK-NC proteins.
TABLE 1: Various Tandem SH2 Ligands (1) IgE yTAM 19mer ~SEQ ID NO 2]
Ac.Asp.Gly.Val.pTyr.Thr.Gly.Leu.Ser.Thr.Arg.Asn.Gln.-Glu.Thr.pTyr.Glu.Thr.Leu.Lys.NH2 (2) IgF ~TAM 15mer ~SEQ ID NO 33 Ac.pTyr.Thr.Gly.Leu.Ser.Thr.Arg.Asn.Gln.Glu.Thr.pTyr.Glu.Thr.Leu.NH2 (3) Ac-[pY4~15] IgE yTAM 25mer ~SEQ ID NO 4]
Ac.Asp.Gly.Val.pTyr.Thr.Gly.Leu.Ser.Thr.Arg.Asn.Gln.-Glu.Thr.pTyr.Glu.Thr.Leu.Lys.His.Glu.Lys.Pro.Pro.Gln.OH

(4) AC-rpy6~l7] IgE yTAM 27mer [SEQ ID NO 5]
Ac.Lys.Ser.Asp.Gly.Val.pTyr.Thr.Gly.Leu.Ser.Thr.Arg.Asn.&ln.-Glu.Thr.pTyr.Glu.Thr.Leu.Lys.His.Glu.Lys.Pro.Pro.Gln.OH

(5) [pY4~15JTCR~TAM 1 (19mer ~1) [SEQ ID NO 6]Ac.Asn.Gln .Leu.pTyr.Asn.Glu.Leu .Asn.Leu.Gly.Arg.Arg.Glu.-Glu.pTyr.Asp.Val.Leu.Asp.NH2 SUB5TITUTE SH~E~ (RULE 26) CA 02226963 l998-02-l2 (6) AC-py[3~l5]-Nleltl]-NH2 (19mer ~2) [SEQIDNO7]
Ac.Gly.Leu.pTyr.Asn.Glu.Leu.Gln.Lys.Asp.Lys.Nle.Ala.Glu.-Ala.pTyr.ser.Glu.lle-Gly-NH2 (7) AC-py[4~153-TcR~3 [SEQIDNO8]
Ac.Asp.Gly.Leu.pTyr.Gln.Gly.Leu.Ser.Thr.Ala.Thr.Lys.Asp.-Thr.pTyr.Asp.Ala.Leu.His.NH2 (8) Ac-[Phe(p-1)3]-TCR~TAM{1 )-NH2 ESEQ ID NO 9]
O ~
o ~ NH2 o ~/
J~ N~ . N~ pTyr.Asn ~ .Leu.Gly.Arg.Ar~ rTyr.Asp.V~ r-p.NH2 HzN O

(9) Ac-F2Pmp[4~ 15] - ~1 NH2 [SEQ ID NO 10]
Ac.Asn.Gln.Leu.F2Pmp.Asn.Glu.Leu.Asn.Leu.Gly.Arg.Arg.Glu.-Glu.FzPmp.Asp.Val.Leu.Asp.NH2 (10) IgE y analog [SEQ ID NO 1 1 ]
Ac.Asp.Gly.Val.pTyr.Thr.Gly.Leu.A~a.Ala.Ala.Ala.pTyr.Glu.Thr.Leu.Lys.NH2 (11) Ac-pY-Thr-nmGly-nmLeu-NH2 [SEQ ID NO 13]
OH
o CH~N~ ~NH2 OHo~ ~ C113 ~ ~

Notes:
(a) Ligands (1), (5) - (10) and (11 ) co-cryst~ 7ed with ZAP-NC. Of those, (5), (7), (8) and (9~ formed dimeric crystals, i.e., containing two ligand:ZAP-NC complexes per asymmetric unit. (1), (5), (6) and (10) formed crystals containing one ligand:ZAP-NC
(containing lead) per asymmetric unit. (1 ) - (5) co-crystallized with SYK-NC, with several molecules of co"l}~lex per asymmetric unit.

SlJBSTlTUTE S}t~E~ tRULE 26) =

W O 97/08300 PCT~US96/13918 (b) The ~Idnda.d triple and single letter codes for abbreviating the names of amino acids are used, i.e., Alanine (Ala, A); Arginine (Arg, R); Aspardyi,le ~Asn, N); Aspartic Acid (Asp, D); Cysteine (Cys, C); Glutamine (Gln, Q); Glutamic Acid (Glu, E); Glycine (Gly, G); Histidine (His, H); Isoieucine (lle, I); Leucine (~eu, L); ~ysine (Lys, K); Methion-ine (Met, M); Phenylalanine (Phe, F); Proline (Pro, P); Serine (Ser, S); Threonine (Thr, T); Tryptophan (Trp, W); Tyrosine (Tyr); and Valine (Val, V). The following terms , are also abbreviated: phosphulyrosine (pTyr, pY), difluoropl~o~pl-onû-,-ethylphenylalanine (F2Pmp), Fluorenylmethyloxycarbonyl (Fmoc), N-methyl (nm) and acetyl (Ac~

Oata Collection Diffraction data were collected with an Rigaku R-AXIS ll area detector with graphite monocl,,u..,dLed Cu Kc~X-rays. Diffraction data were ~ol'e~t~d as 2~ os: " -n images and 5 reduced to integrated illl~--siLies with DENZo.43 Scaling parameters for each image were ~IGui-~d with RoTAVATA44 and applied with AGRoVATA.44 Data sets were cc" ct~d for all SYK
and ZAP crystals (with and without bound iigands) at -160~C except for those collected at room temperature for crystals conldi-lillg ZAP-NC protein colllaill;.lg lead.

10 MIR Analysis and F7efinem~nt SeMet ZAP-NC was cryst~l~ d with TML under the same con.lilions and data collected. Posilions of the lead and selenium atoms were determined from the difference P~ ,on function.
Anomalous dispersion measu-,:m~l-ls were included for both r~tAcet~ Heavy atom parameters were refined, and phases were obldi..ed at 2.8 A with the pruy.d-n MLPHARE.44 The MIR phases 15 were improved with the pruyldrll DM44 with a combination of solvent lldlleni,.g/histogram mapping and phase ~ nsion to 2.0 A. Flectron density maps with MLPHARE and DM phases were c~lcll'-tecl and the polypeptide chain model was built with the pl~uyldlll O45. SIGMAA44 was used to perform several cycles of phase co.. ': .dlion using partial model and experimental phases. Least squares refinement with simulated annealing was done using X-PLoR.46 The 2 0 current model has all residues from Asp 3 to Asn 256 of the protein, all 19 peptide residues of zeta-1, and 113 water molecllles, plus one lead and three selenium atoms. TML is bound to Cys 117. See Table2.

Structural Coordinates, Their Storage and Use 25 The structural couldillales of crystalline colllposiliol1s of this invention may be obtained as described in detail herein. By way o~ example, Appendix 1, Appendix ll and Appendix lll set forth the structural coordinates, in PDB format, for crystalline compositions comprising ZAP-NC: ~1 "monomer" (one molecule of coll,plex per unit cell), ZAP-NC: ~2, and ZAP-NC: ~1 "dimer" (two molecules of complex per unit cell~.
This invention encompasses crystalline cG...po~ilions conldi. ,g a ZAP family protein having a region characterized by structural cooru;..al~:s set forth in Appeu.ltces 1, ll or lll, or by coor~" .aLes having a root mean square dcv;dlion ll.el~:r.u.,. of less than about 1.5 A, p~r~,dbly SUBSTITU~E Si~F~ tRULE ~

=--W O 97/08300 PCT~US96/13918 less than about 1 A, and even more preferably less than about 0.5 A, with respect to ba~ Lone atoms of amino acid residues listed there.

TABLE 2: Statistics for data colle.,lion, phase de~ .inalion, and refinement for ZAP-NC: ~1 "monomer"
Data Collection R~sol~ltionReflections Cc, .., 5L' ~,~ess Psym Rc FCM Phasing ~A) (N) (%) (%) Power (20-2.8 A) TML25 - 2.5 15,~06 98.3 ~.3 SeMet 25 - 2.9 23,978 98.9 4.9 0.71 0.50 1.38 TML
Refinement Model 272 residues, 113 water ~ e ~l~s, 1 lead, 3 selenium atoms ResolutionReflections R-value Free R-value~ Rms deviations (F > 2~) (%) (%~ Bonds (A) Angles (~) 10 - 1.9 23,697 20.9 25.5 0.006 1.58 Notes~
Rsym = ~ Ij x 100 .
Rc = ~ IlFph + Fpl - Fhca~c ~ ¦Fph + Fpl for centric reflections.
Phasing power, Fh/E where E = rms lack of closure error.
FOM = Figure of merit Rvalue = ~ ¦ l Fobsl-l Fcalc~ l Fobslx 100.
subset of data (10%) was excluded from refinement and used for free P~-value c~lc~ tion. All data with F,2~ were used for refinement.

5 As practitioners in this art will app,~,iat~, various computational analyses may be used to determine the degree of similarity between the three di",ensional structure of a given protein (or a portion or complex thereof) and ZAP-NC or another ZAP family protein or portion or co",plex thereof such as are described herein. Such analyses may be carried out with commercially available software applic~lions, such as the Molecular Similarity ~pplic~tion of 1 0 QUANTA (Molecul~r Simulations Inc., Waltham, MA) version 3.3, and as described in the acc~""parlying User's Guide, Volume 3 pgs. 134- 135.

The Molecular Similarity application permits comparisons between dirr~r~"t structures, different conformations of the same structure, and different parts of the same structure. The 1 5 procedure used in Molecular Similarity to compare structures is divided into four steps: (1) load the structures to be co",pal~d; (2) define the atom equivalences in these structures; (3) perform a fitting operation; and (4) analyze the results.

SUBSmUTE SHE~ (RULE 2~i~
.

Each structure is identified by a name. One structure is identified as the target (i.e., the fixed structure); all remaining structures are working structures (i.e., moving structures). Since atom equivalency within QUANTA is defined by user input, for the purpose of this invention we define equivalent atoms as protein backbone atoms ~N, Ca, C and O) for all conserved residues 5 between the two structures being cor."~an3d and consider only rigid fitting ope.dlions.

When a rigid fitting method is used, the working structure is lldnsldlt3d and rotated to obtain an optimum fit with the target structure. The fitting operation uses a least squares fitting algorill,." that computes the optimum l-d -slaliu.. and rotation to be applied to the moving 10 structure, such that the root mean square difference of the fit over the specified pairs of equivalent atom is an :~hsoiut~ minimum. This number, given in ang:,llu-,-;-, is ll:po,led by QUANTA.

For the purpose of this invention, any set of structural coordinates of a ZAP family protein, 15 portion of a ZAP family protein or molecular complex thereof that has a root mean square deviation of conserved residue ba.,~;L,one atoms (N, Ca, C, O) of less than 1.5A when superimposed--using backbone atoms--on the relevant structural coold;.ldles of a protein or co,., '~x of this invention, e.g. the coordinates listed in Appendix 1, Appendix li or A~pendix lll, are conside,ed identical. More l,r~te,dbly, the root mean square deviation is less 2 0 than 1 .oA. Most preferably, the root mean square deviation is less than o.sA.

The term "root mean square dcv;.~lion" means the square root of the arithmetic mean of the squares of the deviations from the mean. It is a way to express the deviation or variation from a trend or object. For purposes of this invention, the "root mean square deviation" defines the 2 5 variation in the backbone of a protein from the backbone of a protein of this invention, such as ZAP-NC, as defined by the structural coordinates of Appendix 1, Appendix ll or Appendix lll and described herein.

The term "least squares" refers to a method based on the p~ ;p's that the best estimate of a 3 0 value is that in which the sum of the squares of the deviations of observed values is a minimum.

In order to use the structural coordinates yene,dled for a crystalline substance of this invention, e.g. the structural coord;nal-3s of ZAP-NC, ~ 2, or the various complexes as dq, i~'2d in Appendix 1, Appendix ll or Appendix lll, it is often necess:~ry or desirable to 3 5 display them as, or convert them to, a three-dimensional shape, or to otherwise ..,ar,-, u'~te them. This is typically ac.,o...~,'' '~ed by the use of cu..----e...i~lly available su~l~.dre such as a program which is capable of generating three-dimensiol1al y(~ph -t representations of motecules or po.liùns thereof from a set of structural coord;..ales.

SUBSTITUTE S~tEE~ ~RULE ;~fi) WO 97/08300 PCTrUS96/13918 By way of illu~lldlion~ a non-exclusive list of computer programs for viewing or otherwise manipulating protein structures include the following:

Midas (University of California, San Francisco) MidasPlus (University of California, San F,2lncisco) MOIL (Univeristy of Illinois) Yummie (Yale University) Sybyl (Tripos, Inc.) Insight/Discover (Biosym Technologies) MacroModel (Columbia University) Quanta (Molecular Simulations, Inc.) Cerius (Molucular Simulations, Inc.) Alchemy (Tripos, Inc.) LabV;sion (Tripos, Inc.) Rasmoi (Glaxo Research and Devel.~ "l) Ribbon (University of Alabama) NAOMI (Oxford University) Explorer Eyechem (Silicon Graphics, Inc.) Univision (Cray Research) 2 0 Molscript (Uppsala University) Chem-3D (Cambridge Scientific) Chain (Baylor College of Medicine) O (Uppsala University) GRASP (Columbia University) 2 5 X-Plor (Molecular Simulations, Inc.; Yale University) Spartan (Wavefunction, Inc.) Catalyst (Molecular Simulations, Inc.) Molcadd (Tripos, Inc.) VMD (University of Illinois/Beckman Institute) 3 0 Sculpt (interactive Simulations, Inc.) Procheck (Brookhaven National Laboratory) DGEOM (QCPE) RE_VIEW (Brunel University) sllcr (Birbeck College, University of London) 3 5 Xmol (Minnesota Supercomputing Center) ~- Protein Expert (Cambridge Scientific) HyperChem (Hypercube) MD Display (University of Washi. IgLoll) PKB (National Center for Biotechnotogy l.lrunll~llion, NIH) SUBSTITUTE ~ RULE 2fi) ChemX (Chemicai Design, Ltd.) Cameleon (Oxford Molecular, Inc.) Iditis (Oxford Molecular, Inc.) 5 For storage, transfer and use with such pl~Jyldllls of structural coo,~ ~dLe. for a crystalline suL,s.lance of this invention, a machine-readable storage medium is provided Colllpli~;lly a data storage material encoded with machine readable data which, when using a machine ployl~mmed with instructions for using said data, e.g. a computer loaded with one or more p~uyldlns of the sort identified above, is capable of displaying a gldphical three- ,lansi~l1al ~e~lesenlalion of t 0 any of the molecules or molecular colll~_lexes des~;,iLed herein. Machine~ adaLlc storage media cG~ ri~ a data storage material include conventional computer hard drives, floppy disks, DAT tape, CD-ROM, and other magnetic, magneto-optical, optical, floptical and other media which may be adapted for use with a computer.

1 5 Even more preferred is a machine-readable data storage medium that is capable of displaying a yr~phb.~i three-dimensional lepre.e"ldlion of a molecule or l,.alecul~r cGI"plex that is defined by the structural coold;.lales of a protein of the ZAP family, e.g. ZAP-NC or SYK-NC, or portion thereof, and in particular, structural coordinates of ZAP-NC:~1 or ZAP-NC:~2 set forth in Appendix 1, Appendix ll or Appendix lll (or derivatives thereof such as zapNC-z1.pdb, 2 0 ~iscl~ssesl elsewhere herein) + a root mean square deviation from the backbone atoms of the amino acids of such protein of not more than 1.5 ~. An illustrative ell,Lodi,-lent of this aspect of the invention is a conventional 3.5" diskette, DAT tape or hard drive encoded with a data set, preferably in PDB format, co"",li~ g the coordinates of Appendix 1, Appendix ll or Appendix l l l .
In another e",Lo~" "ent, the machine-readable data storage medium co"" ,i .es a data storage material encoded with a first set of machine readable data which co"lp~ises the Fourier lld.~sror,,l of the structural coordinates set forth in Appendix 1, Appendix ll or Appendix lll (or again, a derivative thereof), and which, when using a machine ploylclrllllled with 3 0 instructions for using said data, can be cor, ' lad with a second set of machine readable data cGn~p~i.illg the X-ray diffraction pattern of a molecule or Ill-lsclll~r co"lpl~x to dele,lll;"e at least a portion of the structural cooldi,.ales COne ~pOll~ l9 to the second set of machine u ~-' 'IB
data.

3 5 FIG. ~3 illustrates one version of these enlLodi.llerl~. The ~'E,~ d system includes a computer A
corllp~ ly a central p~l cessil,g unit ("CPU"), a working memory which may be, e.g., RAM
(random-access memory) or "core" memory, mass storage memory (such as one or more disk drives or CD-ROM drives~, one or more cathode-ray tube ("CRT") display terminals, one or SUBSTtTUTE !iH~E~ tRULE 7~;) , CA 02226963 l998-02-l2 W O 97108300 PCTrUS96/13918 more keyboards, one or more input lines (iP) and one or more output lines (OP) all of which are i"lt:,~;Gnnected by a con~,~"li~nal bidirectional system bus.

Input haniwdr~ 13, coupled to computer A by input iines, may be implemented in a variety of 5 ways. Machine-readable data of this invention may be inputted via the use of a modem or ",ode",s connected by a telephone line om~ d data line L. Alternatively or additionally the input hardware may comprise CD-ROM drives or disk drives D. In conjunction with the CRT
display terminal, a keyboard may also be used as an input device.

10 Output hardware, coupled to computer A by output lines, may similarly be implemented by conventional devices. By way of example, output ha,dwdr~ may include a CRT display terminal for displaying a graphical repres~"lalion of a protein of this invention (or portion thereof) using a plOy"ll" such as QUANTA as described herein. Output hardware might also include a printer so that hard copy output may be produced or a disk drive to store system output for t 5 later use.

In operation the CPU coordinates the use of the various input and output devices, coor 'inales data ~ccPsses from mass storage and accesses to and from working memory, and deL~r",i.,es the sequence of data p,ucessi"g steps. A number of pluyltl,,,5 may be used to process the machine-2 0 readable data of this invention. E~a""~l~s of such plugldlllS are discussed in reference to thecomputational methods of drug discovery as described herein. Specific ,~rert:nces to components of the hardware system of FIG. 8 are included as apprûpriate throughout the foll~wi.,g desc,i~liu,, of the data storage medium.

2 5 FIG. 9A shows a cross section of a magnetic data storage medium 100 which can be encoded with a machine-readable data that can be carried out by a system such as a system of FIG. 8. Medium 100 can be a conventional floppy diskette or hard disk having a suitable substrate 101 which may be conventional and a suitable coating 102 which may be conventional on one or both sides, containing magnetic domains (not visible~ whose polarity or o,ienldlion can be altered 3 0 magnetically. Medium 100 may also have an opening (not shown~ for receiving the spindle of a disk drive or other data storage device 24.

The magnetic do",ai":, of coating 102 of medium 100 are polarized or orienled so as to encode in a manner which may be conventional, machine readable data such as that described herein for 3 5 ~xeultion by a system such as a system of FIG. 8.

FIG. 9~ shows a cross section of an o~ ally readable data storage medium 110 which also can be encoded with such machine-~e~dSIhle data, or set of instructions, which can be carried out by a system such as a system of FIG. 8. Medium tlO can be a conv~"lional cGr",oa~il disk read only SUBSTiTUTE ~ RULE 26) W O 97/08300 PCT~US96/13918 memory (CD-ROM) or a rewritable medium such as a magneto-optical disk which is optically read~l~lc and magneto-optically writable. Medium 100 prt:~rdbly has a suitable substrate 111, which may be convel,lional, and a suitable coating 1 t2, which may be conventional, usually of one side of substrate 111.
In the case of Ci~-ROM coating 112 is reflective and is impressed with a plurality of pits 113 to encode the machine-readable data. The ar.dngerllent of pits is read by reflecting laser light off the surface of coating 112. A protective coating 114, which pr~erdbly is suL,sldulially transparent is provided on top of coating 112.

In the case of a magneto-optical disk coating 112 has no pits 113 but has a plurality of magnetic do"la:.,s whose polarity or olienl~liol) can be changed magnetically when heated above a certain temperature as by a laser ~not shown). The orientation of the domains can be read by measuring the pola~ ion of laser light reflected from coating 112. The a,l~.,ge"lenl of the 1 5 domains encodes the data as described above.

C. Desc. iplion of the Tertiary Structure of ZAP-NC:~ 1 Solving the X-ray crystal structure of the tandem SH2 region of human ZAP-70 (ZAP-NC) in 2 0 complex with a 1 9meric peptide derived from the sequence of the first ITAM of the ~ subunit of the TCR allowed us to conduct the first three ~illlensiunal characterizaiton of the protein:ligand complex. The cOI~ ' ~ involves an elabordLe array of contacts between the peptide and both SH2 domains. The 65 residue inter-SH2 region exists as a coiled-coil of a-helices and assists in the r~",-dlion of an interface between the two SH2 d~ ai,ls. The structure reveals the 2 5 startling fact that both SH2 domains contribute to the recognition of phosphotyrosine in the second pYXXL motif. This work reveals the first structural insights into the SYK/ZAP family of protein tyrosine kinases and provides the first view of an intracellular component of the TCR.

~ .er~l ~opology 3 0 The first 259 residue segment of ZAP-70 consists of two SH2 dol"ai"s that are connected by a helical region. The overall fold is Y-shaped where the SH2 domains constitute each upper branch and the intervening 65 amino acid domain forms the stem. The fragment of ZAP-70 used in the crystal structure d~le,."i"~.lion ter",i.,~les before the kinase domain; therefore, we refer to the two SH2 regions as ZAP-N and ZAP-C, for ZAP N-terminal SH2 and ZAP C-le.-"i"al SH2"~:suecli~/ely. There is high structural similarity between each of the SH2 dornains and those previously reported e.g., v-Src13 and p56-Lck20 . Each of the individual ZAP SH2 domains posse.ssPs a central anLi,ua, "?I ~-sheet that is flanked by two a-helices. The inter-SH2 region begins as a ~-strand that is a continuation of the central sheet of ZAP-N. This is followed by two antiparallel a-heiices that in~e,L~rine to form a coiled-coil motif. The two SlJBS 11 l UTE SHE~ (RULE 2~i~

W O 97/08300 PCT~US96/13918 SH2 dc,."ai.,s are in a partially staggered oriel,ldlion; the central ~-sheets are separated by about 29 A at an angle of ca. 52~. This andnye..,~"l allows direct contact between the two SH2 domains, which is a requisite for peptide binding. The central ~-sheet in ZAP-C is extended by distinct hydrogen bonds with several residues in ZAP-N, including some side chain contacts.
The ~1 peptide is extended over both faces of the SH2 dor,~ai"s, ~ d.lles both central ,B-sheets, and makes extensive contacts with the protein surface. The binding oriellIdlion is head to tail, that is, the N-terminus of the peptide is in contact with the C-terminal SH2 domain. The N-terminal pYXXL seyl"en~ of the peptide is bound to ZAP-C in a cor,run-,aIiol- similar to that seen for singly-phosphoryiated peptides bound to isolated SH2 domains.20~ 21 The peptide segment that separates the two pYXXL motifs is largely in contact with ZAP-C. The C-terminal phosphotyrosine is bound in~a pocket that is formed by contributions from both SH2 domains.
The remainder of the second pYXXL motif is bound in a fashion similar to the first motif and in other complexe5 20, 21 t 5 The ZAP SH2 domains All residues between Asp 3 - Asn 256 are in good electron density, with no breaks. nesidLIes Gln 2 to Leu 18 of the ~1 peptide reside in good density, and the two terminal residues are in weak, but obseNable density. The nomenclature defined previously20 for structural features of SH2 domains is used here for clarity. For the N-lellll- .al SH2 domain (ZAP-N), the secondary structural elements are conseNed but are slightly longer for strands A, E, F, and G. Due to the 01OngdIion of these strands, the sequence cor,~pol1 ii.,g to a minor i3-sheet (obseNed in previously reported SH2 domains) is an integral part of the central ~-sheet in ZAP-N. More notably, helix A is longer by three re-idues which extends the helix nearly a full turn. The C-2 5 terminal SH2 domain of ZAP (ZAP-C) also possesses minor exlensions to several secondaN
structural elements. Strands B, C, and E are longer by one or two residues Helix A is also extended by a single residue. Strand F consists of only two residues and replaces the FB loop. The BC loop of ZAP-C is extended. There is very strong electron density for a number of structural waters, both within each SH2 domain and in all domain interfaces. The existence of a large 3 0 number of obseNed waters in the phosphotyrosine binding pockets is unique to ZAP-NC.

The Helical Interdomain A
The inter-SH2 spacer begins in a type il reverse turn I~ ed by a long ,~-strand that makes siy.,iricar.l contact to strand A of ZAP-N, thus forming an ~ ensiol1 to the central ,3 sheet.
3 5 Hydrogen bonds exist between main chain atoms of Gln 111 and Tyr 12 and between Gln 111 and Ser 14. A water-mediated contact exists between the main chain atoms of Glu 109 and Tyr 12.
In addition to the hydrogen bonds, h~,dlvphoi,ic packing exists between Leu tO8 and Tyr 12 and , between Pro 110 and Phe 11.

- 2~ -SU8STITUTE ~i}tF~ (RUL~ :2~i) W O 97/08300 PCTnUS96/13918 This segment is followed by a five-turn a-helix (desiylldled helix C) that extends away from both SH2 domains, forming the stem of the overall Y shape of ZAP-NC. This helix is ~ d by a turn consi;,li.,g of Leu 133 and Glu 134. A second a-helix ~helix D) curves around the axis formed by helix C. Helix D is distorted, with a break at Pro 147; a second break occurs at Ala 154 which precedes a short 31o-helix that spans residues Thr 155 - Met 161. Helices C and D
both make several hyd.uphobic contacts to ZAP-C most notably a p-stacked a~.dnye,--e"l of Phe 115 (aC) to Trp 233. Several water-mediated hydrogen bonds exist between helix D and ZAP-C. These anli,uar~llel he~ices form a coiled-coil structure, with direct contact between several hydrophobic residues forming its core.

For proteins that contain multiple SH2 do...di..s the region sepa~dli~-g the two domains is highly variable in length. This region may be as short as 10-15 residues (e.g., PLC-y1, SHPTP-1 and -2), which would force the two SH2 domains into a back-to-back oli~"ldlion. SYK has an inter-SH2 domain region which is of c~"."~ardble length to that of ZAP, exhibits 68% sequence 15 identity to the helical spacer described here. It should Illi~ lldil- the same overall corlrurllldlion observed in ZAP-NC. The tandem SH2 do~"ai,.s of the p85 subunit of pho:~yhLidylinositol 3' kinase (Pl 3-K) are connected by a siy..iricd"lly larger domain of 163 residues which has been pn:di~;i.3d to also form a coiled coil of two antiparallel oc-helices.22 2 0 Bindmg Int~r~,c~ions for U7e Complexed ~1 Peptide The ZAP-NC:~l CGII, I_ includes a 19 amino acid peptide that is pho~,holylated on both tyrosine residues and is based on the first ITAM-col-ltli- ,g segment of the human TCR ~ chain (~1) which has the sequence NQLpYNELNLGRREEpYDVLD [SEC2 ID N0 14] . For clarity,numbering for peptide residues begins at ~ Asn 1. The bound ~;o,-~r-,-dlion of the ~1 peptide is 2 5 largely extended although nearly one full oc-helical turn exists between residues ~ Asn 8 and Arg 12. The backbone con~,....alion for each pYXXL motif is similar to collru~ dliol1s observed for high affinlty com lenes of SH2 domains with singly-phosphorylated peptides.20- 21~ 23 All residues of the ~1 peptide, except for ~ Gly 10 are in contact with ZAP-NC. The area of the 30 peptide-protein interface is over 1300A2. Although this interface area is typical for protein-protein interactions, the nature of the contacts is quite ~ir~e.e-,l from those generally observed.24 For example, interfaces in antibody-antigen complexes and prutease:protein-inhibitor complexes usually contain few bridging waters. The interaction of ZAP-NC with ~1 includes 21 bridgi.,g waters. The majority of contacts in protein-proteir~ interfaces are usually 3 5 classified as h~,d-ophobic. In contrast half of the contacts between ZAP-NC and ~1 are due to direct hydrogen bonds. The total number of contacts observed is consi~lerdbly larger than is observed for protein-protein structures of similar i"ler~auial areas. Binding of phosphorylated peptides to individual SH2 dcj",ai.,s has been des~;,iLed as .e.. ~ .cerl of a "socket and plugU;
this general arrangement is also present in ZAP-C and ZAP-N. Each socket consi ,l:, of a highly 5~85TITUTE ~E~ ~RIJI ~ 2h~

W O 97/08300 PCT~US96/13918 cha.~:d pocket that ~~coy,li~S phosphotyrosine residues and a second pocket that prefers hydrophobic residues at the pY+3 position.

Binding of Motif-l f-pYNEL-J is Exctusive to ZAP-C
5 The amino terminal pYXXL motif of ~1 is ~so~ d exclusively with ZAP-C. The first two residues of ~ Asn 1 and ~ Gln 2, are largely involved in intrapeptide interactions. The single contact between ~ Leu 3 and ZAP-NC, a hydrogen bond between the main chain carbonyl of ~ Leu 3 and NH1 of Arg 170, is typical for the pY-1 residue.

1 0 The pocket for ~ pTyr 4 is formed by residues from helix A, strands B, C, and D, and the BC
loop. Hydrophobic contacts involve residues from ~ D, from which His 210, Tyr 211, and Leu 212 form one edge of the pTyr cavity. In addition, ~ Asn 1 and ~ Gln 2 of the peptide itself form hydlupl,.,ki~ contacts on the opposi"g side. The side chain of Leu 212 is twisted away from the pTyr ring and is packed against Trp 131 from a symmetry-related molecule. This neighboring 15 Trp, which constitutes the only intermolecular crystal contact with any ~1 residue, is also in hydrophobic contact to ~ pTyr 4. Direct hydrogen-bonding contacts to the phosphate are made by only three residues. Arg 170 (o~A) and Arg 190 (,~ B) interact through their terminal nitrogens. Arg 1g2 is the only residue in the BC loop of sufficient length for direct hydrogen bor, ' ,9 to the phosph~le group and interacts via its N~. The BC ioop is extended; thus, the pTyr 2 0 binding region ,~sen,bles a deep groove that continues toward the AA loop. The inclusion of the pY-2 and pY-3 residues as an integral part of the binding site results in the formation of a channel into which the pTyr protrudes. Five waters with very strong density and low temperature factors exist in this region and are part of a large hydrogen-bondi.,g network.

2 5 As is typical for complexes with SH2 domains,20~ 21~ 23 the pY~1 and pY+2 residues are extended along the surface of the protein. The pY+1 residue (~ Asn 5) makes contacts that are similar to those observed in the hamster middle T peptide (...pYEEI...) in complex with the SH2 domains of Lck20 and v-Src.21 The pY+2 residue (~ Glu 6) is directed away from the surface of the protein.
The pocket that surrounds ~ Leu 7 ~pY+3) is very deep and is formed by residues from ~ D, the EF ~oop, helix B and the BG loop. Due to the size of this pocket, ~ Leu 7 is directly conl~d by only 5 residues -- Tyr 211, lle 223, Gly 226, Gly 245, and Leu 246. The depth of this pocket is partially due to the p,est:"ce of a leucine in helix B in ZAP-C that is occupied by a tyrosine in 3 5 many other SH2 domains.23 Even in the absence of tyrosine, very strong density is observed - for two waters near this site. The main chain of ~ Leu 7 is involved in a water-mediated hydrogen bond to the carbonyl oxygen of Pro 224. A second contribution to the overall shape of the pY+3 pocket is provided by a ,eposiliol, ,g of the ~turn in the EF loop. In col"l~lexes of isolated SH2 domains, this loop is involved in forming the steep solvent-~i~,osed wall of the .

SUBSTITUTE SltE~ (RULE 2~i~

WO 97/08300 PCT~US96/13918 pocket. In ZAP-C, the EF loop slides toward strand D to allow the remainder of the peptide to continue on its path toward ZAP-N.

Binding of Intermofif (-NLGRREE-) 5 The peptide segment that separates the pYXXL motifs in ~1 consists of seven amino acids which make the bulk of their contacts to ZAP-C. Since nearly a full turn of an a-helix begins at ~ Asn 8 and continues to ~ Arg 12, many contacts for this sequence are intrapeptide. ~ Asn 8 makes a main chain hydrogen bond to the carbonyl oxygen of Gly 245 (BG), and ~ Arg 12 is invoived in both direct and water-mediated hydrogen bonds to the backbone carbonyl of Glu 225 (}F ioop);
1 0 two other water-mediated hydrogen bonds connect ~ Arg 12 to Gly 226 and Lys 228. The side chains of ~ Leu 9 and ~ Arg 12 close off the pY~3 pocket of ZAP-C.

Two glutamate residues co---p'_~e this sey~ lll of the ~1 peptide, and because they are the pY-1 and pY-2 residues of the second pYXXL motif, they constitute the first contacts to ZAP-I~ Glu 1 5 13 makes a main chain hydrogen bond to the backbone carbonyi of Asp 244. More interestingly, ~ Glu 13 is involved in a direct hydrogen bond through its side chain carboxyl to the side chain amino group of Lys 242 (ZAP-C aB) which is an integral part of the phosphotyrosine pocket of the N-terminal SH2 domain. ~ Glu 13 also maintains van der Waals contact to Lys 242, as well as to Tyr 238 (ZAP-C ~B) and the guanidlnium group of Arg 17 (ZAP-N ocA), which also 20 contribute to the N-terminal pY pocket. ~ Glu 14 maintains the characteristic pY-1 main chain carbonyl hydrogen bond to both terminal nil.ogens of Arg 17 which, in turn, contacts the aromatic ring and phosphate group of ~ pTyr 15.

Binding of Motif-2 (-pYDVL-) ~equires Both Domains 2 5 Perhaps the most remarkable feature of the co,.,plex between ZAP-NC and ~1 is the observation that the recognition pocket of ~ pTyr 15 is co",posed of residues from both S~12 domains. This is the first report of a phosphotyrosine binding site of this nature. ~he i.. F ~y;l-9 of ZAP-C on ZAP-N sequesters ~ pTyr 15 in a deep tunnel. The side chain of ~ pTyr 15 makes van der Waals contacts to Arg 41 (BC loop), Val 47 (,B C), His 58 (,~ D), and Pro 60 (~ D). The side chain of Arg 17 is positioned over the aromatic ring of ~ pTyr 15, forming an amino-~lu.,.dLic contact in addition to bridging the carbonyl of the pY-1 residue to the phosphate oxygens of ~ pTyr 15. The phospl1dL~ group is closely associated with the side chains of Tyr 238 (ZAP-C ~B), Lys 242 (ZAP-C aB), Arg 17 (aA), and Arg 37 (~ B), forming a total of six direct hydrogen bonds. Six water-mediated hydrogen bonds exist between the pl~os~ d~t: group and Arg 17 (aA), Cys 3~ (~
C), Leu 40 (BC loop), Arg 41(BC loop), and Lys 242 (ZAP-C aB). The relative i".~olLa--ce of each residue in this interface may be determined through mutagenesis experiments. Four waters with strong electron density contribute to this extensive network; the pr~sence of these waters may be a consequence of the intrusion of ZAP-C onto residues of the BC loop (v~de infra).

SUBSmUTE ~;~E~ ~RULE 26~

W O 9710830~ PCTAUS96/13918 In this ar,dngel"en~, each oxygen of the phosphate group possesses its full Co"l~ le."ent of hydrogen-bonding partners.

As described for the first pYXXL motif, the pY+1 and pY~2 residues (~ Asp 16 and ~ Val 17) make contacts that are characteristic for these positions in other SH2 complexes.20~ 21~ 23 Leu 18 resides in a hydrophobic pocket that is of similar di,l,ension to the pY+3 pockets observed in high affinity peptide complexes with Src family SH2 domains. A single water-mediated hydrogen bond connects the main chain NH of ~ Leu 18 to the carbonyl of Ala 72 on the EF loop. Contact to several h~,.llo,~)l 2b.~ residues is evident: ~ D contributes Phe ~9; interaction with the EF loop involves lle 71, Ala 72, Gly 73, and Gly 74; helix B presents Tyr 87; and the BG loop makes contact via Gly 93 and Leu 94. Asp 19 Of ~1 resides in weaker density and appears to form oniy one hydrogen bond from its main chain nitrogen to the carbonyl of Gly 93 (BG loop).

Interdomain Contacts Unlike the extensive contact area of ~1 to ZAP-NC, the total interaction area between the ZAP-N
and ZAP-C SH2 domains is small, measuring only ca. 200 A2. The surface area of ZAP-N that is buried by ZAP-C and the inter-SH2 spacer is only about 400 A2; the corresponding buried area in ZAP-C is not siyllitical'~ly larger. Total burial of ZAP-N in the full col,ll,le,c is 620 A2 which accounts for approxillldlely 13% of the total surface area of the domain. Conversely, burial of ZAP-C is computed to be ca. 1000 A2 which constitutes 20% of its total surface area. This ~JirIelence is due to the pl~sence of a large solvent ~ces~:n~ channel formed by the conv~rgence of the convex side of the BC loop of ZAP-N, the FB loop and helix B of ZAP-C, and both helices of the inter-SH2 spacer. This irregularly shaped funnel has an appruxill,ate diameter of 5-7 A, 2 5 and extends fully enclosed for ca. 12 A before flaring open for an ~' Lrnal 8 A. For the interface that is exclusively between the ZAP-N and ZAP-C domains, each SH2 domain contributes nine re-idu.os Most of the contacts are through hydrogen bonds, and most of these are water-mediated. However, some van der Waals cul l~ul~ do exist.

3 0 Given that the total interface that is exclusive to the two SH2 do,llai,ls may not exist in the absence of the peptide, the inter-SH2 spacer is likely to ~Id~ e the appn,priale orienldlio for tandem binding by permitting only minor r~isr!~cements through scissoring or wagging motions. In isoelectric focusing gels, u~lcol", 1~ ~r! ZAP-NC exists as multiple bands which coll-pse into a single band when the ~1 peptide is added. This ll,icluh~ rugeneity observed with uncomplexed ZAP-NC is cullsi;,lelll with co,lrur-,lalional variability.

Comparison to other SH2:phosphop~"~ide c~ /~YPS
Despite the low sequence identity (33%) between ZAP-N and ZAP-C, the similarity in overall fold is notable. Side chain positions are remarkably well-conserved between the two dorllaills.

SUBST~TUTE ~ RULE 2~;~

W O 97/08300 PCT~USg6/13918 The overall backbone root-mean-square (r.m.s.) deviation is 1.07A; the same measurement for ZAP-N or ZAP-C to Src family SH2 do".ai"s (individua!ly) is typically 1.50 A, although the percentage of sequence identity is similar. As .~po,lad for previous structures of individual SH2 domains,14~ 20 21 the loop regions display the largest positional variance, most notably 5 loops AA, BC CD and EF. The CD ioops of both ZAP-N and ZAP-C have a large truncation reiative to the SH2 domains of the Src family; this truncation is also evident from the sequences of a large number SH2 domains.23 Although each pYXXL motif of ~1 resides in a similar backbone co"rul-l-dlion in the co~ ~, the 10 ori~"l~lion of the phos,ol--,lyrosines varies between ZAP-N and ZAP-C. The aromatic ring of pTyr 4 superimposes remarkably well with the pTyr in both p56-Lck20 and v-Src.2t For pTyr 15, however, the ring is repositioned 0.7 A toward the guanidinium of Arg 17 and slips 0.8 A away from strand D. This is likely to be due to the .liit:clion ~1 takes as it moves into the ZAP-C domain as well as the strong hydrogen-bonding interactions between the phosphate 15 group and Tyr 238 and Lys 242 on ZAP-C. Both pTyr pockets of ZAP-NC are large enough to permit the inclusion of several waters; this enlal~yement relative to other SH2 domains is due to the l~pOs;ii~ 9 of the BC loop. The ~xlended position for the BC (phosphotyrosine binding) loop observed for both SH2 do---ai"s of ZAP has been observed previously for u"co""~lex~d SH2 do-,-ai.,s and has been described as a hinge in the binding of tyrosine ~.I.os~uho.ylated and ~0 phosphonated peptides.14~ 21 Although the loop is reoriented, the internal co..f- r--,alion for the BC loop is strongly ",a;.,l~i"ed.

The pY~3 pocket of ZAP-C is strikingly large ccs---l,ared to this site in other SH2 dor,.ai.~s. This is due, in part to leposilioni"g of ZAP-C EF residues Pro 224 and Glu 225 as described 2 5 earlier. Aside from the absence of a Tyr in ~B the location of other side chains that form this pocket are notably similar to the corresponding sites in Lck and Src.

Also, in comparison with all other crystal structures of c~ lexes of SH2 domains, a si~ icanl number of waters are present in ZAP-NC. Several are involved in bridging 3 0 phosphotyrosine to the protein. These intervening water molec~les may contribute to the weak affinity of individual ZAP SH2 domains for phosphorylated ITAM ligands.17~19~ 25Additionally a large number of buried or trapped waters exist in all of the various interfaces.

Biological SJgnificance 35 The structure of the tandem SH2 do---2ii--s of ZAP-70 in cor. ex with a component of the ~ chain of the T cell receptor provides the first molecular glimpse into the intr~ellul~r machinery of the TCR (su."",ari~ed in FIG. 4). Several unique features of this structure suggest that each SH2 domain does not function as an i- ~depel-de, ll module and that interactions between the domains play a critical role in the recoy. - ~ of pho~ orylated ITAM sequences of the TCR by SUBSmUTE ~EE~ ~RULE 2~i~

W O 97/08300 PCTnUS96/13918 ZAP-70. In addition the structural inrvlllldlion is key to the illl~l~Jr~ldlion of genetic and biochemical data and provides a framework for e: ri"y the ",e~.l,an;_." of action of ZAP-70.

The tandem SH2 domains of ZAP-70 exhibit strong selectivity for the phosphorylated ~ and e - 5 subunits of the TCR whiie isolated SH2 domains from other proteins bind more p,~""i~cuously to many tyrosine phosphorylated proteins in total cell extracts.5 Ligand binding and selectivity for isolated SH2 domains is mediated by recoy,-;.ion of a phosphotyrosine and several residues C-terminal to phosphotyrosine particularly the hydlu,uh~b c residue at the pY+3 position12.
The high degree of selectivity of ZAP-70 for doubiy-phosphorylated ITAM sequences appears to 1 0 be a consequence of multiple structural features. The di~lance between the two pYXXL motifs of the ~ or ~ chain provides properly spaced partners for a pair of SH2 don,ai.,s that are tethered in close association by an inter-SH2 coiled coil. Association of the pair of SH2 domains with the phospl1ulyrosines and other ITAM residues st~ a col"or",dlion that permits direct interaction between the domains and hence the formation of a deep pocket for sequesle,il,g one phosphotyrosine at the domain interface.

While ZAP-NC exhibits high affinity for doubly-phosphorylated ITAMS and selectivity for the and e chains the individual SH2 domains of ZAP-70 have not been found to bind appreciably to phosphorylated peptides~. In addition ZAP-NC binds to ..lonopho- ~ horylated ITAM-based 20 peptides with affinities that are 100-tOOO times lower than for the corresponding doubly-phosphoryiated ones.17~19 25 Consequently for high-affinity binding both SH2 domains must cooperate and two phospl1ulyrosine residues must be present and arranged appru~ri~lely.
The structural manifestation of this cooperativity and selectivity is also the most remarkable feature of the complex between ZAP-NC and ~1. that is the convergel1ce of residues from both 2 5 SH2 domains to enmesh pTyr 15.

To this point it has been assumed that SH2 domains adopt their native fold when extracted from their natural molecular context and possess their full abiiity to recognize and bind to phosphorylated proteins.12 t4 We present structural evidence that the N-terminal SH2 3 0 domain of ZAP-70 if expressed in isolaliol1 is incomplete. The groove-like nature of the pY
pocket of ZAP-C suggests that this domain may also require contributions from neiyl.bo-i-lg domains or pl ote;. Is.

From the crystal structure we ascertain that the odellldliun adopted by ZAP-70 upon 3 5 ~Cso~ on with the TCR aligns ZAP-C with the N-proximal pYXXL motif of ~1 and ZAP-N with the C-proximal motif as depicted in FIG. 4. We believe that this orientation may be i",po~ldn for posilioning the catalytic domain of ZAP-70 for its activation and s~hsequentphospl1orylation of d~ alll suiJ~lldles in the signal trar~ ction c~ ie.

S~JBSTITUTE S~E~ tRULE 2~i) CA 02226963 l99X-02-12 WO 97/08300 PCT~US96/13918 All of the ITAMs of the TCR have a spacing of seven residues between the pYXXL motifs, except i~2 which has a spacing of eight. In vitro binding expe,i~ , of ZAP-NC with synthetic phosphopeptides indicate that the binding hierarchy is ~ 2 > ~ 2 ~3.25 These results suggest that one ~r' "'il~nai residue between the pYXXL motifs is tolerated. Conversely, a two amino-acid 5 deletion in the col,~spondi,lg region of ~ drastically reduces ZAP-70 binding and eliminates IL-2 production.17Therefore, the distance between the two pYXXL motifs is illlpOlldlll for societion and signaling. In order to determine the relative contribution of each residue in the ITAM, experiments utilizing CD8-~1 ch Il~l~s were conducted, in which each residùe was sy~ ,nalically replaced with aianine. The results d~,-,ou~l,dte that only the ~eplace,ll~l.L of each 10 pY and pYI3 residue 0l;.1 lal~s siyl -' 19 co", 'e: !y, as measured by IL-2 production.25 With the exce~,lion of these reFidues the speclfic sequence of the ITAM is less illlpGIldlll for selectivity than the d;~ldnce between pYXXL motifs. More radical chdtlges, such as the simultaneous replacement of multiple residues, are necessary to assess the contribution of ITAM sequences to selectivity.

As described earlier, the inter-SH2 region constrains the SH2 domains within a di;.ldnce that permits ~csoci tion. However, because a 5iylli~icdlll portion of the antiparallel helices are directed away from the SH2 dGIllaills1 this region may also be involved in inter- or intramolecular contacts, regulation of kinase activity, and/or receptor clustering. The evidence 20 that this domain forms a coiled coil of cc-hellces is of great interest, since these structural unlts are commonly involved in protein-protein interactions.27 The inter-SH2 region of the p85 subunit of Pl 3-K, which has been pl~ led to form a coiled coil, Is necess~ly and sufficient for interaction of p85 with the pl10 catalytic subunit of Pl 3-K.22 One intriguing possibility evldent from our structure is that the ZAP interdomain is involved In regulation of 25 its kinase activity. The interdomain may inhibit catalytic activity directly or indirectly, and this inhibition might be relieved upon binding of the SH2 domains to the ITAM. Experiments with Pl 3-K25 and SYK23, the PTK ho",~ us to ZAP-70, support such a model. Addition of a phospl1olyrosine-containjng peptide that corresponds to Tyr 751 region of a known Pl-3K SH2 binding site from the PDGF~ receptor causes activation of Pl 3-K in vitro.29 Likewise, 3 0 phospl~orylated ITAM peptides derived from the y subunit of the I~E receptor- increase SYK
kinase activity by 5-10 fold.30 31 Another function for the inter-SH2 region may be to bind to proteins that either regulate ZAP-70 activity, such as Lck and/or Fyn, or that are sub:illdl~s for ZAP-70. Tyrosine 126 in the inter-SH2 region is phosphorylated by Lck in vitro32 and could be involved in interactions with other SH2 domain-co"ldi"ing plu~ ,s. Finally, the 35 inter-SH2 domain may be important for the intermolecuiar assoc,idlion between ZAP-70 ~m~lecl~es which might occur in the activated TCR complex.

SYK should also exhibit these structural features in view of its full.;lional simila,ilies and sequence identity of 57% with respect to ZAP. SYK is ex~ ssed in several types of .

SU'BSTtTUTE ~HEE~ (RULE ~6) WO 97/08300 ~CT~US96/13918 hen.~lopci_~ic cells and functions in mast cells and B cells by binding to ITAM sequences in the cytoplasmic domains of IgE and B cell receptors, respectively.23 By co~ ari-~g the ZAP-70 and SYK sequences,33 most of the residues in ZAP-NC that contact pTyr 15 are conserved in the corresponding positions in SYK. The N-terminal SH2 domain of SYK does not bind to 5 phosphotyrosine ligands or to phosphotyrosine affinity columns,34 which suggestC that, as in ZAP-NC, this phosphotyrosine site also requires the C-terminal SH2 domain in order to form a complete pocket. Doubly-phosphorylated peptides derived from the r ITAM of the IgE receptor induce SYK activation.3~ Our COIll, 'Ek of ZAP-NC with ~1 may therefore represent the co"rur...d~ion of the SH2 don,ai"s adopted in the activated kinase.

ZAP-70 has emerged as an attractive target for the d~velop...ent of safe and potent immunosu~,pressive drugs. ZAP-70 has been shown to be required for T cell-mediated immune responses in humans, and loss of ZAP-70 does not affect other tissues.8 Thus, ZAP antagonists would specifically inhibit T cells and avoid the toxicity of the currently used 1 5 immunosuppressive drugs, FK506 and cyclosporin35~36, which target the more ubiquitously expressed protein calcineurin.37~ 38 This protein phosphatase is required for T cell immune responses, as well as functions in several other tissues, and as a consequence, cy~,lospori., and FK506 cause serious side effects in the kidney and central nervous system which limit their applicdlion largely to pateients with organ l-dnsplant reiection.36 New immunosuppressive 2 0 drugs with less toxicity are needed to expand the routine use of such therapies to autoimmune ; ~

One approach to i"hiLilion of T cell activation is to develop small (i.e., preferably having a molecular weight below about 120~, more preferably below about 750 and even more25 preferably below about 500), preferably non-peptidic, membrane permeant, molecules that bind to ZAP and prevent its association with the TCR. Such a compound may bind, plelerdbly with high affinity, to either SH2 domain of ZAP-70 or to the inter-SH2 domain interaction. Our crystal structure reveals the molecular details of the three dimensional structure of ZAP and provides insights into its interactions with the TCR. The unique structural features of each SH2 3 0 ligand binding site and the unanticipated inter-SH2 ~-~so~;-lion now can be exploited for structure-based design of highly specific small molecule ZAP ligands and structurally biased compound libraries.

D. Use of three-dimensional Structure of ZAP-NC in solving the structures 3 5 of other tandem SH2 proteins Having solved the ZAP-NC structure we conle..."ld~d that other proteins containing two SH2 domains, especially ZAP family members, will have this unique binding pocket formed by in~erdo..,ai" ~cso.. -lion and that it can be ~ d for the design of i-,l~:,le-i,-g compounds. The SUBSTlTUTE ~j~{F~ (RULE 2~i) W O 97/08300 PCT~US96/13918 protein currently conside.~d to be most ctosely related to ZAP is SYK. (see figure of sequence alignment). Using the structure of ZAP-NC, a three-' ,.ensional model of Syk-NC can be obtained through hom~!a,,~ modeiing. Prior to solving the ZAP-NC structure, this would have been difficult if not i."~,ossible since the sequence identity between the SH2 domains of Syk and 5 SH2 dol--a;..s of known structure is low and none of the previously solved SH2 domains contain two S~12 domains. Other currently known proteins with tandem SH2 domains are PLC~, Pl3K, rasGAP, SH-PTPI, and SH-PTP2. Addilional proteins with two SH2 do",ai"s are exf,euled to be discovered through genome sequencing or other cloning methods.

1 0 F, Use of Structure in Drug Discov~ly Utilization of the structure of the tandem SH2 domains of ZAP-70 in computer-aided drug design ~CADD) 15 The availability of the three-dimensional structure of the tandem SH2 domains of the protein tyrosine kinase ZAP-70 (ZAP-NC~ makes structure-based drug discovery approaches possible.
Structure-based approaches include de Novo molec~ r design, computer-aided opli---i~dlion of lead mclec-~'es, and computer-based selection of candidate drug structures based on structural criteria. New peplido...;...~lic modules may be developed directly from the structure of the 20 peptide ligand by design or database searches for co..for...~tionally-restricted peptide replacements. Alternatively, structure-based lead discovery may be acco---pl;~lled using the target protein structure stripped of its ligand. Multiple unco...tJlsx~d states of ZAP-NC can be generated by several methods to provide Pd~ittional target co--ru-,.-alions. The experi-..a..~al coor~ii.,d~s and the resulting u..co...ple,~ed models can be suhier,tPd to techniques such as 2 5 receptor site mapping to identify sites of favorable interaction energies between the structure of the target protein and potential ligands or chemical moieties ("fragments" or 'seeds"). Such evaluation may be followed by procedures such as l-dy...enl seed linking and growth. Fragment seed linking refers to methods for des;y..i--g structures that contain "linked" "seeds", i.e.
chemical structures co"~ ing two or more of the ...apped ~ es app,uplialely spaced to 3 0 reach the respective sites of favorable i"ler~clions. Growth refers to the design of structures which extend, based on receptor site ...appp;..g or to fill available space, a given moiecule or moiety. Based on the receplor site ~--ap~. .g data, one may also select pul~.llial ligands from d~t~hf~cF~s of chemical structures. Potential ligands, or sui ouli...al ligands, of whatever source, can be refined by using the receptor site maps to filter multiple ligand col.k,r...~liolls and 3 5 orie"l~lions according to energetic p.~ft:.~nces. Finally, in view of the high degree of sequence si-- '~~ily to the tandem SH2 domains of p72SYk, the structure of ZAP-NC permits one to generate a high-quality model of Syk-NC by either knowledge-based homology ~ Jldle methods or iterative site-mutations followed by ...;..i...i~liol-s. The generated structure of Syk NC may SU85TtTUTE S}~E~ (RULE ~

W O 97/08300 PCTrUS96/13918 then be treated as an ~' " nal protein target by the llielllo(l:, outlined above. These methods and their ~pplic~lion to ZAP-NC are described in the sections that follow.

r-~ti~G.~ ics of the ~1 peptide may be developed from the bound conformation of a 5 peptide ligand by design, by searching ~ e5 for t~place-"~ , of one or more peptide segments, or by enhancement of existing ligand-protein interactions (i.e., by replacing a component moiety of a ligand with a suhstitllt~ moiety capabie of greater interaction with the target protein, whether through ~cc~ossi 'o protein contact points or by extrusion of otherwise se~luestered waters~. Knowledge of the bound cor"ur",dlion of a peptide can suggest avenues for 10 conrur'''dlional ~ iclion and peptide bond replace-"e"l. A less biased approach involves computer algorithms for searching d~t~h~ces of three dil,~e/,~ al structures to identify replace",~"l~ for one or more portions of the peptide ligand, p.efeldbly non-peptidic replacement moieties. By this method, one can g~ ldl~ compounds for which the bioactive co"rur",ation is heavily popu'~ed i.e., compounds which are based on particularly bioiogically 15 relevant conformations of the peptide ligand. Algorill""s for this purpose are implemented in programs such as Cast-3D (Chemical Abstracts Service), 3D8 Unity (Tripos, Inc.), Quest-3D
(Car..~lidge Crystallographic Data Center), and MACCS/ISIS-3D (r,1~1ec~ r Design Limited).
These geometric searches can be augmented by steric searching, in which the size and shape re~- ~",e"l:j of the binding site are used to weed out hits that have prohibitive dimensions.
2û BnJylduls that may be used to syn.;l,loni~e the geometric and steric requirements in a search applied to ZAP-NC include CAVEAT (University of California, Berkeley), HOOK (MSI), and ALADDIN (Daylight Software). All of these sedl~;l,i,.g protocols may be used in conjunction with existing colyord~e tizlt:lh~ces. the Cal,.bridge Structural Database, or available chemical databases from chemical suppliers.
In addition to the retel,lion of potential pharmacophoric elements that are present in the peptide expiicitly, the incorporation into a ligand structure of hydrogen-bond donating or accepting groups that can di~pl~ce ordered water m~lscl~'es usually provides a siy.,iricanl entropic gain that leads to a favorable free energy of binding. Such ordered waters are identifiable from the 3 0 structure, and other ordered waters may be located during computer simulations of a fully solvated structure, as described more thoroughly in a s~hsequent section.

Ge~ iol~ of alternate binding site conr-,.."~liol1s of the target protein may be desired in view of the flexibility of the phosphotyrosine binding region, the nature of the interface 3 ~ between the two SH2 domains, and overall, in view of the possib y of an induced fit, i.e., co"r~"",d~ional changes in both ligand and protein upon binding. For ~xa,l"~le, the loop that connects ,~-strands B and C (the BC or phosphotyrosine binding loop) has been reported to act as a functional hinge in Src-family SH2 domains. In addition, charged residues in the phos~ olyrosine binding pocket are capable of side chain reorie"ldlions. A variety of theoretical .
- 3~ -SUBST~TUTE S~ RU~E i~6) ods such as Metropolis Monte Carlo or molecular dynamics simulations (i",ule."e"l~:d in ,OI'U91dlllS such as MCPro [Yale Univeristy], AMBER [UCSF], CHARMm [Harvard University~, and GROMOS ~ETH/Groningen~) may be used locally to gellerdle Boll~",anll distributions of l",col"plaxed states and hence provide a set of a~i.lilional coniul"~dlions that are valid for 5 ~, ~le~ r design. Alternate side chain reorie"ldlions can also be examined by Dead End Elimination and A~ alyo,ill""s (University of Southhampton3, by iterative s~slel~dlic conrvlllldliùnal searches of each side chain, or by co,,,lud,i~on of each residue type to members of the Protein Data Bank that have the same backbone torsions. Valid cu,,ru,,,,dlions of the BC
loop (or loops EF and BG~ may be created by searching the Brookhaven Protein Data Bank for 10 loops that have similar anchoring geometries or by imposing random backbone cc,n~ur,,,alions within the selected loops and filtering the results to fit the anchor r~cidues Both of these knowledge-based methods generate initial structures which can be subjected to force-field ",i,.i",i,alions to produce feasible geometries.

15 In addition to the flexibility inherent to the peptide binding site the interface between the two SH2 domains provides opportunities for exploring additional conformational states. The interface that is exclusive to the two SH2 domains provides a total buried surface area of only about 200 ~2 and consists largely of hydrogen bonding contacts many of which are ",edidl~:d by water. Experiments with isoelectric focusing gels suggest that u"-jolll,ul~ d ZAP-NC exhibits 20 co..tu""alional mobiiity between the two SH2 domains that is s~hduPd upon binding to the peptide. Since ZAP function requires that both SH2 do",ai"s associate simultaneously with a doubly-phosphorylated ITAM of the TCR, gross ~icr~ia~elllelll~ between the two SH2 domains may play a regulatory role. Thus, co,,~u,,,,dlions in which the SH2 dor"di"s are separdled may lep.~senl an inactivated state and inhibitors that stabilize this olie"ldlion become attractive.
2 ~ Molecular dynamics simulations of a fully solvated ZAP-NC may provide insight into the structural manifestation of a possible dissociation between the SH2 domains, and an addilional target coniu-",alion of the unco",plexed protein.

rlec~ or site ~ i..,J enco",passes a variety of computational procedures that identify 3 0 energetically favorable binding sites on ma~;, u, "olEcules The most straiyl ,~u, ~ . drd procedures involve pai,,liny~ a solvent-~ccesc;'-le surface (or an otherwise generated cast) of the ",ac~l"olecular target according to empirically determined physical properties such as elec;~lùsldlic or lipophilic potential degree of curvature and hydrogen-bonding character. Such methods for thus characLt:ri~i"g the surface of a mac:lo" ~lec~le are incorporated in IJlU91dll\:~
35 such as Grasp (Columbia University), De~Phi (Biosym Technologies), MO~CAD (Tripos, Inc.), and Hint (Virginia Corl".,ou;.ealth University~. S~hse~luent molecule design involves idel~ ation or design of ligands that possess features co" ~ I,entary to the identified surface characteristics. More advanced alyolilllllls involve the actual c~icl~l~tion of interaction enthalpies between the target and potential ligands or ~dy"~e"ls. In practice, the coor, Idles of -SUBSTITUTE ~ E~ ~RULE ;~6) W O 97/08300 PCTnUS96/13918 the protein or protein fragment of interest (which may be rotated or otherwise tran~u,,,led) are ~ ,ped of any undesired ligand (or portion thereof) and/or of any ul,desi-,3d solvent molec~'?~ The coordinates are then processed to attach molecuiar mechanics pardmt:L~r~ to the atomic posilions to provide a p,ucessed target for ",appi.,g. The target may be partitioned into 5 discrete binding sites. The target or partitioned sites thereof are flooded with given functional group fragments that are subsequently allowed to relax into desired locations, as in the ploy,~
MCSS (Molecular Simulations, Inc.), or are encased within a regular lattice of site points on which single fragment probes are positioned sequentially; examples of pro~.dr":, that exploit the site-lattice algorithm include Grin/Grid (Molecu~r Discovery, Ltd.), Ludi (Biosym 10 Technologies), Leapfrog (Tripos, Inc.), and Legend (University of Tokyo). In both techniques, the enthalpic contribution to binding affinity is estimated with a molecular mechanics force-field, and appropri~le positions of selected functional groups are determined sy~ ..,atically.

In the site-lattice approach, a box is defined enclosing a desired portion of the target within a 1 5 defined lattice. The lattice resoiution, i.e., the distance between lattice points, may be defined by the practitioner or may be set by the computer program. Likewise, other parameters of points within the lattice, such as hydrophobicity or other characteristics. may be similarly defined.
Probes (i.e. computer models) of one or more selected moieties, functional groups, molecules or molecuiar fragments are positioned at lattice points and the interaction energy of the probe-2 0 target pair is d~lel",;"ed for each such lattice point. The data for each selected moiety,functional group, etc. is collected and may be recovered as a data set, visualized on a computer monitor or printed out in various text or graphic formats.

As an alternative to positioning a moiety at each of a set of lattice points. one may, as previously 2 5 mentioned, flood the target (defined by the coordinates as described above~ with multiple copies of a selected fragment, moiety, molecule, etc. by superi,,,~vosi~g the multiple copies into the vicinity of the protein target. The model is then s~hjected to group ",i" "i~alion (i.e., molecular mechanics mi"i".ization~ calculations to identify points or areas of favorable interaction. Data may be handled as in the lattice approach.
One application of this method to the structure of ZAP-NC involves the crystal structure coordinates stripped of both the peptide ligand (~1) and expe.i",t:ul~lly observed water mo'_cllles The binding site so revealed comprises all protein residues that reside within van der Waals distance of any position previously occupied by the peptide. This "conventional"
3 5 binding site is eniarged to inciude the bu~k of the p.~"~i."al protein surface, hence additional crevices and depr~ssiùns not occupied by known ligands for any SH2 domains are considered as potential "auxiliary" binding regions, and their occllr~tion could contribute siylliricanlly to the i"hibiiiol1 of ZAP association with the T cell receptor. Similar definition of the binding face of ZAP-NC appiies to any alternate coor~li-,~les derived experimentally or via the modeling SUBSTlTUTE ~E~ ~RUI E 26 CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 procedures descd,bed above. Receptor site l,.app..,g, as well as other methods described herein, may be applied to the 3-D structure of a ZAP famiiy member to design or select ligands capabie of binding to an S~2 domain or other site within the ZAP-NC (or ZAP rd,l, ~y NC) structure.

5 Receptor site maps provide the seeds for-ligand evolution via D~ e~ sea~hes, which are described above, and for G~ 7~ o<~a for de Novo design of new .;I,e" ' entities.
~l,ayl7dms for ligand growth first access e)ctensi,~le fragment dictionaries in order to place app.~plidle ful.~;liol,al groups at site points. A genetic algorill"" or a subgraph iso,l,u"~his", protocol is then invoked to connect the fragments with small aliphatic chains or rings.
10 Stc,cha:,lic enhancelllents may be introduced by ",oJiric~lion of internal degrees of freedom as well as l,dnslalion and rotation of the candiJdl~: model within the binding cavity. The resulting sets of ll,- sc~les are scored and filtered by functions that conside~ the steric conslldi"ls of the binding site, the co,l,~uli.,lellldrity of elec-l~usla~ and hydrophobic interactions, and a solvation estimate. Programs of this type that could be applied for the design of new ligands for ZAP-NC
15 include Ludi (Biosym Technologies), Leapfrog (Tripos, Inc.), Legend (University of Tokyo), Grow (Upjohn~, BuildertDelegate (University of California, San Francisco), and Sprout (University of Leeds). Clique detection methods provide an alternative strategy to site md,4,~7;.19 and ligand growth. DOCK (University of California, San Francisco) and similar programs fill a given binding site with the smallest set of atom-sized spheres possi_,le; a ~t~h~e search then 20 dll~ , to orient ligands such that the atoms su,~li,llpose onto the centers (or "nuclei") of the site-filling spheres. The shape col",~,l;,l,e"ldrity is auy",6",led by scoring functions that include the steric requir,-l~"_lll, of the cavity and a poLet~lidl energy function.

GIJ~ of ligands (from any source) may be enhanced usiny the three dimensional 2 5 structural of ZAP-NC. Use of receptor site maps or hyd,~pdll"c profi,'es of ZAP-NC may be used to identify preferred positions for functional group co~".~ol)el,l~, of iigands. and can be used to filter or constrain conformational searches of ligand structures which would otherwise typically be controlled by minimal steric considerations of the ligand structures themselves.
The availability of an explicit binding site also permits one to d~l~r",i"e the mode of ligand 3û binding to the target protein via methods that utilize force-fields directly in simulated annealing, distance geometry, Mel-opo.'i~ Monte Carlo, or ~,lu~ l-aslic searches for binding modes.
Exd~"~les of programs that can be applied to rationalize ligand binding to ZAP-NC include Autotock (Scripps Clinic), DGEOM (QCPE i~590), Sculpt (Interactive Simulations, Inc.), or any of the molecnl~r dynamics pl0yldlll5 desc,ibed above. Once a tractable set of possible 3 5 binding orie.,ldliol1s is obtained, one can readily identify the approplidle mode of binding through Illodiliodlio~s in test ligands designed to alter in a p"~d- ~'6 fashion the binding affinity of each model under consiJ,-lali,~n. ,=or i"sld,~ce, a ligand may be modified to contain a functional group at a position which is incot,s;il~"l with one binding model, yet cons,i ,lt:l.l with another model. Binding data can then be used to weed out "disproven" models. Once iterative -SUBSTITUTF Si~E~ ~RULE 2~) -CA 02226963 l998-02-l2 W O ~7~Q8300 PCT~US96/13918 weeding of unlikely binding modes generates an apprupliaLt: model, po-~' ' -s for improvement of the lead become readily apparenl from the local protein env;.~ ",~"l.

An alternative protocol for ligand op~ dLioll involves 3D database searching in conjunction 5 with knowledge of the binding site. IV odE' ,9 can reveal multiple candiddLes for the bioactive conrurllldlion of a given ligand. A probe for the correct cor,ru""dlion can include a 3D search to identify several constrained mimics of each possible co-~rur-"er. Structure-activity elaliollsl,i~s of the unconsL,di"ed ligand would suggest which functional groups shouid be retained in the con:,l,di-,ed mimics. Finally, the steric and electrostatic requirements of the 1 û binding site could constitute a filter for prioritizing the resultant possibilities.

The structure of ZAP-NC permits accurate model-building of hol"ologous proteins, and their sl~hsequent use in drug design. The SH2 domains and inter-domain coiled coil regions of the protein tyrosine kinase p72SYk share a high degree of sequence similarity with ZAP-70. The 15 ZAP-NC structure may be readily used in the development of a reliable model of Syk-NC by either knowlege-based te""~late building methods, or by iterations of directed point mutations followed by local ~"olecl~r mechanics u, ,;..,i~alions. Examples of programs that can be applied in the development of a model of Syk-NC include Composer (Birbeck College), Modeler (MSI~, and l lo~, ~lo~ (Biosym Technologies). The resultant model can then be subjected to any of the 2 0 CADD lecl""~es described above.

F. Characl~ricdlion of Compounds Compounds designed, selected and/or o~ d by methods described above may be evaluated for 2 5 binding activity with respect to proteins containing one or more SH2 domains of interest using various approaches, a number of which are well known in the art. For illbLdnce, compounds may be evaluated for activity as competitive inhibitors of the binding of an SH2 domain with a phG:"ollorylated ligand thereto. See e.g. Pawson, US Patent No. 5,352,660 (4 October 1994).
Surface plasmon resonance (SPR) technology may be used for evaluating the binding properties 3 0 of compounds with respect to one or more SH2 ~iullldills of interest ~see e.g., Panayotou et al, 1993, Molecular and Ceilular Biology 13: 3~67-3~76), dS can fluorescence proximity methods, and other methods known in the art.

SPR methodologies measure the interaction bl:~ een two or more ma-;,ur,.olec~ '?S in real-time 3 5 through the generation of a quantum-me.;l,d,.ical surface plasl-.on. The SPR methodology as - i by the BlAcore Biosensor ~) (Pharmacia Biosensor, Biscdld~y, NJ~ focuses a beam of poly~,hlc""dLic light at the interface between a gold film (provided as a ~1; pos~hle biosensor "chip") and a buffer compartment that can be regl~ t~d by the user. Attached to the gold filrn is a 100 nm thick "hydrogel" composed of carboxylated dextran which provides a matrix for the .

SU~STITUT~ S}{E~ tRULE 26 CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 covalent i,.""obi~:~,,lion of analytes of interest. When the focused light interacts with the free electron cloud of the gold film, plasmon resonance is enhanced. The resulting ~e:rle~;led light is spectrally depleted in wav_lrnyllls that optimally evolved the resonance. By sepdldlillg the reflected polycl"ur,.alic light into its cc.rl,~uonellL wavelengths (by means of a prism), and 5 determining the frequencies which are depleted, the BlAcore establishes an optical illl~l~dce which accurately reports the behavior of the generated surface pla:""o" resonance. When designed as above, the plas"lun resonancc and thus the depletion spectrum--is PY~ isi~e~y sensitive to mass in the evanescent field (which co,lt:bponds roughly to the ll '~,ess of the hydrogel). If one component of an interacting pair is i,l""obili~ed to the hydrogel, and the 10 interacting partner is provided through the buffer compartment, the interaction between the two co,ll~,ol)ents can be measured in real time based on the accumulation of mass in the e~,anesc~ l field and its corresponding effects of the plasll,on ~:sonance as measured by the depletion spectrum. This system permits rapid and exremely sensitive real-time measurement of the molecular interactions without the need to label either component Fluorescence polari~alion (FP) is a measurement tecl,ll ,Je that can readily be applied to protein-protein and protein-ligand interactions in order to derive IC50s and Kds of the ~c50~i tion reaction between two 11~18~ ~les In this technique one of the molecu'~6 of interest must be conjugated with a fluotophore: this is generally the smaller molecule in the system (in 2 0 the case of a SH2 system, a phospho-tyrosine-containing peptide). The sample mixture, conldi"il,g both the ligand-probe conjugate and the protein receptor, is excited with vertically polari~ed light. Light is absorbed by the probe fluorophores, and re-emitted a short time later.
The degree of polarization of the emitted light is measured. Polali>dlion of the emitted light is dependent on several factors, but most illl~Jolldlllly on viscosity of the solution and on the 2 5 apparent moiecular weight of the fluorophore.

With proper controls, changes in the degree of polarization of the emitted light depends only on changes in the apparent molecular weight of the fluorophore, which in-turn depends on whether the probe-ligand conjugate is free in solution, or is bound to a protein receptor. Binding assays 3 0 based on FP have a number of illl~?OIIdlll advdllldges. Key among these are the measurement of lC50s and Kds under true homogenous eql ' ' ,ium con~liliolls, speed of analysis and amenity to aulùmdlion, and ability to screen in cloudy suspensions and colored solutions.

Aulu",dlion of such an FP-based assay is achieved using a 96-well fluorescence pola,i~aliùn 35 plate reader. This reader can read pola,i~dlion values at a sensitivity level of InM for fluorescein-labeled molecules, and can read an individual plate in 3 minutes.

SUBSTITUTE ~i~ E~ ~RULE 2fi~

W O 97/0830~ PCTrUS96113918 Fluo~t:scence pola~ lion equiiibrium binding assays have been adapted for ZAP, Syk, and Src domains. A binding curve of a doubly-pho:"~holylated ~-1 sequence to N,C-ZAP, with ~-~soc~ d Scalcl1ald plot of the data is shown in FIG. 5.

5 It will often be pler~:r,ed that a compound pr~l~renlially inhibits the interaction of a particular SH2-conl~i.,;"g protein with its natural ligand (or a portion thereof or analog based thereon), e.g. at least an order of magnitude, and even more pr~l~r~bly, at least two orders of ,,,ay better (by any measure) than it inhibits some other Stl2-~igand interaction.

10 Such compounds may be further evaluated for activity in inhibiting cellular or other biological events mediated by a pathway involving the interaction of interest using a suitable cell-based assay or an animal model. Cell-based assays and animal models suitable for evaluating inhibitory actvity of a compound with respect to a wide variety of cellular and other biological events are known in the art. New assays and models are regularly developed and reported in the t 5 scientific literature.

For example, compounds which bind to ZAP-70 may be evaluated for bioloy;_al activity in inhibiting T cell activation using any conventional assay methods and materials. Thus, compounds which bind to ZAP may be assayed for i,.l,iLilion of CD4+ and CD8+ T-lymphocytes 2 0 in vitro and for lack of in vitro toxicity on cytotoxic T-cells within the dose range used to de...onsl,~le in vitro activity. A battery of in vivo models may be used to profile the breadth of the compound s immunosu,upressive activity and cor..~ar~ the profile to those of positive controls such as cyclosporin and FK506. Co...,oa-i~u--s may also be made to other currently accepted immunosu~pl~ssive compounds, i.e. rapamycin, cy-,lopl1ospha..,ide, and leflunomide.
25 Initial in vivo screening models include: Delayed type hypersensitivity testing, Allogeneic skin transplantation. and Popliteal Iymph node hyperplasia. Compounds demonsl-dli-,g optimal profiles in the above models are advanced into more so,l~h;,~ic~ d models designed to confirm immunosuppressive activity in specific therapeutic areas including: Rheumatoid arthritis, T~dns~JldnlaLion, Graft vs. host disease, and Asthma.
Compounds which bind to SYK may be evaluated for i..h :lury activity in a mast cell or basophil degranulation assay. The inhibitory activity of a compound of this invention with respect to cellular release of specific mediators such as hislar-;"e, leukotrienes, hormonal mediators and~or cytokines as well as its bLlcgical activity with respect to the levels of35 phosphatidylinositol hydrolysis or tyrosine phosphorylation can be chara~le-i ed with conventional in vitro assays as an il, n of biological activity. (See e.g. lgE-induced histamine release from rat basophilic leukemia cell lines: isolaLion of releasing and nonreleasing clones . Edward L. Barsumian, Chaviva Isersky, Ma.ianne G. Petrino and Reuben P. Siraganian. Eur. J. Immunol. t 981. 11:317-323; Forrest, MJ, 1991, Biochemical SUBSTlTUTE S~EE~ ~RU~E 26) W O 97/08300 PCT~US96/13918 Pharmacology 42:1221-1228 (measuring N-acetyl-,~glucosaminadase from activated netrophils); and Stephan, V.M., et al., l. Biol. Chem. 267:5434-5441 ~1992~). For e~dr..,~le, hl~ld",i"e release can be measured by a . 'ic: "~"u--oassay using a kit available from AMAC Inc.
(Westbrook, ME). One can thus evaluate the ~ y;cal activity of compounds which bind to SYK
and cor"~.dre them to one another and to known active compounds such as leflunomide (and its active metabolite, A771726), ~,dnadale, stau-uspo-i-,e, genistein, or other compounds, including clinically relevant compounds, which can be used as positive controls.
Generally speaking, in such assays ICso scores of 150-300 ,~LM are con~ ert:d of interest, 1 0 scores of 50-150 ,uM are consideled good, and scores below about 50 uM are of high interest.

Compounds which bind to SYK may also be tested in an ex vivo assay for their ability to block antigen-stimulated contraction of sensitized guinea pig tracheal strip tissue. Activity in this assay has been shown to be useful in predi_li.,g the efficacy of potential anti-asthma drugs.
1 5 Numerous animal models of asthma have been dcveloped and can be used (for reviews, see Larson, "Experi",en~dl Models of Reversible Airway Obstruction", in THE LUNG, Scientific Foundations, Crystal, West et al. (eds.), Raven Press, New York, pp. 953-965 (1g91);
Warner et~L, 1990, Am. Rev. Respir. Dis. 141:253-257). Species used in animal models of asthma include mice, rats, guinea pigs, rabbits, dogs, sheep and ~,.i."ates. Other in vivo models 20 available are described in Cross et al., Lab Invest. 63:162-t70 (1990)); and Koh, et al., S cie n ce . 256: 1210-1213 (1992~) .

By way of further illustration, compounds which bind to an SH2-bearing protein involved in the trar-cduction of a signal involved in the ;.,ilidlion, maintenance or spread of canceruus 2 5 growth may be evaluated in relevant conventional in vitro and in vivo assays. See e.g., Ishii et al., J. Antibiot. XLI1:1877-1878 (1989) (in vitro evaluation of cytotoxiclantitumor activity); Sun et al, US Patent 5,206,249 (issued 27 April 1993)(in vitro evaluation of growth inhibitory activity on cultured leukemia cells); and Sun et al, supra (xenoy,d~l models using various human tumor cell lines xel~oyldrled into mice, as well as various l-dnsgenic 3 û animal models).

Single and multiple (e.g., ~ to 7 days) dose inve:,liydlive toxicology studies are typically performed in the efficacy test species using the intended route of ad,,.~ l-d~iun for the efficacy study. These investigative ~.~xicolog~ studies are pe.rum.ed to identify maximum tolerated dose, 35 subjective bioavailability from the intraperitoneal or oral routes of ad...;..i;,l.dlion, and e:jli."dlion of an initial safety margin. Initial bioavailability and pharmacokinetics (blood clearance) of the compounds may be deler"~;..ed, with ~lan~:ldl-3 cold or ,ddi;)ac;live assay ...etl,ocls, to assist in defining ap,u.upridle dosing ~~yi,nel1s for the compounds in the animal models.

SUBS-I 11 UTE ~;~F~ ~RULE 2~;) W O 97/08300 PCTrUS96/13918 Illustration of drug design To illustrate one approach to using the structure of a ZAP family member in drug design, we used the structurat coor~ ,aLes of the ZAP-NC: ~1 complex (see e.~. Appendix 1) to characterize 5 amino acid residues of interest with respect to their c~r~hility for interaction with ligand l"~12cl~es For instance, using the pruyldlll Sybyl we identified amino acid residues from the N-terminal SH2 domain and C-terminal SH2 domains which are within 10 angsl,-,r"s o~ the ~-1 peptide ligand and which reside on the protein sur~ace. Residues from that region which are capable of ~"l~li"~ hy~.u~hr~i~ interactions with moieties on ligand ",olecu'~ are listed in 1 0 Table A. Acidic residues from that region which are capable of entering hydrogen-bonding interactions or ionic (salt-bridge) interactions with moieties on ligand molecules are listed in Table B. Basic residues from that region which are capable of entering hydrogen-bonding interactions or ionic (salt-bridge) interactions with ",~ie~ on ligand molecules are listed in Table C. Neutral residues from that region which are capable of entering hydrogen-bonding 1 5 interactions with moieties on ligand molecules are listed in Table D. n~ es from that region having ap~.opridlely rlisposed backbone amide carbonyls which are capable of entering hydrogen-bond acc~,li"g interactions with moieties on ligand molec~ s are listed in Table E.
ne~ es from that region having a~ o,~,,idL~ly ~icrosed backbone amide nitrogens which are ~r~hlE of ~"l~ril,y hydrogen-bond donating interactions with moieties on ligand molecules are 20 listed in Table F.
Table A Table B Table C Table D Table E Table F
ALA18 GLUt9 ARG17 SER14 PHE56 ARG17 LEU48 ASP90 HIS52 CYS3g GLY73 CYS96 SUBSTITUTE S~tE~ ~RULE 2~

W O 97/08300 PCT~US96/13918 Similarly we have identified amino acid residues from the C-terminal domain and the N-terminal domain which reside at the interface between these two domains which would be capable of interacting with ligand molecl '?~ in such a manner as to disrupt the jll~t~posi~iot ,g 5 of domains necessary for binding ZAP-70 to the phosphorylated T-cell ,eceplur. Residues from that region which are capable of enl~:,i"g hydrophobic interactions with moieties on ligand molecules are listed in Table G. Acidic residues from that region which are capable of entering hydrogen-bonding interactions or ionic (salt~bridge~ interactions with ",Gi~lies on ligand molecules are listed in Table H. Basic residues from that region which are capable of entering 1 0 hydrogen-bonding interactions or ionic (salt-bridge) interactions with moieties on ligand mclQcllles are listed in Table 1. Neutral residues from that region which are capabie of entering hydrogen-boncli"g i"Le,d~;lions with moieties on ligand molecuies are listed in Table J.
Taklç G Table H Table I Table J

1 ~; Similarly we have identified amino acid residues from the interdomain (also called spacer A) region which reside at the interface between the two a-helical coils of this region and which would be capable of interacting with ligand l,~e Qcl 'es in such a manner as to disrupt the observed folding of the NC-ZAP domain. Res~ es from that region which are capable of enLe,i"g hydluphobic interactions with moieties on ligand malec~les are listed in Table K.
20 Acidic residues from that region which are capable of entering hydrogen-bonding il,le~.ilions or ionic (salt-bridge) interactions with l"oi~:ties on ligand molecules are listed in Table L.
Basic residues from that region which are capable of entering hydrogen-bonding interactions or ionic (salt-bridge) interactions with moieties on ligand moiecuies are listed in Table M.

SUBSTITUTE S~ tRULE 2{i~

W O 97/08300 PCT~US96/13918 Neutral residues from that region which are capable of entering hydrogen-bonding interactions with moieties on ligand molecules are listed in Table N.
Table K Table L Table M Table N

ILE153 GLU150 ARG124 THi'~156 LE~J133 ARG160 TYR126 5 The amino acid residues listed in Tables A-N can be used to define binding sites on the ZAP-70 protein for moieties on ligand molecules. A binding site comprises any subset of the foregoing residues which are within about 10 any~ u",s of one another. For t:x~ lc, the residues CYS3g, ARG41, SER42, PRO60, GLU62, LYS220, and ASP230 co""uri:,e such a binding site.

1 0 We co,-l~,..,ulate a new class of ligands for ZAP family members based on the foregoing type of evaluation. Specifically, this class comprises compounds containing one or more moieties which are each capable of interacting with one or more of the ~oregc:..g resirh~es, preferably with one or more binding sites defined by the foregoing resiri~eci A subset of such compounds are those which contain at least two moieties, of which at least one is a s~hstit~lted or uns~hstit~tQd 1 5 phosphate or phGsl,hale mimic ~e.g., a sl-hstitllt~d or un~hstittltPd phosphonate moiety). In embodiments in which those moieties are substituted, the substituent may be alkyl, aryl, or arylalkyl .

The term alkyl is intended to include both saturated and unsaturated straight chain, branched, 20 cyciic, or polycyclic aliphatic hydrocarbons which may contain oxygen, sulfur, or nitrogen in place of one or more carbon atoms, and which are optionally s~hstitutPd with one or more functional groups selected from the group consi~li"g of hydroxy, C1-Cg alkoxy, acyloxy, carbamoyl, amino, N-acylamino, ketone, halogen, cyano, carboxyl, and aryl. Alkyl groups are pr~el~bly lower alkyl, i.e. containing 1 to 8 carbon atoms.
The term aryl is intended to include stable cyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated C3-C14 moieties, ~xel"yli.ied but not limited to phenyl, biphenyl, naphthyl, pyridyl, furyl, thiophenyl, i",idazoyl, pyrimidinyl, and oxazoyl; which may further be substituted with one to five members selected from the group consisli"g of 30 hydroxy, C1-Cg alkoxy, C1-Cg branched or straight-chain alkyl, acyloxy, carbamoyl, amino, SUBSTITUTE S~tE~ ~RULE ;~

WO 97/08300 PCT~US96/13918 N-acylamino, nitro, halogen, trifluoromethyl, cyano, and carboxyl (see e.g. Katritzky, Handbook of Heterocyclic Ghemistry).

The iigands may contain one or more amide bonds, but are preferably non-peptidic. Plt r~ldbly the molec~ r weight of the ligands is under 1200, more pr~ierdbly under 750, more p~ .dbly under 500. Peptides and peptidic molecules comprise two or more naturally occurring oc-amino acids linked by peptide bonds (primary amide bonds, except where the amino acid is proline).

The ability of a ligand or a moiety on a ligand to interact with a particular residue or set of residues in a binding site may be determined by noting the pro,~ -ily of a ligand moiety to a residue of interest. rlO~ y may be determined by physical methods such as x-ray cryst-"-y~dphy or NMR evaluation of a co-cO~ of the protein and ligand, or may be dt:Ie.ll .ed through modeling studies in which the structure of the ligand is docked with the structure of the protein using plug,a,,ls such as described above. A number of commercially available programs are capable of conveniently evaluating a modeled or experimentally deler. M ,ed structure and identifying atoms involved in hydrogen-bonding or hydrophobic interactions. Generally, hydrogen bonding (which inctudes salt bridge and other ionic illIeld~;lions) occurs across ~ ldnces of about 2.8 - 3.5 any~;l.ur"s, more usually up to about 3.2 any~l.u,l,s, and through donor-H-acceptor angles of about 180~ + 60~. Hydrophobic interactions occur accross distances of up to about 5 any5l,u~"s, more ,ur~te~dL)ly up to about 4.5 any~I.u,ns and more frequently up to about 4 any;,l,u",s, dependi-lg on the nature of the atoms involved. Again, any of a number of col"",en,idlly available computer pluylallls may be used to identify hydrogen bonding and hy~JIupl~ob.c interactions between ligand moieties and protein atoms.

G. Pharmaceutical Compositions and Uses of Inhibitors o~ ZAP family members 3 0 Compounds which bind to one or more ZAP family members may be used as b -Icy;cal reage"l~
in binding assays as described herein for functional clas~iri-;dlion of an SH2-bearing protein, particularly a newly discovered protein, based on ligand specificity.

Moreover, compounds ider,li~ied as described above can be used to inhibit the occurrence of biGlogical events resulting from molecular interactions mediated by a ZAP family protein conldi" ,g one or more SH2 iOIll~ills. This invention thus provides a method and ",dlelials for il~hibiLi"g (totally or partiaily) the interaction between such a protein and a natural ligand thereto (i.e., a naturally occurring protein (typically), or a portion or analog thereof, which binds in a cell to the ZAP family protein) or a biological activity mediated by such interaction.

SUBSTlTUTE S~tEE~ tRul-E 26) WO 97/n8300 PCTrUS96/13918 In this method, a compound ider,li~ied or obidii,ed as described herein is combined or conl~clad with the ZAP family protein, such as by introducing the compound into a cell in which the molecular interaction is to be i"hii ited. rolluwi"g introduction of the compound, the interaction of the ZAP family protein and its natural ligand is illh bi- ~ as may be readily detected.
5 Inhibiting such interactions can be useful in research aimed at better u"de~ ndi,)g the biology of SH2-mediated events.

In general, i"l,iibilor:i of SH2-mediated interactions would be useful, for ~amplc, in the diagnosis, prevention or treatment of conditions or r~iceA~es resulting from a cellular prucesses 10 mediated by the interaction of SH2 bearing protein with a natural ligand therefor. For example, a patient can be treated to prevent the occurence or pl~,yll:s~ion of osteoporusis or to reverse its course by ad".;~.;slt:,il,g to the patient in need thereof an SH2 binding or i 'ocki"g agent which selectively binds Src SH2. There are many other condilions for which SH2 binding or blocking agents may be useful therapeutically, including breast cancer where the SH2 domain-containing 15 proteins Src, PLCg and Grb7 have been i"-l lic~ Other relevant cond;tiol1s include prostate cancer, in which case ldry~li"g Grb2, PLCg, and Pl3K, all of which contain SH2 clomai"s, may be useful in treatment or prevention of the ~ice~e~ Inh;i,iliol1 of the interaction of Grb2 or Abl Sl 12 domains with Bcr-abl may be useful to treat chronic mylogenous leukemia (CML) or acute myelogenous le~ "ia (AML). Still other relevant ~ppli~hlions of an SH2 inhibitor would be to 2 0 prevent interferon-, growth factor-, or cytokine-mediated diseases (e.g. inflammatory e~es) by targeting the SH2 domains of STAT proteins.

Of particular interest are agents that block the interaction of ZAP family members with their natural ligands. For instance, inhibitors of interactions involving ZAP-70, which is believed to 2 5 be involved in activation of T-cells, would be useful as an immunosuppressant in the treatment and prevention of autoimmune diseases and to prevent rejection of skin and organ lldns,uldnl~.
Inhibitors of interactions of SYK with natural ligands would be useful in the treatment and prevention of asthma and untoward allergic reactions.

30 An inhibitor selected or ide"li~ied in acco,dance with this invention can be formulated into a pharmaceutical composition conl~i"i.,g a pharrr~z~ceutic~lly acceptable carrier and/or other ~xc;~.ier,l(s) using conventional materials and means. Such a cu""~osilion can be ad",i";~-~eled to an animal, either human or non-human, for therapy of a disease or con.liLion resulting from celluiar events involving a moleu~r interaction mediated by a ZAP family protein.
35 Ad",;.,;~L,dlion of such composition may be by any conventional route (parenteral, oral, inhalation, and the like) using appropriate formulations as are well known in this art. The i"l ' ~cr of this invention can be employed in admixture with conventional excipients, ie, pharmaceutically ~ccel.l~ lE organic or i~olgal1ic carrier sui.~ld,1ces suitable for parenteral administration.
.

SU~STITUT~ S~E~ (RULE 2~;~

.

W O 97/08300 PCT~US96/13918 Pharmaceutical applications By virtue of its capacity to inhibit protein-protein interactions required for cellular events of pharrrAr~lGy;c i,."~o,ldnce, a compound idenLiried as described herein may be used in 5 pharmA-~eutic~i compositions and methods for l,edll.,e"L or prevention of various diseases and disorders in a mammal in need thereof.

Ma.l~l"dls include rodents such as mice, rats and guinea pigs as well as dogs, cats, horses, cattle, sheep, non-human primates and humans.

The preferred method of such treatment or prevention is by ad,ll;.,;~lering to a mammal an effective amount of the compound to prevent, alleviate or cure said disease or disorder. Such effective amounts can be readily determined by evaluating the compounds of this invention in conventional assays well-known in the art, including assays described herein.

Therapeutic/Prophylact~c A-l",i"i~ ion & Pharm~7~eotic~l Compositions The invention provides methods of treating, preventing andlor allcvidLillg the s~/lllplullls and/or severity of a disease or disorder referred to above by ad,. ,i:,l,dlion to a subiect of a in an amount effective therefor. The sub~ect will be an animal, including but not limited to animals 2 0 such as cows, pigs, chickens, etc., and is pr~l~rdbly a mammal, and most preferably human.

Various delivery systems are known and can be used to ad,. ' .i-~L~7r the inhibitor, e.g., ençAps~ tion in liposomes""icropa~li.,les, mi~;lvc~pslll~-c~ etG One mode of delivery of interest is via pulmonary ad",;.,;~L,dlion, as detailed more fully infra. Other methods of 2 5 introduction include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, sl~hcutAneous. intranasal, epidurat and oral routes. The i"hibi~ol may be a.ll"i.,i:jler~:d by any convenient route, for example by infusion or bolus iniection, by absor~,lion through epithelial or mucocutArleous iinings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be a.l~ d together with other L::lC9k!A;IY active agents.
30 Admini:,lld~ion can be systemic or iocal. For l,edl",er,l or prophylaxis of nasal, bronchial or pulmonary conditions, preferred routes of a~",' ,;.,I,dLion are oral, nasal or via a bronchial aerosol or nebulizer.

In specific e."bodi",ents, it may thus be desirable to ad",;..;~ r the inhibitor locally to the area 3 5 in need of treatment; this may be achieved by, for exd"-~le, and not by way of limitation, local infusion during surgery, topical Applichlion~ by injection, by means of a cdll,t L~r, by means of a suppository, or by means of a skin patch or implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic me...l-ranes, or fibers.

SUBSTITUTE S}~}EE~ (RULE 26) This invention also provides pharmaceuticai co,-"~osilions. Such compositions comprise a therapeutically (or prophylactically) effective amount of the inhibitor. and a pharmaceut-ically ~ccept~hle carrier or e , -Qnl. Such a carrier includes but is not limited to saline, buffered saline, de,~ se, water, glycerol, ethanol, and cor, ' :.ldliol1s thereof. The carrier and - 5 composition can be sterile. ~he formulation should suit the mode of adl,l;";sL,dlion.

The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. The cor"~ osiliol1 can be a liquid solution, suspension. emulsion, tablet, pill, capsule, sustained release formulation, or powder. The co""~osiLion can be formulated as a 10 suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharrnacelltic~l grades of mannitol. Iactose, starch, ,,ay,.esium stearate, sodium saccharine, c--" ~'c~se, magnesium cari ondle, etc.
In a specific e",bociil"ent, the co"")osilion is formulated in accordance with routine procedures 15 as a pharrr~ el~tic~l composition adapted for intravenous aci", lial,dlion to human beings.
Typically, co""~osilions for intravenous a i",~ l,dlion are solutions in sterile isotonic aqueous buffer. Where necess~ry, the co"")o:,;lion may also include a sol~ - ,9 agent and a local anesthetic to ease pain at the side of the i"je ~; n. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for exar" '~, as a Iyophilized powder or water 20 free concelllldle in a hermetically sealed conldi"el such as an ampoule or sachette indicating the quantity of active agent. Where the co",posilivt) is to be a(Ju,;.l;;,Lt:red by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
Where the composition is administered by injection, an ampoule of sterile water for iniection or saline can be provided so that the ingredients may be mixed prior to admilli~lldlion.
Administration to an individual of an effective amount of the inhibitor can also be acco"",lished topically by ad",;"i:,lering the compound(s) directly to the affected area of the skin of the individual. For this purpose, the inhibitor is a il";..;~ d or applied in a co",posilion including a pharmacoiogically acceptable topical carrier, such as a gel, an ointment, a lotion, or a cream, 3 0 which includes, without limitation, such carriers as water, glycerol, alcohol, propylene glycol, fatty alcohols, triglycerides, fatty acid esters, or mineral oils.

Other topical carriers include liquid petroleum, isopropyl palmitate, polyethylene glycol, ethanol (95%), polyoxyethylene monolaurate (5%) in water, or sodium lauryl sulfate (5%) 35 in water. Other materials such as anti-oxidants, humectants, viscosity stabilizers, and similar agents may be added as necesst.~y.

SUBST~TUTE S~E~ (RULE 2~;3 CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 In ad.lilion, in certain instances, it is expected that the inhibitor may be ~ osed within devices placed upon, in, or under the skin. Such devices inctude patches, implants. and i.,jeclions which release the compound into the skin, by either passive or active release me~hau;-cllls.

5 Materials and methods for producing the various formulations are well known in the art lsee e.g. US Patent Nos. 5,182,293 and 4,837,311 (tablets, capsules and other oral formulations as well as intravenous formulations~].

The effective dose of the inhibitor will typically be in the range of about û.01 to about 50 10 mg/kgs, pr~r~bly about 0.t to about 10 mg~kg of "~d-l.r"alian body weight, ad-";~ ,le~ed in single or multiple doses. Generally, the inhibitor may be ad., ~ .;~Lered to patients in need of such treatment in a daily dose range of about 1 to about 2000 mg per patient.

The amount of the inhibitor which will be effective in the l,edl",erll or prevention of a 15 particular disorder or condi;ion will depend on the nature of the disorder or condition, and can be delel.";"ed by standard clinical techniques. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
The precise dosage level of the inhibitor, as the active CG~pOlle~ S), should be d~ r,-,i,led as in 20 the case of all pharm~ceutic~l treatments, by the dll~n~;.,g physician or other health care provider and will depend upon well known factors, including route of ad",;nisl"llion, and the age, body weight, sex and general health of the individual; the nature, severity and clinical stage of the disease; and the use (or not) of Concolll ' nL therapies.

25 The invention also provides a pharmP~eutiC~I pack or kit cGIllplis;~g one or more containers filled with one or more of the ins.~ s of the phar.-~ceutic~l compositions of the invention.
Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharrrl~euti~i or biological products, which notice reflects approval by the agency of manufacture, use or sale for human 3 0 administration.

Pulmonary Administration In one embodiment of this invention, the inhibitor is ad~..;n;~ d by pulmonary ad" .i~l~dlion, e.g. via aeroso!i~tion. This route of administration may be particularly useful 35 for treatment or prophylaxis of br~ncl~ial or p~'"onary infection or tumors.

Pulmonary ad..~ lldLion can be acco",plisl1ed, for example, using any of various delivery devices known in the art (see e.g., Nc..."all, S.P., 1984, in Aerosols and the Lung, Clarke and Davia (eds.), Butter~"ll.s, London, England, pp. 197-224; PCT Pllhlic:ltinn No. WO

SlJBSTlTUTE S~iE~ (RULE 2~;~

CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 92/16192 dated October 1, 1992; PCT Pllhlioslt;on No. WO 91108760 dated June 27, 1991;
NTIS Patent ~rplic~tion 7-504-047 filed April 3, 1990 by Roosdorp and Crystal), including but not timited to nebulizers, metered dose inhaiers, and powder inhalers. Various delivery devices are commercialiy available and can be employed, e.g., Ultravent nebulizer 5 (M-" ~ rudt, Inc., St. Louis, Missouri); Acorn ll nebulizer (Marquest Medical Products, [r~ rood, Colorado), Ventolin metered dose inhaler (Glaxo Inc., Research Triangle Park, North Carolina); Spinhaler powder inhaler (Fisons Corp., Bedford, Massachusetts) or Turbohaler (Astra). Such devices typically entail the use of formulations suitable for dispensing from such a device, in which a ~Jru~Qllanl material may be present.

Ultrasonic nebulizers tend to be more efficient than jet nebulizers in producing an aerosol of respira~le size from a liquid (Smith and Spino, "Pharmacokinetics of Drugs in Cystic Fibrosis," Consensus Cor"e,ence, Clinical Outcomes for Evaluation of New CF Therapies, Rockville, Maryland, December 10-11, 1992, Cystic Fibrosis Foundation).

A nebulizer may be used to produce aerosol particles, or any of various physiologically ~ccept~le inert gases may be used as an aerosc' lg agent. Other col",uone"l:i such as physiologically acceptable surfactants (e.g., glycerides), ex :, ienls (e.g., lactose), carriers, and diluents may also be included.
This invention is not to ~e limited in scope by the specific embodiments described herein.
Indeed, various modificd~ions of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing desc.i~,liou. Such modiri~dlions are intended to fall within the the scope of the appended claims.
Various patents, patent Arplic~ions and publicaLiol1s are cited herein, the disclosures of which are incorporated by reference in their entireties.

Experimental Examples I. Protein Preparation A. ZAP-NC: Expression, Purification and Complex Formation 3 5 Cloning The ZAP-NC was expressed as a glutathione-S-l,dn~rerdse (GST) fusion protein. The DNA
sequence encoding residues 1-259 from human ZAP 70 (A.C. Chan, M. Iwashima, C.W.Turck, A.
Weiss Cell71 649-662 ~1992)) was cloned into the pGex ex~.,ussion vector (D.B. Smith, K.S. Johnson Gene 67, 31-40 (1988))and l,an~lurllled into E. coli BL21 or E. Coli B834. The SUBSTtTUTE S~E~ (RULE 2B~

W O 97t08300 PCT~US96/13918 resulting construct coded for a IhrulllLi.l cieavage site and two extra residues ~G and S) at the N-terminus of the ZAP-NC.

Expression 5 In a typical preparation the ZAP-NC was produced by the growth and induction of two iiters of culture (BL21) in BHI medium. The culture was grown at 25~C to an OD 595nm of 0.8 and induced with 1mM IPTG for 5 hours.

The selenomethionyl (SeMet) ZAP-NC was produced using the au~ol,uph ~ strain of E coli 834 1 0 (D.J. Leahy, H.P. Erickson, I. Aukhil, P. Joshi, W. Hendrickson Proteins 19 48-54 (1~94)) with the selenomethionine replacing the m~ on .e in a defined media. The SeMet ZAP-NC was grown in 10 liters of defined media (J.O.Boles, W.H. Tolleson, .I.C. Schmidt, R.B. Dunlap, J.D.
Odom, J. Biol. Chem. 267, 22217-22223 (1992)) supplemented with 0.5% thiamine using 50mg/L of D,L selenomethionine. The culture was grown at 30~C to an OD 595nm of 0.8 and 1 5 induced for 10-15 hours.

Purification The GST fusion proteins were isolated using glutathione agarose and then cleaved with Ih.o...Li.l.
ZAP-NC was separated from the GST by binding the tandem SH2 domain to a phosphuL~,~rosine 2 0 agarose column and eluting with a salt gradient. Subsequently the ZAP-NC was further purified by hydrophobic interaction ~I~ru",~lvy,~.l"~ on a phenyl sepharose column. The protein was stored under argon with 500mM NaCI and 10mM ~ l.iull,r~itol at 4~C. A typical purification is listed below. i3Oth the ZAP-NC and the SeMet ZAP-NC were judged to be >95% pure by N-terminal analysis and SDS gel ele~ ,plloresi ,. Mass spectrometric analysis of the ZAP-NC and 2 5 SeMet ZAP-NC indicated >95% incor,uo~dtioll of the selenomethione.

Gomplçx preparation Complexes of the ZAP-NC plus the ~ 1 peptide (NQLpYNELNLGRREEpYDVLD) were p,~uar~d by adding a 2-fold excess of peptide to the protein and then running the sample on a gel filtration 3 0 column. The peptide was dissoived in 200ul of 100mM Tris, pH 8Ø and added to 6mg of protein. The sample was incubated at room ~e",pe,t,l-lre for ~30min, then filtered through a 0.2 micron filter. A Superdex 75 16i60 column was eq~ '~rated in 20mM Tris containing 100mM NaCI and 5mM DTT, pH 8.0 and the sampie was loaded and 3mL fractions were collected.
The complex eluted at 65.6mL and peak fractions were pooled based on protein A(280).
3 5 Analysis of con,~' ~ n was done on a ho".ogel-ous 20% native gel.

SUBSTtTUTE S}t EE~ tRuLE 2~i) CA 02226963 l998-02-l2 A typical Zap-NC Purification Cell lysis:
1) Lysed ~20g cells using French pressure cell in 40mL of BuKer A:
2) Diluted 1 :1 with Buffer B
3) Centrifuged at ~30,000 xg for 30mln & removed the supernatant.
., Glutathione Column 2.6x10:
1) Loaded the supernatant onto a glutathione column equilibrated into Buffer B.
1 0 2) Washed with ~lOOmLBuffer B then Buffer C to baseline.
3) Eluted in Buffer D; 5mL fractions were collected and pooled.

Thrombin Cleavage:
1~ Added 200mM NaCI to the pooi, then added human Ill,ur"L,i,l at 1ug/mg protein 1 5 2) Incubated on nutator at room temp. Samples were taken & run on an SDS gel while continuing to incubate. Reaction was complete at 40min. (PMSF can be added to stop the reaction .) 3) Diluted the pool x5 when cleavage was cori"~l~Le with 20mM Tris pH 8/5mM DTT.
2 0 Phosphotyrosine Column: 26x7.5cm:
1) Loaded the pool onto the column eqL"b dled in Buffer E:
2) Washed& eluted using a 5 CV gradient to buffer F. 5mL fractions were collected.
3) Pooled peak.

2 5 Phenyl Sepharose Column 2~x17.5cm:
1) Diluted the pool 1:1 with 3M (Nff4)2S04 2) Equilibrated the column with Buffer G:
3) Loaded the protein, washed to baseline, then eluted in a 3 CV gradient to Buffer H:
Pooled peak fractions.
3 0 4) Added 500mM NaCI to peak pool and 5mM DTT. Stored at 4~C under argon.

Buffers Used:
Glutathione PhosPhotyrosine Phenyl Separose Buffer A Buffer E: Buffer G:
PBS/0.5% Triton 20mM Tris pH 7.6 20mM Tris pH 8 400mM NaCI 50mM NaCI 1.5M ~NH4)2S04 5mM DTT 5mM DTT 5mM DTT
lmM Pefabloc Buffer F: Buffer H:
Buffer B 20mM Tris pH 7.6 20mM Tris pH 8 PBS/0.5% Triton 2M NaCI 5mM DTT

SUBSTi~UTE S~ET tRULE 2~) W O 97/08300 PCT~US96/13918 5mM DTT 5mM DTT
Buffer C
PBS/
5mM DTT
Buffer D:
100mM Tris pH 8 100mM NaCI
20mM reduced glutathione 2mM DTT
B. Syk-NC

Cloning and Exur~ssi~ n 5 The DNA sequence encodi.,g residues ~-265 of human Syk was cloned into the pET e~.-e-~sion vector and transfor.,led into E. coli BL21(DE3) (Shiue, L., et al. Molecular and Cellular Biology 15, 272-281 (1995)) In a typical preparation Syk-NC was produced from the growth and induction of two liters of culture in BHI medium supplemented with 200ug/mL ampicillin. The culture was grown at 25~C to an OD at s95nm of 1-2, induced with 1mM IPTG, and harvested 4 1 0 hours later.

Purification All operations were performed in a cold room at 4~. The cells were Iysed using a French pressure cell and 2X volumes of Iysis buffer, 20mM Tris pH 8, 500mM NaCI, 5mM DTT, and 1 5 1 mM pefabloc. The super"~ta"L was collected by high speed centrifugation, diluted 2-fold with buffer A (20mM Tris pH 8, 5mM DTT) and applied to a 1.6x10 cm polyethylenimine anion exchange column equilibrated with the same buffer. The flow through was dialyzed overnight vs.
buffer B (20mM Tris pH 7.4, ~mM DTT, 50mM NaCI~ and then loaded onto a 50mL
phosphotyrosine agarose column. The Syk-NC protein bound to the column and was eluted with a 2 0 salt gradient, 50mM to 2M NaCI in 4 CV. The Syk-NC protein was collect~d and dialyzed into buffer C: 50mM Mes pH 6.2, 5mM CaCI2 5mM DTT. After dialysis the protein sample was centrifuged at high speed and then applied to a Source 1~S column ( 16x10cm) equ ' ~rdled in buffer C. The column was then washed with buffer C and eluted using a salt gradient, 0 to 750mM NaCI in 5 CVs. The peak fraction was pooled. SDS gel electrophoresis indicated that the 25 protein was ~95% pure. N-terminal sequencing and mass spec analysis col.Ii,-.,ed the expected sequence. The protein col1ce"lld~ion was determined by measuring the abso.~lion at 280nm. The purified protein was stored at 4~ with 10mM DTT.

Syk-NC and oeptide comr~lexes 3 0 Co".~' ~ have been made with a number of ~ilt~r~hl ~ and ~ peptides of dirlt:rt:"l lengths. In a typical experiment, a two fold excess of peptide was di~solved in 100mM Tris buffer and added to 10mg of Syk-NC. The sample was incuhS~t~~d at RT for 30 minutes, and then run on a Superdex SVBSTITUTE ~ RULE 2~i) -WO 97/08300 PC~rUS96/13918 75 column (16x60cm) equ"' ~ted in 20mM Tris pH 8, 100mM NaCI. 10mM DTT. Three mLfractlons were collect ~d and the peak was pooied.

C. Syk-C Experimental Cloning and ex~u,~ssion The C-terminal SH2 domain of human Syk encoding residues 163-265 was cloned into the pGEX2TK expression vector and Ir~n~i~ur~led into E. coli BL21(DE3) (Shiue, Lr etal.
Molecular and Cellular Biology15, 272-281 (1995); Law, C.L., et al. J. Biol. Chem. 269, 1 0 12310-12319 (1994)). Isotopically labeled glutathione-S-transferase (GST)-Syk-C was produced from the growth and induction of two liters of culture in M9 medium supplemented with 19/L of t5NH4CI and/or 3g/L of 13C glucose to obtain uniformly labeled Syk-C SH2. The fractionally labeled (~10%) 13C Syk-C sample was prepared by supplementing the M9 medium with 4.15g/L of a mixture containing a 9:1 ratio of unlabeled glucose:13C glucose just 1 5 prior to induction. In a typical preparation the culture was grown at 25 C to an optical density (OD) at 595nm of 1.0, induced with 1mM isopropyl-b-D-thiog~l~ctopyranoside (IPTG), and harvested 5 hours later. Cells were stored at -80~C until use.

Purification 2 0 The cells were Iysed and the protein was affinity purified over glutathione agarose. The GST
fusion protein was cleaved with ~I"~.r"~i", and further purified over phosphotyrosine agarose and ion t~ han~e resin to yield an SH2 domain that was >98% pure by SDS gel ele~ pho,~si~.
A typical p-,iriL;dlion is outlined below. N-terminal sequencing and mass spectroscopic analysis have confirmed the expected sequence. The purified protein was stored under argon with an 2 5 excess of dithiothreitol (DTT).

Complex Preparation Syk-C SH2 protein: pTyr76 peptide complex samples were prepared by adding a two fold molar excess of the pTyr76 peptide dissolved in 0.smL NMR buffer (50mM Tris-d11, 0.15N NaCI, 3 0 10mM DTT-dg, 0.025% NaN3, pH=7.Q) to the Syk-C protein dissolved in the same buffer.
This mixture was incubated overnight at 8~C then conce"l,dled and further equiiibrated using Centricon10 microconce,,l.~lurs at 14~C. Five exchanges of buffer, 2mL to 200mL, ensured complete eq~ dlion. Aliquots of the filtrate and the final complex solution were taken and analyzed by HPLC. All NMR samples conl~ ;.,ed 2-4mM protein.

SUB51 1TUTE S~FE~ (RULE 2~i) W O 97/083~ PCT~US96/13918 A typical Syk-C purification Cell Lysis.
1 ~ About 7g frozen pelleted cells were thawed in two voiumes of PBS, 0.5% Triton X-100, 500mM NaCI, 5mM DTT, 2mM EDTA, 1mM PMSF.
2) The resulting ho",oyendLe was Iysed using a 20K Manual-Fill FRENCH Pressure Cell at 16,000 psi for two passes.
3) Lysed celts were again diluted with two volumes fresh Iysis buffer, stirred for 10 minutes, then centrifuged for 40 minutes at 30,600 x g to sediment cell debris.
1 0 4) Supernatant was filtered through 0.8,um Supor membrane filters prior to column loading. All actions carried out at 4~C.

Glutathione Açlarose Chr-Jnldluyldully:
1) 26 x 100mm Glutathione Agarose column was equilibrated with PBS, 2mM DTT.
1 5 2) Filtered bacterial Iysate was loaded at 2 ml/minute, then column was washed with PBS, 0.5% Triton X-100, 500mM NaCI, 2mM DTT, followed by PBS, 2mM DrE
3) GST fusion protein was eluted with 100mM Tris, 100mM NaCI, 20mM Reduced Glutathione, 2mM DTT, pH 8Ø

2 0 Enzymatic Cleavage of GST Fusion Protein:
1) 1 unit of human Ll,ru,,~' , was added per mg of total protein in the Glutathione Agarose eluate.
2) The thrombin was allowed to react for~16 hours at 4~C with slow magnetic stirring.
3) Completion of cleavage was verified by 20% SDS gel, then the reaction was stopped 2 5 with 1 mM PMSF.
4) Cleaved fusion protein was filtered through 0.2~Lm Supor membrane prior to loading on Pl,osphotyrosine Agarose column.

Fl ,osphulyrosine Agarose Ch~ o" ~dL~gl d,Uh y 3 0 1) 26 x 100mm Phosphotyrosine Agarose column was equilibrated with Buffer A
~20mM Tris, 100mM NaCI, 5mM DTT, pH 7.4.) 2) Cleaved fusion protein was loaded at 2 ml/minute then washed back to baseline with Buffer A.
3) Syk-C was eluted with a 0-100% B yldd;_.lL in 4 column volumes. Buffer B = A +
3 5 1.9M additional NaCI.

PEI Chrur,,aLou,,d,uhy:
1) 16 x 53mm polyethyleneimine column was equilibrated with Phosphotyrosine Buffer A.

SUBSTITUTE S~E~ (RULE 2~i~

W O 97/08300 PCTnUS96/13918 2) Pooled Pi,ospl1c,lyrosine peak was loaded over PEI at 5 ml/minute then washed with Buffer A. Syk-C was in the flowthrough.

D. ZAP-C Experimental Cloning and ~ ,ession The C-terminal SH2 domain of human ZAP 70 was produced as a glutathione-S-IIdn~ se (GST) fusion protein. Residues 155-258 of ZAP 70 were cloned into a pGEX e~ SSiOI1 vector and L,~n:,rur,,,ed into E. coli BL21. In a typical fermentation ZAP-C was produced from the 1 0 growth and induction of four liters of culture in LB media su~ ed with 200mg/m~
a,.") - " .. The culture was grown at 37~C to an OD at 595nm of 1, induced with 1mM IPTG and harvested four hours later. Just prior to induction the te",yerdlure was dropped to 25~C. 15N-labeled ZAP-C was produced from the growth and induction of culture in M9 mediumsupplemented with 1g/L of 15NH4CI. Cells were stored at -80~C.

Purification The ZAP-C cells were Iysed and the protein was affinity purified over glutathione agarose. The GST fusion protein was cleaved with ll.ru..lLi", and further purified over phosphotyrosine agarose to yield an SH2 domain that was ~95% pure by sodium dodecyl sulfate (SDS) gel electrophoresis. N-terminal sequencing confirmed the expected sequence. The purified protein was stored under argon with an excess of dill II"eit~l (DTT).

A typical ZAP-C purification 2 5 Cell Lysis:
1) 50g of frozen ZAP-C cells were thawed in two volumes of PBS, 0.5% Triton, 500mM
NaCI, 5mM DTT, 2mM EDTA, 1mM PMSF.
2) The resulting homogenate was Iysed using a Minnie Rannie cell disruptor at 16,000 psi for three passes.
3 0 33 The cell Iysate was centrifuged for 40 minutes at 30,000 x g.
4) The supernatant was collected and filtered through a 0.8mm membrane prior to column loading. All actions were carried out at 4~C.

Glutathione AS~arose Ch,ur,.~Luy,~phy:
1) A 26 x 100mm glutathione agarose column was equilibrated with PBS, 2mM DTT.
2) Filtered bacterial Iysate was loaded at 2mllminute, then column was washed with PBS,0.5% Triton, 500mM NaCI, 2mM DTT followed by PBS, 2mM DTT.
3) GST fusion protein was eluted with 100mM Tris, 100mM NaCI, 2mM DTT 20mM
reduced glutathione pH 8.

SUBSTITUTE ~ tRULE ~fi) Enzymatic Cleavage of GST Fusion Protein 1) 1 unit of human II,ru, l . was added per mg of protein in the glutathione agarose eluate.
2) The lhlumL;.~ was allowed to react overnight at 4~C with slow stirring.
3) Additional ll,ro,llbi" (1uniVmg protein) was added to the protein solution in the ~OI~ ,9 and the cleavage reactlon was l..or ~r~d by SDS gel. Upon corl-pl~lio u the reaction was stopped with 1mM PMSF.

1 0 Phosphotyrosine Agarose Chlullldluyl~rlly 1) A 26 x 80mm phospholyrosine aga,~se column was equil;l,l~led with Buffer A
(20mM Tris, 100mM NaCI, 2mM DTT, 2mM EDTA pH 7.4. ) 2) One-half of the cleaved fusion protein was loaded on the column at 2mUminute and then washed to baseline with Buffer A. The ZAP-C was eluted with a 0-100% B gradient 1 5 in 4 column volumes. (Buffer B=AI1.9M NaCI.) 3) The phosphotyrosine h.u...~l,,graphy was then applied to the second half of the cleaved fusion protein. The ZAP-C fractions were collected and analyzed by UV/visible spectroscopy.

2 0 l l . Pr~ar~tion Of Ligands All peptides were sy"ll,esi ed by aulu~dll3d solid-phase synthesis on Applied Biosystems 431A
or 433A synthesizers using N-fluorenylmethoxycarbonyl (Fmoc) amino acids bearing TFA-labile side chain protection. Sy"ll,eses were performed on a 0.26 to 0.5 mmol scale on Rink resin (Rink H. Jetrahedron Lett. 1987, 28, 3787-3790). Amino acids (1.0 mmol) were coupled using HBTU/HOBt/DlEA (1:1:2) as activating agents. Coupling reactions are 30-50 min. Assembled peptides are acetylated (Ac2Ofpyridine in DMA) either prior to phosphorylation (single 5 min reaction) or after phos~ orylation t2 x 10 min reaction).

3 0 Phosphorylation39~40 Resin-bound peptide (0.25 mmol~ and It:lldzole (25-40 equiv/OH~ are combined and dried under vacuum in the presence of NaOH pellets in a d~icc~ -r overnight. The flask is then flushed with N2 and DMA (6 mL) added. (tBUo)2pNEt2 (10 equiv/OH) is added and the mixture sc",icaled for 60-90 min. The resin is filtered, washed with DMA (3 x 5 mL) and CH2C12 (4 x 3 5 5 mL). CH2C12 (5 mL) and mCPBA (2-5 equiv per OH) are added and the mixture so.li ;dled for a further 20-50 min. The resin is filtered washed with CH2C12 (6 x 6 mL), and dried under suction .

SUBSTITUTE S~FE~ tRULE 2~;~

-WO 97/08300 PCTrUS96/13918 Cleavage and De~roleclion.
Phosphorylated peptide-resin is treated with either TFA: phenol: water (90:5:~), or TFA:
water: ethanedithiol: anisole: phenol (95:5:5:5:2) for 90-~20 min. The resin is filtered, washed with TFA and the filtrate concenl,dled by rotary ev~pola~ion. Diethyl ether is added to precipit~t~ the crude peptide, which is filtered, washed with Et20 and dried.
Peptides are purified by a co~ ,alion of gel filtration, preparali~/e I IPLC, and gel desalting.
Gel ~ill,alion. Crude peptide is dissolve in 0.1M NH4HC03 (10-20 mL) and applied to a Sephadex G-25 column (2.6 x 100 cm) eluted at ca. 0.5 mL/min. Eluent is r"onitor~d at 254 or 278 nm and product-cor,l~i" ,g fractions are ide-,li~ad by analytical HPLC, pooled, and 1 0 Iyophilised.

Preparative HPLC. Peptides were purified on a reversed phase Kromasil C8 column (10 micron particle size, 100 A pore size, 20 x 250 mm) with UV moni~u,i,lg at 220 nm. Product was eluted with a gradient of either 60t40 MeCN/H2O (0.1% TFA) in 0.1% aq. TFA, or 60/40 1 5 MeCN/25mM Et3N pl~osphd~e pH7 in 25mM Et3N phosphate. The latter buffer required that the isolated pure peptide be des~'terl, which was achieved by applying the Iyopl,;1;3cd product to a Sephadex G-10 or G-15 column (2.6 x 30 cm) eluted with 0.1M NH4HCO3 at 1-2 mUmin.

Li~}and (9) The solid phase synthesis of ligand (9) was pe,~u,l"ed accordi.lg to the procedures described above, using Noc-Fmoc-(O,O-diethyl-a,a-difluorophosphonomethyl)phenylalanine (Fmoc-F2Pmp(OEt)2OH) (Burke, T.R.; Smyth, M.S.; Otaka, A.; Nomizu, M.; Roller, P.P.; Wolf, G.;
Case R.; Shoelson, S.E. Nonhydrolyzable Fho.uholyrosyl Mimetics for the Preparation of Phosphatase-Resistant SH2 Domain Inhibitors. Bioct7em.1994, 33, 6490-6494) The peptide was cleaved from the resin using TFA:phenol:H20:ethanedithiol:anisole (18:1~ 13 to afford the crude bis-O,O-diethyl difluorophosphonate-containing product. Final deprotection was achieved by treatment of the crude product with TMS-l:MeCN (1:1) for 20 min at RT. The solvent was evdpordLed and the residue di:,solved in 0.2M sodium phosphate (plt 7.0: ~0 mL).
The solution was washed with diethyl ether (6 x 15 mL) and l~cpl, -~. The product was 3 0 purified as described above.

I l l . Crystallization & Structure Determination A. ZAP-NC was crystallized in cor"plexes with various ligands (see Table 1) as follows:
1. Zap/~1: The binary complex of ZAP-NC and the ~1 19mer (Ligand 5, Table 1) wasconce,lL.tlled to 30 mg/ml in a buffer conL~i,.;-,g 20 mM Tris at pH 8.5, 200 mM sodium chloride, and 20 mM ~lill~ic,ll..eilol. The co,..plex of ZAP-NC with ~1 peptide was further treated with 4 mM trimethyllead ~:et~te- Crystals :")onl~neously grew within 3 weeks in hanging drops containing 13.5 mg/ml protein complex and 10% polyethyleneglycol 4000, 50 mM sodium SUBSTITUTE S~{E}~ tRULE ~

~ ;

.

citrate at pH 6.2, 100mM w"",onium acetate, 0.005% sodium azide and 20 mM dill,;oll,ieitol over reservoirs of 20% polyethyleneglycol 4000 and 20 mM .lill~ ll.reilol. Large crystals were obtained overnight through microseeding. The crystals are monoclinic (P21, a=50.11, b=63.37, c=54.00 A, and ,13=114.44~), with one molecule per assymetric unit. Crystals of 5 ZAP-NC complexed with Ligand 8 (Table 1) were obtained under the same c-~ndilions.

2. Zap/~2: Crystals of the binary complex of ZAP-NC and the ~2 19mer (Ligand ~, Table 1) were obtained under con~lilions similar to those used for Zap/~t, with the few modifications noted below. Protein was concel.l.d~ed in 10 mM Tris at pH 8.5, 0.5 M sodium chloride, 20 mM
1 0 DTT. 20 to 26 mg/ml protein was treated with 2mM l,i",a"ll-yllead ~ccet~t~ for one hour before cryst~f~ tion set-up . The drops conl~i-,ed 20 mM sodium ~ccet~te and 0.2 M sodium chloride in addition to the condilions described for Zap/~1 co.-, ' : The final pH in the drops is 6.4 to 6.5. The crystallization was with Zap/~1 microseeding. ~no spol,ldnoues cryst~ tion was obtained).The crystals are monoclinic (P21, a=50.00, b=63.19, c=54.22 A, and ,~
1 5 =114.6~), with one molecule per assymetric unit, and diffracted x-rays to a resolution of 2.2 A.

3. Zap/~3: Crystals of the binary complex of ZAP-NC and the ~3 19mer ~Ligand 7, Table 1) were obtained as described for ZAP-NC/~2 except for the inclusion of sodium ~rcef~tP in the 2 0 drops. Cryst~ tion was obtained following microseeding with Zap/~1 crystals. The crystals are monoclinic (P21, a=49.85, b=63.38, c=54.01 ~, and ~ =114.43~), with one molecule per assymetric unit, and diffracted x-rays to a res~lution of 2.6 A.

4. Zap/difluorophosphono-~1: Crystals of the binary eor", lex of Z~P-NC and the 2 5 difluorophosphono analog of ~1 19mer ~Ligand 9, Table 1) were obtained as described for ZAP-NC/~1 foliowing microseeding with Zap/~1 crystals. The crystals are monoclinic (P21, a=49.77, b=60.87, c=53.58 A, and ~=117.09~), with one molecule per assymetric unit, and d,fr~ ed x-rays to a resolution of 2.2 A.

5. Zap/lgE yTAM 19mer: Crystals of the binary co""~.lex of ZAP-NC and the IgE ~TAM 19mer (Ligand 1, Table 1) were obtained as described for ZAP-NC/~1, but at pH 6.6, following microseeding with Zap/~3 crystals.

6. Zap/lgE ~TAM 16mer analog: Crystals of the binary cu,,,, :ry of ZAP-NC and the IgE ~TAM
16mer analog (Ligand 10, Table 1) were obtained as described for ZAP-NC/~1, but at pH 7.0 with microseeding of Zap/gama crystals in the present of 2% glycerol.

7. Zap/Ligand 11: ZAP-NC was mixed with 3mM Ligand 11 ~Table 1) and treated withtrimethyllead ~et~te Crystals were obtained from a mixture of 12.5 mg/ml ZAP-NC protein, SUBST~TUTE SH~ RULE 2~;) W O 97/08300 P~T~US96/~3918 1.5 mM Ligand 11 and 1.5 mM trimethyllead acetate in a solution of 10% PEG 4K, 50 mM Tris at pH 8.23 and 10 mM DTT.

B. SYK-N~: was cry.st~lli7ed with and without ligand (see Table 1), as follows:
1. SYK-NC (without ligand) was conce.,l,~l~d in 20 mM Tris at pH 8.0, 0.2 M sodium chloride, 40 mM DTT. Crystals were obtained with 12.5 mg/ml protein in 10% PEG 4k, 0.2 M sodium chloride, 50 mM phosphate buffer, pH 7.3, 30 mM DTT.

2. syk/~1: Crystals of the binary complex of SYK-NC and the ~1 19mer (Ligand 6, Table 1) 1 0 were obtained with 11mg/ml sylc/~1 complex in 50 mM Hepes at pH 7.2, 9% PEG4k, 4% 2-propanol, 0.25 M sodium chloride, 30 mM Dl~.

3. syk/r 19:
Crystals of the binary complex of SYK-NC and the IgE r 19mer (Ligand 1, Table 1)1 5 were obtained with 11mg/ml syk/~1 complex in 50 mM Tris at pH 7.68 or 50 mM l", ~ !e at pH 7.36, 11% PEG4k, 3.5% 2-propanol, 0.3 M sodium chloride, 30 mM DTT.

4. syk~y15: Crystals of the binary co...plex of SYK-NC and the IgEy 15mer (Ligand 2, Table 1~ were obtained under several dir~.enL sets of con.Jilions:
a. 18mg/ml complex in 10% PEG 4K, 50mM citrate/~ ospl1ate buffer at pH 5.6, 0.1 M
ammonium chloride, 0.01% sodium azide, 30mm DTT.

b. 18mg/ml complex in 10% PEG 4K, 50mM sodium citrate buffer at pH 5.6, 0.1 M
ammonium acetate, 0.5% methylpe..l~ne.liol, 0.01% sodium azide, 30mM Dl~.
25 ' c. 18mg/ml complex in 10% PEG 6K, 50mM phosphate buffer at pH 6.2, 0.2 M sodium chloride, 50 mM ammonium ~r,cet~t~, 0.01% sodium azide, 30mM DTT.

5. syk/r25: Crystals of the binary complex of SYK-NC and the IgE r 2~mer (Ligand 3, 3 0 Table 1) were o~tained under several dir~:rel,l sets of conditions:
a. 12.5 mg/ml SYK-NC/ligand complex in 16% PEG 2K, 50 mM sodium citrate, 5%
glycerol, 20 mM DTT, pH6.46.

b. 12.5 mg/ml SYK-NC/ligand complex in 10% PEG 4K, 50 mM sodium citrate, 0.1 M
3 5 ammonium ~cet~te, 20 mM Dl~, pH6.3.

6. syk/rTam 27mer: Crystals of SYK-NC with the IgE r 27mer (Ligand 4, Table 1) were ~ obtained as described immediately above in the case of the IgE r 25mer (~ igand 3, Table 1).

SUBST~TUTE ~ RlJLE ;~

C. ZAP-NC:~1 three dimensional stru-,lur~
X-ray diffraction data obtained using crystals of the ZAP-NC:~-1 complex (one Lo.,.f'e-~ per unit cell~ were analyzed as described etsewhere (see also Table 2~, yielding courd;..~l~s defining the three dimensional structure of the crystalline complex. The structure of the ZAP-5 NC:~2 co..,plex was determined by molQcl~ replacement using the X-ray dirr,dctiol- data for the ZAP-NC:~2 con,plex and the structure of the ZAP-NC:~-1 complex as represented by the coordil.ales of Appendix 1. Rigid body refinement was conducted using the ZAP-NC:~1 model. The resultant model was rebuilt by lepldce---ent of the ~1 peptide with ~2, ~c"~.ed by conventional refinement. The X-ray data of the ZAP-NC:~-1 "dimeric" complex (two CGIl r le,ces per unit 10 cell) was also solved by molecular replacement using the ZAP-NC:~ "monomer") structure. Rigid body refinement was conducted using the complete ZAP-NC:~-1 '...csnor..eric"
model, followed by rigid body r~i--e...el)L using individual SH2 domains and rebuilding of the helical domain region. Those structural coo.u!;.)ctles are set forth in Protein Databank format in Appendix I (ZAP-NC:~-1 comp~ex, "monmeric"), Appendix ll ( ZAP-NC:~2 complex) and 15 Appendix lll (ZAP-NC:~-1 co",pl~ dimeric~), below. Such data may be l,dn:,~er,t:d to any desired medium, and formatted as desired, for thg practitioner's computer.

This invention encc,...,uasses those coor~,.al~s as well as any l.dnsld~ion or rotation or the like thereof which maintains the internal coor-~ ,les, i.e., which maillldills their intrinsic, 20 internal relationship. Those skilled in the art will a~,,ecid~e that the coordinates may be subjected to other l.d..~ror."dli.",s including, e.g. molQc~ r mechanics ~lc~lAtions such as dynamic simulation, I";~L lli~dliOII, etc. This invention further enco,..~asses the use of coordinates of ZAP-NC or the corl~:,,uonl~ing region of other ZAP family members, and in particular, the coordinates set forth in Appendix 1, Appendix ll or Appendix lll, in conducting 2 5 such transformations (or more extensive lldn:jfc nlldlions such as the generation of alternative conformations), as well as the products of such tranciolllldlions ~i.e., derivatives of the coordinates) .

I V . Modeling To illustrate the receptor site mapping approach, we used the Molecular Discovery suite of programs (Molecular Discovery Ltd; Goodford, P.J. "A Computational Procedure forDetermining Energetically Favorable Binding Sites on Biologically Important Macromolecules"
J. Med. Chem. 198~, 28, 849-857) on a Silicon Graphics Onyx wu,k:ilalion running Irix 5.2 3 5 to evaluate ZAP-NC as follows:

(1) The Protein Data Bank (PDB~ cOO~ ldl~: file of ZAP-NC + ~t was stripped of the ~1 peptide and all crystallographically observed water molecules (using the Remove Atom feature of Sybil) .

SUBSTITUTE S~E~ (RULE 2~i~

W O 97/08300 PCT~USg6/13918 (2) The resultant PDB file was merged with a set of molecular mechanics pald~ rb that are suitable for the study of proteins. (Suitable such parameter sets include the user extensible data files which typically acconl~ any ~he computer program.) (3) A three-dimensional box that encapsu~ated the entire peptide binding face of each SH2 domain and the interfacial regions between the two domains was generated. The box dimensions were 60~ x 40A x 37A, and a regutar lattice of points positioned at 0.5A intervals was desiy"dled to fill the box. The box position is illustrated in FIG. 6.

(4) At each lattice point, 46 atomic and polyatomic probes were positioned sequentially. These probes encompass parameters that are representative of a large variety of chemical moieties.
The energy of interaction between each probe with the protein was computed at each point of the lattice according to an empirical potential energy function that includes explicit terms for 15 Lennard-Jones, ele.illo:,lalic, and hydrogen-bonding potentiats. The degree of burial for each probe was computed by the method of images.

(5) A binary contour map was generated, which can be used to visualize the sites of favorable interaction of a given probe at a given potential energy. An example is provided in FIG. 7.
Data from this receptor site mapping experiment were ~ ":j~e-~d to a DAT tape written in tar format on a Silicon Graphics Onyx worh-~ldlion running Irix 5.2. The map data uses the file extensions .cnt and .lont for the binary contour maps and the ASCII output, respectively. The orientation of the maps corresponds to our file zapNG-z1.pdb, which is in the Brookhaven 25 Protein l:)atabank format. The contour files are readable by Sybyl 6.1 ~Tripos, Inc., St. Louis, Mo). Filenames correspond to the probe nomenclature in the Molecular Discover P.uy-d,,lllles~
Version 1 2.

Information provided by site mapping via these or other programs as described in the 3~ Computational Methods section can be used to deler",il-e the spatial a"ange--,ent of potential pharmacophores, and thus provide the seed points for searches of 3-D databases or de Novo p-uy-dr..s that attempt to grow from or link together the selected points. For an illustration of a pharmacopho,ic substructure for use in computational approaches, see e.g. Fesik (19g3) cited elsewhere herein.
For example, the data defining binary contour maps may be displayed as 3D structures identifying preferred locations for selected functional groups using a software pl~yldlll such as ~ Sybyl. By visual inspection of those displayed represe-,ldlio,)s, one can select co,.espon-li,-y compounds conldi.,ing ."oielies app~ ,idlely ~isr70sed with respect to each other such that they SUBST~TUTE ~}~E~ (RULE 2 WO 97/08300 PCT~US96/13918 coM~,;de with p-~r~l.ed locations shown by the maps (i.e., locations idenlitied for each selected functional group characterized by favorable interaction energies with the target protein). Using computer pr~y~ s such as Leaprrug one may "grow" a compound slocl ,a:.Licaily from one or more selected ,. ~ie''icc. located within applup.i~lely mapped locations. Alternatively, starting 5 with mapped favorable locdliot1s for two or more ., ~ s, one may define"vectors" defining the spatial reldlionshi~ between those moieties, and then use those vectors to select or design compounds embodying the selected Illoi~:~ies in the app,u,~ ridle spatial r,31dtionsll, . D~t~h~es co..l~i..;.lg 3D structures of potential ligands contain experimentally d~l~r,-.;"ed or computationally gt:ne.t~ d structures. The selection or design process may be conducted with the 1 0 aid of computer using a p~uy,~"-s such as A~ADDIN (Van Drie et al, 1989, J Comput-Aided Mol Des 3, 225-251), MACCS-3D (Moock et al, 1990, Chemical Information Systems, (Eds, R: :den & Mitchell, Chichester, pp 42-49), 3D SEARCH, ChemDBS-3D. SYBYL/3DB and CAVEAT. See e.g., Fesik, t9~3, J Biomolecular NMR 3, 261-269.

1 5 V. Assays (1) Binding Assays (a~ CQ,."~elili~e Binding Assays: Binding may be measured by cump~lilioll using surface 2 0 plas",on resonance and allied techl)oloy;es (Malmqvist, M. Current Opinions in ImmLrnology5, 282-286; (1993); Malmqvist, M., Nature 361:186-187 (1993); Jonsson, U. and Malmqvist, M., ~dvances in Biosensors, JAI Press Ltd., London, 1992, pp. 291-336; Jonsson, U. et aL, BioTechniques 11(5):620-627 (1991~. SH2 domains are typically pre-incubated with various conce..l.~lions of test compound and the ability of the test compound to 25 competitively inhibit SH2 binding to an i",r"obili~ed phosphopeptide ligand measured. P~esults are compared to binding measured in the absence of competitor and expressed as percent inhibition. IC50 values reflect the concentration of inhibitor required to reduce binding by 50%. Specifics of individual assays are described below. All asssays are run in HEPFS Buffered Saline (HBS) composed of ~0 mM I IEPES (pH 7.4) / 150 mM NaCI / 3.4 mM EC~TA / 0.05%
3 0 Tween 20 ~ 10 mM DTT at 25~C.

Primary Screen -- Test compound (e.g. 50uM) is preinull~s~t~sd with the target SH2 in HBS i 10 mM DTT for a minimum of 1 hr at 4~C. The ability of the compound to inhibit binding of the SH2 domain to a target pho:,phope,uli~ is measured using SPR. Compounds that inhibit 35 SH2/,ul1osphopetide ~soristion by a pre-determined il~c~e..-e~l (e.g. ~50%) are subjected to a secondary screen.

Secondary Screen -- Log diiutions of test compound (10-4, 10-5, 10-6, ..) are prelncllh~ted with the target SH2 in HBS i 10 mM DTT. The ability of the compound to inhibit binding of the -SVB5TITUTE ~H E~ ~RULE 2~i~
, .

W O 97108300 PCT~US96/13918 SH2 domain to the target phosphopeptide is measured using SPR. IC50s are del~,-"i.,ed from the plot of per cent i,lhiLilion (compared to SH2 domain in the absence of i"l- It-~l) vs. compound concenl- ~lion.

5 ~ s,~c~;rics of Tandem ZAP Assay: A peptide co"espon-Jing to the ~-chain ITAM-1 of the human T-cell receptor [NQLY(PO4)NELNLGRREFY(PO4?DVLD] [SEQ ID NO ~5] was synthesized as a part of a larger peptide [AC-KGGNQLY(PO4)NELNLGRREEY-(PO4)DVLD-NH21 [SEQ ID NO 16]and used to generate a ZAP-sensitive biosensor surface. Specifically a o~ 3sor Chip CM5 was activated with 200 mM EDC 150 mM NHS to generate a surface reactive to primary amines and the ITAM peptide i",l"ol~ili ed through the N-terminal Iysine. Unreacted sites were b~ocked with ethanolamine (1 M in water) and the chip cleaned of non-covalently bound peptide using 6 M guanidine hydrochloride. Assays were run in HBS + 10 mM DTT using 10 nM pp70ZAp(1-259) +/- test inhibitor.

15 ~ Specirics of N-ZAP Assay: A peptide cor,~ ol-ding to the ~-chain ITAM-1 of the human T-cell receptor [NQLYNELNLGRREEY(PO4)DVLD] ~SEQ ID NO 17]was sy"Ll,esi ed as a part of a larger peptide [Ac-KGGNQLYNELNLGRREEY-(PO4)DVLD-NH2] [SEQ ID NO 18]
and used to ~ene,dl~ a ZAP-sensitive biosensor surface as described above. Assays were run in HBS I 10 mM DTT using pp70zAP(1-25s)R1s6K (a mutant where Arginine-195 is replaced by Lysine to inactivate the C-terminal SH2 domain) +I- test inl1iLi~or.
~ S~cit;cs of t::-ZAP Assay: A peptide correspor ,g to the ~-chain ITAM-1 of thehuman T-cell tece~olor [NQLYNELNLGRR~EY(PO4)DVLD3 ~SEQ ID NO 171 was synthesizedas a part of a larger peptide [Ac-KGGNQLYNELNLGFlREEY-(P04)DVLD-NH2] [SEQ ID NO
2 5 18] and used to generate a ZAP-sensitive biosensor sur~ace as described above. Assays were run in HBS + 10 mM DTT ustng pp70ZAP(1-259)R37K (a mutant where Arginine-37 is replaced by Lysine to inactivate the N-terminal SH2 domain) or pp70ZAP (161-259)+/- test inhibitor 3 0 ~ S~ecilics of Tandem Syk Assay: A pp72sYk peptide ligand cor,~spondi"g to the y-chain ITAM of human Fc~RI [DGVY(PO4)TGLSTRNQETY(PO4)ETLK][SEQ ID NO 19] was synthesized as part of a larger peptide [Ac-CGGDGVY(PO4)TGLSTRNQETY-(PO4)ETLK-NH23 ~SEQ ID NO 20] and used to generate a Syk-sensitive biosensor surface. Specifically a Biosensor Chip CM~ was activated with 200 mM ethyl-3-(3-dimethylaminopropyl)-ca,Lodii",ide hydrochloride (EDC)/ 50 mM N-hydroxysucci"i",ide (NHS) to generate a surface reactive to primary amines; treated with ethylenediamine to generate a surface rich in primary amines; activated with m-maleimidoben~oyl-N-hydroxysuccinimide ester (sulfo-MBS; 50 mM in 25 mM NaHCO3) to generate a surface reactive to free thiols; and the ITAM peptide immob -~ through the N-terminal cysteine. U",~a~led sites were SUBSTlTUTE ~E~ tRULE 2~i~

WO 97/08300 PCT~US96/13918 blocked with ~-mercaptoethanol and the chip cleaned of non-covalently bound peptide using 6 M guanidine hydrochloride. Assays were run in HBS using 20 nM pp725Yk(1-265) +/-test inhibitor.

5 ~ S~ecirics of C-Syk Ass~y: A pp72sYk peptide ligand corresponding to a her", 'nosuhorylated y-chain ITAM of human Fc~RI [DGvy(po4)TGLsTF~NQETyETLKl wassynthesized as part of a larger peptide [Ac-CGGDGVY(PO4)TGLSTRNQElYETLK-NH2] andused to generate a C-Syk-sensitive biosensor surface as described above for tandem syk.
Assays were run in HBS using 270 nM pp725Yk(163-265) +/- test inhibitor.
1 ~) (2) Cell-based Assays (a) T cell assay (T cell receptor-dependent transcription~
Purpose and desc,;f,lion of assay:This assay measures the ability of a compound to 15 inhibit TCR activation of the IL-2 L,dns~ ion pathway in the human Jurkat T cell line. These Jurkat cells have been ltdn~ ed with a construct containing the ,i3-g~ t~sid~e gene under the control of an u~sl,~a", u,u",uler e~ement, the NF-AT binding site, which normally re9~ t~s IL-2 production.18 When cells are activated, ~-gz~ osi~R~e is produced.

20 Drug 7~e_t~ei~1 ~f Cells and Stimul-~;on:The compounds to be assayed are serially diluted into assay buffer and each dilution is added to the Jurkat cells for a 1 hour pre-inr-uh~1ion. After the pre-incubation, the cells are transferred to plates coated with antibody to the CD3 component of the TCR. This antibody ~ussli-~h, the TCR, leading to activation of receptor signaling pd~ ys. The cells are inc~h~t/~d for 4 hours, then the amount of ~-gal 2 5 produced is measured.

Measuren,elit of ~3-gs~Llosi~ se: The assay is used to c~uantitate the amounts of ,B
-g~i~ulos:~lA~e produced is the MUG assay. MUG, 4-methylumbellir~rune g~ ctose, i5 cleaved by ,B-galactosidase to form a fluorescent derivative, 7-hydroxy-4-methylcoumarin. The observed 30 fluorescence cor.tl~les with the amount of cleavage product, and thus with the amount of ,B
-g~i~ctosi~l~Re. Production of ~-gal without the addition of compound determines the 100%
value for each well. The raw data is converted into "percent of control", ~ licdle wells are averaged, and then the data is plotted as % of control release vs. conce~ dliol1 of test compound.

3 5 ~b) Cytotoxic T Lymphocyte killing Purpose and descri~liol~ of assay~ This assay measures the ability of a compound to inhibit the cytolytic function of human cytotoxic Iymphocyte lines. Human CD8+ CTL were generated from ,-,iLugen-stimulated peripheral blood Iymphocytes. Mitogen activated cells were grown in IL2 and re-stimulated every 3 weeks with anlibo-lies directed against the T cell SUBSTITUTE S~tE~ tRlJLE 26~

receptor complex and CD8+ cells were sorted and cloned. Clone T9 was selected for use in the CTL assay. Since the T cells were sele.;lt:d nonspecifically, i.e. no specific antigen was used for induction, the target chosen for the assay was the B cell hybridoma OKT3. This cell line ~,~,u,~sses anti-CD3 on its surface(an antibody against one of the subunits of the T cell 5 receptor). The recoy~ on of the T cell receptor by the antibody induces the cytolytic process of the target f Drug Ti ,~I",en~ of Cells and St~tnuls~tion:The compounds to be assayed are serially diluted into assay buffer and each dilution is added to the CTL's for a 1 hour pre-inc~lh~tion.
10 After the pre-incubation, the cells are mixed with 51Cr labelled OKT3 cells at a ratio of 3:1 (effector:target) and inc~h~ted for 3 hours. This ratio of effector to targets results in approximately 30% specific release.

Measu,~",enl of 51Crelease: The cell mixture is centrlfuged and the supernatant is 1 5 removed. The amount of 51Cr released into the media is measured on a y counter and the specific release is d~le"";.,ed using detergent Iysed target cells as the 100% value. The data is plotted as % specific release vs. conce"l.dliol1 of test compound.

(3) Animal Models:

(a) DFI AYED TYPF HYP~RSENSmVlTY
An initial screening model is delayed type hypeu,el1sili-/ity. Mouse abdo",ens are painted with sen~ i,.g chemicals (ser~ ion) such as di"il,urloL-,obenzelle or oxazalone. Seven days later the ears of sensitized mice are painted (challenge) with a lower conce..l.dlion of the 25 compound. Antigen processing and presentation T Iymphocyte activation. Ieukocyte infiltration humoral mediator release increased microvascular permeability and plasma exudation all result from challenge of sensitized mice and lead to edema rorllldliol~. Edema pl~senl:, as a two-to three- fold increase in ear thickness within twenty-four hours.

3 0 The test compounds or ~l~ndal-ls can be applied (topical or pare"ler~l) at various times before or after the sensi~ liol) or challenge phases. Increased ear thickness is prevented by several compounds including immunosu~plessive agents and steroids. This model is a primary model for contact dermatitis.

3 5 (b) ALLOGFNEIC SKIN TRANSPLANTATION
An allogeneic skin transplant model is used to identify immunosL",pressive activity of test compounds. In this model donor mouse thoracic skin (Balb/c) is surgically grafted onto the thorax of recipient mice (C57bl/~). Host rejection of the graft is evidenced by erythema, drying out and ~ clion of donor skin. The mean graft survival time is 10 to 11 days with SUBS I 1 i UTE S}~E~ tRULE 2~i~

W O 97/08300 PCT~US96/13918 80% of the grafts being reiected by 12 days. Active novel immunosll~,plessive compounds, iike existing immunosu~prt:ssive compounds, will prolong graft survival.

~c) POPLITEAL LYMPH NODE HYPERPLASIA
5 This model directly ~csesses T Iymphocyte pr~''~.~lion in vivo. Spleen cells, obtained from Balb/c mice, are isolated and al., ' ,._~en:d into the foot pads of C3H mice. Within four days, the popliteal Iymph nodes can be removed from the recipient mice and weighed. Other hen ' Ic~';, I
assessments including FACS scanning for T Iymphocyte subpopulations may also be pt:,fu,-,,ed.
Active compounds, like existing immunosu~.plessive compounds, will inhibit the increase in 1 0 node mass.

(d~ RHEUMATOID ARTHRITIS
Several models are available for assessment of anti-arthritic activity, including adjuvant-induced, carageenan-induced, and collagen-induced arthritis in rats and/or mice. Paw pads are 1 5 injected with one of these agents. Paws increase in volume, and measurements are made between 20 and 30 days later. The ability of test compounds to prevent the induction of paw swelling is tested with daily treatment for 12 consecutive days lollo i.,g the i"3e-,lion of inducing agent.
The ability for the test compounds to reverse the prog.~ssion of the paw swelling is tested by ad...i.,i~,dlion of the compound for 12 consecutive days beginning on the twelfth day fGII~,: ;.Ig 2 0 the inJection of inducing agent. Paw ~ g measurements are made by water dicp'~-ement plethysmography. Histology is also an appropridle endpoint for these studies. The MRL/lpr-mouse model, described above, is required for the rheumatoid arthritis i"dicalion. Th;s model is a s~u"laneous ~ut: ",.,une model that develops rheumatoid arthritis resembling the human conclilion, including the presence of circulating rheumatoid factor, pannus formation, and bone 2 5 and cartilage erosion.

~e) SYSTEMIC ~uPus ERYTHEMATOSUS
Systemic lupus erythematosus is another autoimmune disease with several animal models.
Several murine strains develop sponl~neous S~E. One such strain is MRL/lpr-mice. These 3 0 mice, over time (20 to 30 weeks) develop auto-antibodies against dsDNA, nuclear antigens. and renal basement ,I.el"Lldne. This leads to culll~,le,--e,lL fixation and immune cGIl,r'- folll,alion.
Damage to the kidney becomes ~ppalt:r,l with the onset of proteinuria. Many of the other ph~: ' l gic, helll~ ,', and immunologic abe"dlions cles~,iL,ed below for the CGVHD model are present. Immunosu~p~essive compounds such as cy~,lo3po,i", cy.,lopl1o~phamide, and 3 5 leflunomide can prevent and reverse the course of disease in this model. Inle~esli"yly, these mice also develop pathologies akin to rheumatoid arthritis.

SUBSTITUTE S~tEE~ (RULE 2~i) Ths murine chronic graft versus host disease model (CGVHD, desc,i~ed below) is a modei of SLE
that cG~ ills many o~ the clinical features of SLE. Activity in this model has been shown to be predictive of activity in the more clinically relevant SLE models.

(f~TRANSPLANTATION
Ailograft tran~planl~lion (skin graft) assay is often used as an initial test of immunosu~,~Jn:ssive activity. While this model is useful as a screen it may be su,u,uleh,enled with assays based on animal lldnsl la"l models involving L,dnsplanhlion of internal organ (heart, liver, kidney, bone marrow) with use of "clinically acceptable" physiologic end~oMI~
10 to assess graft survival. Efficacy of test compounds in oniy a very limited number of these rodent models is required. Following observation of activity in a rodent model, the test compounds are typically tested in further animal models (e.g., canine, porcine or non-human primate). Active compounds decrease acute and chronic rejection and prolong l,~n:,~.lar,l survival.

(g)GRAFT VS.HOST DISEASE
Chronic GVHD (CGVHD) can be used to model CD4+-dependt "l humoral immunity. It is induced in BDF1 mice (which are progeny of DBA/2 male XC57BU6 female matings) by ad,l,;.,i,l~l;"g to them isolated spleen:lymph node cells from DBA/2 mice. This results in: a) disregulation and 20 stimulation of CD4+ T Iymphocyte (Ly1+; murine marker) activity due to incompatibilities at MHC ll moleculesl and b) abnormal T-B Iymphocyte cooperation. The resulting pathological statel in many ways, mimics systemic lupus er~il,e",alosus (SLE). Several measurable endpoints develop within 14 days; including circulating anti-host IgG and IgE ar.liLo~ s altered T and B Iymphocyte proliferation activity measured in vitro, complement utilization 25 hemagglutination slow progressive wasting dermal aber,dlions. splenomegalyl Iymphoid hyperplasia and proteinuria. Only a few of these en ~I_G..~ need to be measured. Active compounds are are those which limit T Iymphocyte disregulation and abrogate changes in these variables. Many steroids (e g. prednisolone) cyclosporine FK-506 cyclophosphamide, and leflunomide are all active in this model and can be used as positive controls The acute GVHD model (AGVHD) is also produced in BDF1 mice. In this case, isolated spleen:lymph node cells from C57BU6 mice are a.l,,,i,,iciLe~t3d. This results in disregulation and stimulation of CD8+ T Iymphocytes due to i"co""~ iL ie~ in the MHCI " -'sc~les. Elevated cytokine levels and donor clonal e~,ansion occurs. Ultimately, donor cytotoxic T Iymphocytes 3 5 and NK cells rapidly reject host tissue and cause relatively rapid death of the recipient. The pruy,ession of AGVHD in this model is ~c~essed by measurement of he" ~ al)no",l- -s (including T cell number and type)l cytokine elevations (TNFI IL-1 IL-2, and/or IL-4), low body weight, hy~orylobulinemia circulating hematologic characlelislics indicative of aplastic anemia (granulocytopenia thrombocytopenia) ex vivo NK or CTL activity, and host survival.

SUBST~TUTE SH E~ (RULE 2 Active compounds are those which a~,ug~Le .~ nges in the varfables, and prolong survival over 4 to 6 weeks.

(h) AsTHMA
5 Asthma offers another opportunity for safe immunos~prt:ssive therapy. Atopic asll,l-.d~ics have antibody mediated hypersensitivity and the often occurring late phase reaction is likened to a DTH response. Asthma has only recent~y been defined as an i"~la-"",dtory disease (1992). Since then, several pllhlio~tions from p~u~i ,enL a~ dlologists der,.onsl,~le the presence of activated C :)4 ~ and CD8+ T Iymphocytes in bruncl~oalveolar lavage fluid and blood of atopic 1 0 a:,ll.."~lios. The ratios of these cells cl.anges in a:~lhllldlic col,diLiu"s. Furthermore, several of the T cell associated cytokines (IL-1, IL-2, IL-4, IL-5, and TNF) are all ill~pli~ lPd in clinical and experimental asthma. lr,na.,l,,,d~uly events in asthma are now considered to be T Iymphocyte driven. Initial clinical trials with inhaled cyclosporin suggest that local immunos~ plession can ameliorate airway hyperreactivity - the underlying defect in asthma.

= ~
The guinea pig model of antigen-induced pulmonary abe";~lions is used as a model for asthma.
These animals are actively sensili~ed to ovalbumin to generate high circulating titers of anti-ovalbumin antibody with seroconversion to the IgE class, as is the case with atopic a:,ll,--,dlil:s.
Aerosoi challenge of sensili,:ed guinea pigs results in measurab~e eosinophil rich pulmonary 20 i"iill.~les (approximately a 16-~old increase in eosi..opl.;ls), pulmonary edema, and mucous plugging of the small airways; all cul., Idlillg in the e~ ssion of the underlying defect in asthma- airway hyperreactivity (approximately a 3 to 4-fold increase in reactivity). Acute brunl;l,ocon~ ion is obviously present and points the a~urt~ n~ioned prt:s~:..ce of the pathoph~ir'ryio seq~lelfle Active compounds are those which lessen or ablu~dlt: such s~ lu.-,s.
The above description is meant to iliustrate, rather than limit the scope of the invention. Given the fon:gGi.,g descli,ulioll, numerous v~ri~lions in the materials or methods e", '~yed in performing the invention will be obvious to one skilled in the art. Any such obvious variation is to ~e considered within the scope of the invention.

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SUBSTITUTE S~ F~ ~RULE 2~) , CA 02226963 l998-02-l2 A~endix I: Coordinates for the 3D structure o~ ZAP-NC:zl*

REMARK FTT~N~M~="test-slow.pdb"
REWARK TOPHl9.pep -MACRO for protein seguence created by user: marcos Atom Atom amino acid temp Nll~hertype residue x v z occ factor ATOM 1 CB ASP 3 -1.489 -4.706 36.906 1.00 37.30 ATOM 2 CG ASP 3-2.232-3.399 37.163 1.00 38.04 ATOM 3 ODl ASP 3-2.949 -3.304 38.181 1.00 39.49 ATOM 4 oD2 ASP 3-2.094 -2.461 36.353 1.00 34.64 ATOM 5 C ASP 3-1.755-4.886 34.408 1.00 34.63 ATOM 6 O ASP 3 -0.595 -4.867 34.003 1.00 34.56 ATOM 7 HTl ASP 3-0.506 -6.812 35.572 1.00 0.00 ATOM 8 HT2 ASP 3-1.947 -7.433 34.967 1.00 0.00 ATOM 9 N ASP 3-1.527-6.899 35.753 1.00 40.12 ATOM10 HT3 ASP 3-1.707 -7.382 36.652 1.00 0.00 ATOM 11 CA ASP 3 -2.095 -5.522 35.754 1.00 36.56 ATOM12 N PRO 4-2.771-4.385 33.690 1.00 31.82 ATOM13 CD PRO4-4.186 -4.460 34.087 1.00 32.51 ATOM14 CA PRO4-2.640 -3.73g 32.379 1.00 29.95 ATOM15 CB PRO4-4.058 -3.243 32.113 1.00 30.71 ATOM 16 CGPRO 4 -4.895 -4.275 32.774 1.00 31.34 ATOM17 C PRO 4-1.652-2.579 32.341 1.00 28.61 ATOM18 O PRO 4-1.211-2.170 31.265 1.00 30.48 ATOM19 N ALA 5-1.333-2.029 33.509 1.00 25.13 ATOM20 H ALA 5-1.777-2.325 34.322 1.00 0.00 ATOM 21 CA ALA 5 -0.411 -0.905 33.592 1.00 21.95 ATOM22 CB ALA5-1.029 0.206 34.437 1.00 20.80 ATOM23 C ALA 50.973-1.261 34.121 1.00 20.21 ATOM24 O ALA 51.884-0.442 34.064 1.00 19.51 ATOM25 N ALA 61.151-2 504 34.553 1.00 19.03 3~ ATOM 26 HALA 6 0.413 -3.137 34.469 1.00 0.00 ATOM27 CA ALA 62.422-2.958 35.124 1.00 18.99 ATOM28 CB ALA62.339 -4.443 35.462 1.00 22.76 ATOM29 C ALA 63.674-2.679 34.296 1.00 16.60 ATOM30 O ALA 64.755-2.485 34.847 1.00 14.22 SUBS I ITUTE S~E~ tRULE 2~) CA 02226963 l998-02-l2 W O 97/0830~ PCTAUS96/13918 ATOM 31 NHIS 73.527 -2.665 32.977 1.00 15.98 ATOM 32 HHIS 72.628 -2.813 32.643 1.00 0.00 ATOM 33 CAHIS 74.660 -2.422 32.091 1.00 16.26 ATOM 34 CBHIS 74.424 -3.096 30.736 1.00 16.78 ATOM 35 CGHIS 7 3.194 -2.622 30.027 1.00 16.42 ATOM 36CD2 HIS 73.033 -1.729 29.021 1.00 16.56 ATOM 37NDl HIS 71.933 -3.092 30.324 1.00 15.90 ATOM 38HDl HIS 71.674 -3.788 30.967 1.00 0.00 ATOM 39CEl HIS 71.049 -2.511 29.534 1.00 16.52 ATOM 40 NE2 HIS 7 1.692 -1.681 28.734 1.00 17.76 ATOM 41HE2 HIS 71.276 -1.120 28.048 1.00 0.00 ATOM 42 CHIS 75.014 -0.943 31.891 1.00 17.19 ATOM 43 ~ HIS 76.082 -0.629 31.357 1.00 18.03 ATOM 44 NLEU 84.125 -0.038 32.300 1.00 14.61 ATOM 45 HLEU 8 3.316 -0.310 32.782 1.00 0.00 ATOM 46 CALEU 84.382 1.393 32.143 1.00 14.75 ATOM 47 CBLEU 83.106 2.216 32.371 1.00 15.09 ATOM 48 CGLEU 82.051 2.374 31.267 1.00 19.47 ATOM 49CDl LEU 82,669 2.167 29.891 1.00 21.37 ATOM 50 CD2 LEU 8 0.911 1.417 31.472 1.00 23.01 ATOM 51 CLEU 85.481 1.879 33.085 1.00 13.31 ATOM 52 OLEU 85.432 1.628 34.288 1.00 13.01 ATOM 53 NPRO 96.478 2.609 32.551 1 00 13.43 ATOM 54 CDPRO 96.691 2.982 31.141 1.00 13.38 ATOM 55 CAPRO 9 7.571 3 113 33.385 1.00 12.50 ATOM 56 CBPRO 98.523 3.736 32.363 1.00 12.42 ATOM 57 CGPRO 97.617 4.159 31.267 1.00 14.81 ATOM 58 CPRO 97.117 4.122 3g.440 1.00 10.81 ATOM 59 OPRO 97.783 4.297 35.459 1.00 12.13 ATOM 60 NPHE 10 5.985 4.776 34.200 1.00 11.91 ATOM 61 HPHE 105.502 4.601 33.371 1.00 0.00 ATOM 62 CAPHE 105.451 5.761 35.140 1.00 11.80 ATOM 63 CBPHE 104.981 7.029 34.406 1.00 10.49 ATOM 64 CGPHE 104.009 6.769 33.289 1.00 12.16 ATOM 65 CDl PHE 10 2.642 6.722 33.536 1.00 11.91 ATOM 66CD2 PHE 104.460 6.579 31.985 1.00 12.16 ATOM 67CEl PHE 101.738 6.492 32.505 1.00 14.05 ATOM 68CE2 PHE 103.561 6.348 30.949 1.00 11.03 ATOM 69CZ PHE 102.198 6.305 31.210 1.00 10.40 SUBSTTTUTE S~EE~ tRULE 26) CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATOM70 C PHE 104.3485.220 36.063 1.00 10.35 ATOM71 O PHE 103.6485.994 36.714 1.00 9.59 ATOM72 N PHE 114.1723.901 36.085 1.00 10.23 ATOM73 H PHE 114.7523.312 35.559 1.00 0,00 5 ATOM 74 CAPHE 11 3.179 3.263 36.944 1.00 9.09 ATOM75 CB PHE112.539 2.060 36.241 1.00 8.78 ATOM76 CG PHE111.602 1.266 37.119 1.00 8.82 ATOM77 CDl PHE 110.374 1.787 37.504 1.00 9.98 ATOM78 CD2 PHE 111.949 -0.011 37.548 1.00 12.08 10 ATOM 79 CEl PHE 11 -0.497 1.046 38.301 1.00 10.58 ATOM80 CE2 PHE 111.083 -0.759 38.345 1.00 11.57 ATOM81 CZ PHE11-0.141 -0.230 38.722 1.00 10.29 ATOM82 C PHE 113.9042.819 38.214 1.00 10.01 ATOM83 O PHE 114.8902.084 38.157 1.00 10.38 15 ATOM 84 N TYR 12 3.421 3.279 39.360 1.00 8.54 ATOM85 H TYR 122.6453.868 39.342 1.00 0.00 ATOM86 CA TYR124.050 2.962 40.628 1.00 7.85 ATOM87 CB TYR124.154 4.229 41.471 1.00 9.01 ATOM88 CG TYR125.234 5.165 40.994 1.00 9.41 20 ATOM 89 CDl TYR 12 5.079 5.911 39.829 1.00 11.88 ATOM90 CEl TYR 126.098 6.737 39.371 1.00 10.68 ATOM91 CD2 TYR 126.432 5.275 41.688 1.00 10.27 ATOM92 CE2 TYR 127.444 6.094 41.242 1.00 10.04 ATOM93 CZ TYR127.275 6.821 40.086 1.00 10.17 25 ATOM 94 OHTYR 12 8.296 7.629 39.659 1.00 14.36 ATOM95 HH TYR128.048 7.993 38.798 1.00 0.00 ATOM96 C TYR 123.3981.856 41.436 1.00 8.85 ATOM97 O TYR 123.9091.466 42.483 1.00 9.35 ATOM98 N GLY 132.2781.340 40.950 1.00 11.20 30 ATOM 99 H GLY 13 1.920 1.683 40.111 1.00 0.00 ATOM100 CA GLY131.597 0.284 41.669 1.00 12.09 ATOM101 C GLY 130.7620.814 42.818 1.00 12.99 ATOM102 O GLY 130.2661.940 42.769 1.00 12.85 ATOM103 N SER 140.6350.010 43.865 1.00 12.55 35 ATOM 104 H SER 14 1.068 -0.867 43.854 1.00 0.00 ATOM105 CA SER14-0.167 0.356 45.02i 1.00 14.38 ATOM106 CB SER14-0.680 -0.931 45.685 1.00 13.42 ATOM107 OG SER14-1.532 -0.657 46.784 1.00 21.30 ATOM108 HG SER14-1.068 -0.007 47.331 1.00 0.00 SUBSTiTUTE ~ ~ (RULE 2fi) CA 02226963 l998-02-l2 W O 97/08300 P ~ AUS96~13918 ATOM 109 C SER140.542 1.232 46.060 1.00 15.49 ATOM 110 O SER140.894 0.760 47.144 1.00 18.54 ATOM 111 N ILE150.748 2.506 45.737 1.00 14.76 ATOM 112 H ILE150.428 2.829 44.869 1.00 0.00 ATOM 113 CAILE 15 1.390 3.423 46.676 1.00 12.31 ATOM 114 CB ILE152.571 4.210 46.04Q 1.00 12.37 ATOM 115 CG2 ILE 15 3.712 3.256 45.687 1.00 13.51 ATOM 116 CGl ILE 15 2.101 5.014 44.827 1.00 11.08 ATOM 117 CD ILE153.131 6.016 44.347 1.00 12.11 ATOM 118 C ILE 15 0.354 4.398 47.226 1.00 10.69 ATOM 119 ~ ILE15-0.750 4.488 46.701 1.00 11.71 ATOM 120 N SER160.700 5.099 48.299 1.00 8.45 ATOM 121 H SER161.588 5.018 48.689 1.00 0.00 ATOM 122 CA SER16-0.219 6.053 48.899 1.00 12.16 ATOM 123 CBSER 16 0.073 6.199 50.393 1.00 8.73 ATOM 124 OG SER161.380 6.711 50.597 1.00 11.59 ATOM 125 HG SER161.483 6.783 51.560 1.00 Q.00 ATOM 126 C SER16-0.073 7.411 48.225 1.00 11.37 ATOM 127 O SER160.883 7.640 47.474 1.00 10.80 ATOM 128 N ARG 17 -1.006 8.315 48.509 1.00 10.26 ATOM 129 H ARG17-1.743 8.056 49.105 1.00 0.00 ATOM 130 CA ARG 17 -0.944 9.657 47.947 1.00 8.92 ATOM 131 CB ARG 17 -2.148 10.492 48.385 1.00 9.48 ATOM 132 CG ARG 17 -2.033 11.962 47.998 1.00 8.28 2~ ATOM 133CD ARG17 -3.228 12.766 48.448 1.00 8.69 ATOM 134 NE ARG 17 -4.417 12.388 47.701 1.00 8.47 ATOM 135 HE ARG 17 -4.400 11.503 47.308 1.00 0.00 ATOM 136 CZ ARG 17 -5.470 13.173 47.505 1.00 10.19 ATOM 137 NHl ARG 17 -5.499 14.402 48.002 1.00 10.59 ATOM 138 HHll ARG 17 -4.717 14.750 48.520 1.00 0.00 ATOM 139 HH12 ARG17-6.295 14.988 47.859 1.00 0.00 ATOM 140 NH2 ARG 17-6.490 12.734 46.789 1.00 8.14 ATOM 141 HH21 ARG17-6.457 11.804 46.413 1.00 0.00 ATOM 142 HH22 ARG17-7.292 13.305 46.629 1.00 0.00 3~ ATOM 143C ARG17 0.342 10.321 48.426 1.00 11.05 ATOM 144 O ARG 17 1.039 10.974 47.649 1.00 12.01 ATOM 145 N ALA 18 0.666 10.131 49.704 1.00 9.21 ATOM 146 H ALA 18 0.067 9.605 50.279 1.00 0.00 ATOM 147 CA ALA 18 1.872 10.708 50.286 1.00 11.20 SUBST~TUTE S~F~ ~RULE ~

CA 02226963 l998-02-l2 ATOM 148 CB ALA182.001 10.301 51.745 1.00 15.06 ATOM 149 C ALA183.123 10.303 49.521 1.00 12.57 ATOM 150 O ALA183.959 11.152 49.193 1.00 12.90 ATOM 151 N GLU193.250 9.008 49.240 1.00 11.57 ATOM 152 H GLU 19 2.542 8.381 49.517 1.00 0.00 ATOM 153 CA GLU 19 4.403 8.488 48.514 1.00 11.99 ATOM 154 CB GLU 19 4.364 6.960 48.465 1.00 13.36 ATOM 155 CG GLU 19 4.482 6.297 49.820 1.00 20.61 ATOM 156 CD GLU 19 4.358 4.790 49.742 1.00 21.71 ATOM 157OEl GLU 19 5.400 4.108 49.647 1.00 29.81 ATOM 158 OE2 GLU 19 3.216 4.285 49.774 1.00 19.69 ATOM 159 C GLU 19 4.449 9.043 47.099 1.00 11.13 ATOM 160 O GLU 19 5.524 9.357 46.584 1.00 12.79 ATOM 161 N ALA 20 3.280 9.155 46.472 1.00 12.51 ATOM 162H ALA20 2.463 8.875 46.939 1.00 0.00 ATOM 163 CA ALA 20 3.177 9.681 45.109 1 00 13.22 ATOM 164 CB ALA 20 1.730 9.596 44.616 1.00 10.29 ATOM 165 C ALA203.679 11.127 45.052 1.00 11.20 ATOM 166 O ALA204.466 11.494 44.175 1.00 11.31 ATOM 167 N GLU 21 3.243 11.933 46.009 1.00 10.24 ATOM 168 H GLU212.638 11.588 46.693 1.00 0.00 ATOM 169 CA GLU213.652 13.328 46.071 1.00 10.86 ATOM 170 CB GLU212.804 14.091 47.082 1.00 7.73 ATOM 171 CG GLU211.349 14.202 46.656 1.00 8.58 ATOM 172 CDGLU 21 0.488 15.002 47.625 1.00 10.14 ATOM 173 OEl GLU 21 -0.692 15.230 47.308 1.00 9.72 ATOM 174 OE2 GLU 21 0.985 15.414 48.693 1.00 13.94 ATOM 175 C GLU 21 5.142 13.468 46.374 1.00 12.31 ATOM 176 O GLU 21 5.780 14.425 45.942 1.00 13.09 ATOM 177N GLU22 5.706 12.487 47.073 1.00 13.22 ATOM 178 H GLU 22 5.162 11.739 47.388 1.00 0.00 ATOM 179 CA GLU 22 7.124 12.508 47.394 1.00 11.25 ATOM 180 CB GLU 22 7.454 11.396 48.389 1.00 16.27 ATOM 181 CG GLU 22 8.811 11.551 49.035 1.00 25.51 ATOM 182CD GLU22 9.194 10.364 49.891 1.00 32.11 ATOM 183 OEl GLU 22 8.324 9.852 50.631 1.00 36.02 ATOM 184 OE2 GLU 22 10.371 9.948 49.818 1.00 34.67 ATOM 185 C GLU 22 7.942 12.345 46.107 1.00 11.86 ATOM 186 O GLU228.902 13.080 45.873 1.00 10.75 -SVE~STtTUTE S~E~ ~RULE 2fi~

CA 02226963 l998-02-l2 WO 97/08300 PCTnUS96/13918 ATOM 187 N HIS237.537 11.406 45.255 1.00 9.76 ATOM 188 H HIS236.741 10.889 45.512 1.00 0.00 ATOM 189 CA HIS238.226 11.162 43.987 1.00 9.26 ATOM 190 CB HIS237.651 9.927 43.286 1.00 7.86 ATOM 191 CGHIS 23 8.087 8.634 43.903 1.00 10.39 ATOM 192 CD2 HIS 23 9.315 8.090 44.050 1.00 8.91 ATOM 193 NDl HIS 23 7.205 7.746 44.482 1.00 14.23 AT~ i~4 HDl HIS Z3 ~.236 7.854 44.576 1.00 0.00 ATOM 195 CEl HIS 23 7.873 6.713 44.960 1.00 10.97 ATOM 196NE2 HIS 23 9.156 6.898 44.711 1.00 13.67 ATOM 197 HE2 HIS 23 9.898 6.306 44.998 1.00 0.00 ATOM 198 C HIS238.156 12.361 43.045 1.00 10.69 ATOM 199 O HIS239.148 12.708 42.394 1.00 10.64 ATOM 200 N LEU246.986 12.992 42.978 1.00 10.63 ATOM 201 H LEU 24 6.232 12.680 43.521 1.00 0.00 ATOM 202 CA LEU246.792 14.159 42.117 1.00 10.53 ATOM 203 CB LEU245.309 14.532 42.046 1.00 10.68 ATOM 204 CG LEU244.393 13.515 41.350 1.00 11.63 ATOM 205 CDl LEU 24 2.935 13.881 41.539 1.00 9.03 2Q ATOM 206CD2 LEU 24 4.724 13.449 39.874 1.00 7.43 ATOM 207 C LEU247.636 15.343 42.599 1.00 11.35 ATOM 208 O LEU248.165 16.110 41.790 1.00 11.67 ATOM 209 N LYS257.790 15.472 43.914 1.00 11.16 ATOM 210 H LYS257.347 14.841 44.523 1.00 0.00 ATOM 211 CALYS 25 8.595 16.548 44.480 1.00 10.68 ATOM 212 CB LYS258.465 16.587 46.001 1.00 9.16 ATOM 213 CG LYS257.135 17.068 46.517 1.00 6.98 ATOM 214 CD LYS257.109 16.971 48.018 1.00 8.43 ATOM 215 CE LYS255.794 17.436 48.586 1.00 9.56 ATOM 216 NZLYS 25 5.858 17.440 50.075 1.00 9.88 ATOM 217 HZl LYS 25 6.621 18.081 50.375 1.00 0.00 ATOM 218 HZ2 LYS 25 6.068 16.480 50.403 1.00 0.00 ATOM 219 HZ3 LYS 25 4.953 17.769 50.472 1.00 0.00 ATOM 220 C LYS2510.051 16.323 44.125 1.00 12.70 ATOM 221 O LYS 25 10.728 17.226 43.634 1.00 15.29 ATOM 222 N LEU2610.518 15.096 44.334 1.00 14.74 ATOM 223 H LEU269.913 14.405 44.690 1.00 0.00 ATOM 224 CA LEU2611.906 14.746 44.057 1.00 16.13 ATOM 225 CB LEU2612.231 13.357 44.618 1.00 13.92 SU~STlTUTE SitF~ ~RULE 2~;) CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 226 CG LEU 26 12.231 13.216 46.14S 1.00 13.80 ATOM 227 CDl LEU 26 12.430 11.772 46.521 1.00 16.36 ATOM 228 CD2 LEU 26 13.320 14.072 46.761 1.00 17.12 ATOM 229 C LEU 26 12.252 14.818 42.574 1.00 18.06 ATOM 230O LEU 26 13.427 14.852 42.207 1.00 19.38 ATOM 231 N ALA 27 11.226 14.853 41.730 1.00 19.46 ATOM 232 H ALA 27 10.312 14.818 42.076 1.00 0.00 ATOM 233 CA ALA 27 11.414 14.926 40.285 1.00 20.96 ATOM 234 CB ALA27 10.309 14.154 39.576 1.00 19.82 ATOM 235 C ALA 27 11.495 16.356 39.741 1.00 20.81 ATOM 236 O ALA27 11.713 16.551 38.544 1.00 24.10 ATOM 237 N GLY28 11.285 17.352 40.596 1.00 20.02 ATOM 238 H GLY28 11.099 17.182 41.546 1.00 0.00 ATOM 239 CA GLY28 11.369 18.723 40.132 1.00 19.49 ATOM 240 C GLY 28 10.100 19.554 40.161 1.00 21.05 ATOM 241 O GLY28 10.164 20.764 39.955 1_00 22.70 ATO~ 242 N SEM29 8.946 18.926 40.374 1.00 20.23 ATOM 243 H SEM29 8.927 17.952 40.496 1.00 0.00 ATOM 244 CA SEM29 7.669 19.650 40.438 1.00 21.17 ATOM 245 CBSEM 29 7.641 20.595 41.645 1.00 24.34 ATOM 246 CG SEM29 7.505 19.914 42.994 1.00 28.45 ATOM 247 A SEM29 5.834 18.935 43.183 1.00 33.82 ATOM 248 CE SEM29 4.660 20.332 43.772 1.00 30.42 ATOM 249 C SEM29 7.311 20.438 39.177 1.00 19.69 ATOM 250 O SEM 29 6.640 21.471 39.250 1.00 18.65 ATOM 251 N ALA30 7.749 19.948 38.025 1.00 19.92 ATOM 252 H ALA30 8.251 19.114 38.032 1.00 0.00 ATOM 253 CA ALA 30 7.459 20.612 36.760 1.00 20.38 ATOM 254 CB ALA30 8.314 20.023 35.641 1.00 20.76 ATOM 255 C ALA 30 5.985 20.454 36.428 1.00 21.88 ATOM 256 O ALA30 5.346 19.494 36.857 1.00 22.02 ATOM 257 N ASP31 5.434 21.423 35.705 1.00 21.51 ATOM 258 H ASP31 5.990 22.173 35.411 1.00 0.00 ATOM 259 CA ASP 31 4.034 21.367 35.304 1.00 22.50 ATOM 260CB ASP 31 3.582 22.700 34.704 1.00 26.22 ATOM 261 CG ASP 31 3.559 23.818 35.723 1.00 32.04 ATOM 262 ODl ASP 31 2.465 24.354 35.985 1.00 38.46 ATOM 263 OD2 ASP 31 4.632 24.163 36.265 1.00 39.17 ATOM 264 C ASP 31 3.897 20.263 34.271 1.00 18.87 SVBSTlTUTE S~tEE~ tRu~ E 2~) CA 02226963 l998-02-l2 W 097/08300 PCT~US96/13918 ATOM 265 O ASP 314.762 20.106 33.407 1.00 18.52 ATOM 266 N GLY 322.826 19 488 34 376 1 00 17 28 ATOM 267 H GLY 322.174 19.611 35.099 1.00 0.00 ATOM 268 CA GLY 32 2.609 18.403 33.445 1.00 15.03 ATOM 269 C GLY 323.263 17.108 33.890 1.00 15.03 ATOM 270 O GLY 323.047 16.073 33.263 1.00 18.44 ATOM 271 N LEU 334.079 17.159 34.942 1.00 15.47 ATOM 272 H LEU 334.234 18.007 35.398 1.00 0.00 ATOM 273 CA LEU 334.746 15.965 35.470 1.00 14.99 10 ATOM 274 CB LEU 335.765 16.359 36.545 1.00 14.41 ATOM 275 CG LEU 336.585 15.272 37.248 1.00 15.28 ATOM 276 CDl LEU33 7.603 14.664 36.297 1.00 14.45 ATOM 277 CD2 LEU33 7.278 15.869 38.461 1.00 12.37 ATOM 278 C LEU 333.648 15.093 36.078 1.00 13.99 1 5 ATOM 279 O LEU33 2.833 15 582 36 868 1.00 12.54 ATOM 280 N PHE 343.625 13.810 35.726 1.00 13.31 ATOM 281 H PHE 344.305 13.484 35.098 1.00 0.00 ATOM 282 CA PHE 342.581 12.918 36.224 1.00 13.12 ATOM 283 CB PHE 341.410 12.877 35.225 1.00 10.40 20 ATOM 284 CG PHE 341.713 12.111 33.955 1.00 13.52 ATOM 285 CDl PHE34 1.269 10.798 33.796 1.00 13.58 ATOM 286 CD2 PHE34 2.460 12.694 32.934 1.00 10.22 ATOM 287 CEl PHE34 1.567 10.078 32.640 1.00 14.14 ATOM 288 CE2 PHE34 2.762 11.985 31.776 1.00 12.23 25 ATOM 289 CZ PHE 342.314 10.671 31.628 1.00 13.01 ATOM 290 C PHE 343.050 11.494 36.462 1.00 11.75 ATOM 291 O PHE 344 097 11.083 35.967 1.00 12.17 ATOM 292 N LEU 352.240 10.738 37.197 1.00 11.21 ATOM 293 H LEU 351 413 11 119 37 565 1.00 0.00 30 ATOM 294 CA LEU 352.522 9 336 37 470 1.00 8.87 ATOM 295 CB LEU 353 428 9.168 38 701 1 00 8 10 ATOM 296 CG LEU 352 980 9 520 40 123 1.00 8 50 ATOM 297 CDl LEU35 2 063 8.438 40.681 1 00 9 19 ATOM 298 CD2 LEU35 4 209 9 637 41.002 1.00 6.81 35 ATOM 299 C LEU 351.190 8.615 37.637 1.00 7.92 ATOM 300 O LEU 350.153 9.251 37.855 1.00 8.48 ATOM 301 N LEU 361.209 7.297 37.498 1.00 8.12 ATOM 302 H LEU 362.057 6.836 37.350 1.00 0.00 ATOM 303 CA LEU 360.000 6.502 37.626 1.00 8.05 SU1~STtTUTE S~E~ (RULE 2~;~

ATOM 304 CB LEU 36 -0.2585.734 36.327 1.00 9.30 ATOM 305 CG LEU 36 -1.6765.210 36.089 1.00 15.30 ATOM 306 CDlLEU 36 -2.6356.386 35.956 1.00 15.10 ATOM 307 CD2LEU 36 -1.7164 348 34.832 1.00 17.89 5 ATOM 308 C LEU360.164 5.S3238.789 1.00 8.05 ATOM 309 O LEU361.238 4.96138.991 1.00 8.20 ATOM 310 N ARG37-0.887 5.38039.581 1.00 8.30 ATOM 311 H ARG37-1.714 5.88239.404 1.00 0,00 ATOM 312 CA ARG 37 -0.8534.468 40.716 1.00 8.39 0 ATOM 313 CB ARG 37 --0.5835.229 42.015 1.00 6.96 ATOM 314 CG ARG 37 --1.5086.396 42.282 1.00 6.89 ATOM 315 CD ARG 37 -0.9747.196 43.451 1.00 10.99 ATOM 316 NE ARG37--1.722 8.42843.678 1.00 8.74 ATOM 317 HE ARG 37 -1.5299.196 43.101 1.00 0.00 1 5 ATOM 318 CZ ARG 37 -2.6478.577 44.617 1.00 10.85 ATOM 319 NHl ARG 37 -2.9567.567 45.423 1.00 9.35 ATOM 320 HHllARG 37 -2.5006.681 45.337 1.00 0.00 ATOM 321 HH12ARG 37 -3.6587.697 46.120 1.00 0.00 ATOM 322 NH2ARG 37 -3.2369.751 44.775 1.00 8.78 ATOM 323 HH21ARG 37 -2.98810.517 44.184 1.00 0.00 ATOM 124 HH22ARG 37 -3.9159.870 45.480 1.00 0.00 ATOM 325 C ARG37-2.166 3.70640.783 1.00 6.82 ATOM 326 O ARG37-3.161 4.12540.193 1.00 8.12 ATOM 327 N GLN38-2.150 2.54741.432 1.00 8.06 ATOM 328 H GLN38-1.324 2.26841.866 1.00 0.00 ATOM 329 CA GLN 38 -3.3531.735 41.549 1.00 9.21 ATOM 330 CB GLN 38 -2.9960.311 41.974 1.00 13.08 ATOM 331 CG GLN 38 -4.203-0.585 42.170 1.00 18.32 ATOM 332 CD GLN 38 -3.832-1.990 42.590 1.00 18.70 ATOM 333 OElGLN 38 -2.998-2.195 43.472 1.00 19.47 ATOM 334 NE2GLN 38 -4.463-2.968 41.967 1.00 22.25 ATOM 335 HE21GLN 38 -5.116-2.694 41.275 1.00 0.00 ATOM 336 HE22GLN 38 --4.267-3.889 42.210 1.00 0.00 ATOM 337 C GLN38-4.293 2.35942.565 1.00 10.19 ATOM 338 O GLN38--3.848 2.85643.594 1.00 12.74 ATOM 339 N CYS39-5.589 2.33942.278 1.00 11.02 ATOM 340 H CYS39-5.895 1.88741.464 1.00 0.00 ATOM 341 CA CYS 39 --6.5692.909 43.194 1.00 12.42 ATOM 342 CB CYS 39 -7.9183.079 42.496 1.00 9.94 SU85TITUTE ~}~E~ ~RIJLE 2fi~

W O 97/08300 PCTrUS96113918 ATOM 343 SGCYS 39 -9 2053.852 43.504 1.00 12.92 ATOM 344 C CYS 39 -6.7202.008 44.414 1.00 12.91 ATOM 345 O CYS 39 --6.7360.782 44.291 1.00 13.19 ATOM 346 N LEU 40 -6.7762.620 45.592 1.00 10.63 ATOM 347 H LEU 40 --6.6803.598 45.633 1.00 0.00 ATOM 348 CALEU 40 -6.9341.875 46.833 1.00 12.90 ATOM 349 CBLEU 40 --6.1392.543 47.965 1.00 11.53 ATOM 350 CGLEU 40 -4.6292.680 47.747 1.00 13.24 ATOM 351 CDlLEU 40 -4.0203.500 48.863 1.00 12.45 1 0 ATOM 352 CD2 LEU 40 -3.969l .317 47.657 1.00 12.54 ATOM 353 C LEU 40 -8.4011.789 47.226 1.00 11.01 ATOM 354 O LEU 40 -8.7481.127 48.201 1.00 12.23 ATOM 355 N ARG 41 -9.2692.412 46.439 1.00 10.95 ATOM 356 H ARG 41 -8.9572.869 45.631 1.00 0.00 1 5 ATOM 357 CA ARG 41 -10.690 2.431 46.758 1.00 12.13 ATOM 358 CBARG 41 -11.1853.872 46.820 1.00 10.86 ATOM 359 CGARG 41 -10.3904.754 47.756 1.00 10.97 ATOM 360 CDARG 41 -10.8556.190 47.675 1.00 14.51 ATOM 361 NEARG 41 -10.7496.723 46.321 1.00 13.81 20 ATOM 362 HEARG 41 -9.8596.768 45.924 1.00 0.00 ATOM 363 CZARG 41 -11.7747.178 45.612 1.00 16.54 ATOM 364 NHlARG 41 -12.9967.177 46.121 1.00 18.89 ATOM 365 HHllARG 41 -13.1616.844 47.050 1.00 0.00 ATOM 366 HH12ARG 41 -13.7607.526 45.579 1.00 0.00 25 ATOM 367 NH2ARG 41 -11.5827.602 44.373 1.00 21.20 ATOM 368 HH21ARG 41 -10.6667.569 43.973 1.00 0.00 ATOM 369 HH22ARG 41 -12.3557.948 43.842 1.00 0.00 ATOM 370 C ARG 41 -11.6031.636 45.846 1.00 13.35 ATOM 371 O ARG 41 -12.6721.203 46.274 1.00 14.24 3 0 ATOM 372 N SER 42 -11.210 1.472 44.589 1.00 14.81 ATOM 373 H SER g2 -10.3621.815 44.255 1.00 0.00 ATOM 374 CA SER 42 -12.0320.738 43.637 1.00 15.10 ATOM 375 CB SER 42 -12.4711.660 42.496 1.00 16.52 ATOM 376 OG SER 42 -11.3572.145 41.768 1.00 17.93 35 ATOM 377 HG SER 42 -11.7152.592 40.982 1.00 0.00 ATOM 378 C SER g2 -11.298-0.476 43.080 1.00 15.55 ATOM 379 O SER 42 --10.080--0.598 43.220 1.00 16.20 ATOM 380 N LEU 43 -12.054-1.394 42.g90 1.00 15.52 ATOM 381 H LEU 43 -13.012-1.234 42.420 1.00 0.00 SUE~STITUTE ~ RU~E 2~i) CA 02226963 l998-02-l2 WO 97/08300 PCTrUS96/13918 ATOM 382 CA LEU43-11.484 -2.600 41.904 1.00 16.45 ATOM 383 CB LEU43-12.504 -3.741 41.923 1.00 19.56 ATOM 384 CG LEU43-12.877 -4.324 43.285 1.00 21.50 ATOM 385 CDl LEU43 -13.998 -5.333 43.111 1.00 22.99 r 5 ATOM 386CD2 LEU 43 -11.661 -4.976 43.916 1.00 21.68 ATOM 387 C LEU43-11.064 -2.319 40.470 1.00 15.54 ATOM 388 O LEU43-11.874 -1.871 39.657 1.00 16.36 ATOM 38g N GLY44-9.786 -2.542 40.184 1.00 15.64 ATOM 390 H GLY44-9.170 -2.822 40.896 1.00 0.00 ATOM 391 CAGLY 44 -9.267 -2.324 38.846 1.00 16.00 ATOM 392 C GLY44-9.138 -0.875 38.411 1.00 15.01 ATOM 393 O GLY44-8.965 -0.602 37 222 1.00 16.12 ATOM 394 N GLY45-9.188 0.048 39.368 1.00 12.81 ATOM 395 H GLY45-9.242 -0.234 40.305 1.00 0.00 ~5 ATOM 396 CAGLY 45 -9.075 1.459 39.044 1.00 10.47 ATOM 397 C GLY45-7.666 1.983 39.226 1.00 9.12 ATOM 398 O GLY45-6.795 1.292 39.766 1.00 9.20 ATOM 399 N TYR46-7.443 3.220 38.800 1.00 9.58 ATOM 400 H TYR46-8.185 3.734 38.409 1.00 0.00 ATOM 401 CATYR 46 -6.137 3.859 38.914 1.00 10.00 ATOM 402 CB TYR46-5.426 3.889 37.548 1.00 10.79 ATOM 403 CG TYR46-5.110 2.528 36.977 1.00 12 05 ATOM 404 CDl TYR46 -4.019 1.793 37.440 1.00 11.46 ATOM 405 CEl TYR46 -3.758 0.514 36.960 ;.00 10.52 ATOM 406CD2 TYR 46 -5.931 1.952 36.010 1.20 13.57 ATOM 407 CE2 TYR46 -5.678 0 674 35.525 1.00 13.97 ATOM 408 CZ TYR46-4.592 -0.037 36.007 1.00 14.16 ATOM 409 OH TYR46-4.362 -1.311 35.554 1.00 15.79 ATOM 410 HH TYR46-5.246 -1.670 35.351 1.00 0.00 ATOM 411 CTYR 46 -6.340 5.290 39.376 1.00 9.80 ATOM 412 O TYR46-7.472 5.747 39.525 1.00 9.96 ATOM 413 N VAL47-5.243 5.967 39.679 1.00 9.60 ATOM gl4 H VAL47-4.355 5.549 39.641 1.00 0.00 ATOM 415 CA VAL 47 -5.298 7.365 40.057 1.00 9.96 ATOM 416CB VAL 47 -5.092 7.619 41.573 1.00 9.82 ATOM 417 CGl VAL47 -5.205 9.113 41.861 1.00 7.41 ATOM 418 CG2 VAL47 -6.117 6.867 42.390 1.00 10.33 ATOM 419 C VAL 47 -4.180 8.045 39.286 1.00 8.75 ATOM 420 O VAL 47 -3.044 7.561 39.261 1.00 6.17 ~JBSTITUT~ ~HE~ ~RULE 2~i) W O 97/08300 PCT~US96/13918 ATOM 421 N LEU48-4.536 9.117 38 590 1.00 9.67 ATOM 422 H LEU48-5.470 9.398 38.5gl 1 00 0.00 ATOM 423 CA LEU48-3.585 9.907 37.827 1.00 10.81 ATOM 424 CB LEU48-4.275 10.520 36.604 1.00 14.82 ATOM 425 CGLEU 48 -3.499 10.808 35.312 1.00 18.26 ATOM 426 CDl LEU 48 -4 357 11.691 34.420 1.00 19.66 ATOM 427 CD2 LEU 48 -2.178 11.482 35.582 1.00 16.76 ATOM 428 C LEU48-3.174 11 022 38.786 1.00 9.47 ATOM 429 O LEU48-4.020 11 754 39.302 1.00 9.86 ATOM 430 N SER 49 -1.888 11.119 39.064 1.00 8.65 ATOM 431 H SER49-1.257 10.496 38.640 1.00 0.00 ATOM 432 CA SER49-1.386 12 145 39 956 1.00 12.04 ATOM 433 CB SER49-0.590 11.479 41.084 1.00 13.48 ATOM 434 OG SER49-0.103 12 428 42.009 1.00 30.10 ATOM 435 HGSER 49 0.614 12.893 41.557 1.00 0.00 ATOM 436 C SER49-0.510 13.088 39.125 1.00 10.25 ATOM 437 O SER490.481 12.655 38.537 1.00 11.37 ATOM 438 N LEU50-0.888 14.361 39.040 1.00 12.50 ATOM 439 H LEU50-1.689 14.672 39 504 1.00 0.00 ATOM 440 CALEU 50 -0.114 15.319 38.252 1.00 13.14 ATOM 441 CB LEU50-0.803 15.591 36.906 1.00 14.83 ATOM 442 CG LEU50-2.188 16.241 36.861 1.00 18.60 ATOM 443 CDl LEU 50 -2.066 17.749 36.713 1.00 18.66 ATOM 444 CD2 LEU 50 -2.959 15.691 35.681 1.00 22.06 ATOM 445C LEU50 0.181 16.629 38.973 1.00 14.34 ATOM 446 O LEU 50 -0.481 16.982 39.951 1.00 14.49 ATOM 447 N VAL 51 1.190 17.339 38.481 1.00 13.90 ATOM 448 H VAL 51 1.680 17.006 37.698 1.00 0.00 ATOM 449 CA VAL Sl 1.591 18.615 39.052 1.00 14.39 ATOM 450CB VAL51 3.124 18.688 39.277 1.00 13.58 ATOM 451 CGl VAL 51 3.512 20.051 39.833 1.00 12.21 ATOM 452 CG2 VAL 51 3.581 17.592 40.218 1.00 12.91 ATOM 453 C VAL511.218 19.757 38.111 1.00 16.09 ATOM 454 O VAL511.329 19.637 36.890 1.00 17.31 ATOM 455 N HIS 52 0.755 20.857 38.688 1.00 17.95 ATOM 456 ~ HIS520.631 20.876 39.664 1.00 0.00 ATOM 457 CA HIS520.417 22.050 37.930 1.00 19.66 ATOM 458 CB HIS52-0.950 21.947 37.264 1.00 21.46 ATOM 459 CG HIS52-1.278 23.126 36.400 1.00 25.94 SU~STITUTE S~ RI~E 25) CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATOM 460 CD2 HIS 52 -2.324 23.985 36.417 1.00 26.46 ATOM 461 NDl HIS 52 -0.447 23.555 35.385 1.00 27.09 ATOM 462 HDl HIS 52 0.379 23.112 35.092 1.00 0.00 ATOM 463 CEl HIS 52 -0.965 24.630 34.818 1.00 24.62 5 ATOM 464 NE2 HIS 52 -2.105 24.911 35.426 1.00 27.73 ATOM 465 HE2 HIS 52 -2.713 25.644 35.178 1.00 0.00 ATOM 466 C HIS 52 0.429 23.217 38.899 1.00 21.92 ATOM 467 O HIS 52 -0.241 23.176 39.926 1.00 20.84 ATOM 468 N ASP 53 1.245 24.221 38.592 1.00 26.19 ATOM 469H ASP 53 1.857 24.140 37.845 1.00 0.00 ATOM 470 CA ASP 53 1.374 25.421 39.415 1.00 26.69 ATOM 471 CB ASP 53 0.043 26.185 39.499 1.00 30.60 ATOM 472 CG ASP 53 -0.369 26.803 38.176 1.00 37.06 ATOM 473 ODl ASP 53 0.465 26.855 37.246 1.00 41.34 ATOM 474OD2 ASP 53 -1.537 27.243 38.070 1.00 39.93 ATOM 475 C ASP 53 1.859 25.075 40.811 1.00 25.96 ATOM 476 O ASP 53 1.337 25.589 41.802 1.00 27.13 ATOM 477 N VAL 54 2.844 24.181 40.876 1.00 24.42 ATOM 478 H VAL 54 3.192 23.818 40.037 1.00 0.00 ATOM 479CA VAL 54 3.441 23.735 42.136 l.Q0 25.36 ATOM 480 CB VAL 54 4.218 24.896 42.834 1.00 25.58 ATOM 481 CGl VAL 54 5.100 24.360 43.949 1.00 27.09 ATOM 482 CG2 VAL 54 5.077 25.639 41.816 1.00 30.24 ATOM 483 C VAL 54 2.395 23.130 43.083 1.00 24.41 ATOM 484O VAL 54 2.551 23.140 44.310 1.00 24.03 ATOM 485 N ARG 55 1.338 22.576 42 500 1 00 22.42 ATOM 486 H ARG 55 1.250 22.563 41.527 1.00 0.00 ATOM 487 CA ARG 55 0.273 21.957 43.272 1.00 23.20 ATOM 488 CB ARG55 -0.956 22.865 43.334 1.00 28.27 ATOM 489 CGARG 55 -0.807 23.981 44.356 1.00 39.63 ATOM 490 CD ARG55 -2.051 24.848 44.467 1.00 48.23 ATOM 491 NE ARG55 -1.954 25.777 45.595 1.00 56.45 ATOM 492 HE ARG55 -2.462 25.560 46.404 1.00 0.00 ATOM 493 CZ ARG55 -1.222 26.891 45.602 1.00 60.28 ATOM 494NHl ARG 55 -0.509 27.240 44.535 1.00 63.46 ATOM 495 HHll ARG55 -0.514 26.661 43.716 1 00 0.00 ATOM 496 HH12 ARG55 = 0.028 28.083 44.550 1.00 0.00 ATOM 497 NH2 ARG 55 -1.192 27.657 46.686 1.00 60.77 ATOM 498 HH21 ARG55 -1.725 27.400 47.491 1 00 0.00 - 8~ -SUBST~TUTE S~E~ t~ULE 2~i) CA 02226963 l998-02-l2 W O 97/083~0 P ~ GUS96/13918 ATOM 499 HH22 ARG 55 -0.647 28.494 46.685 1.00 0.00 ATOM 500 C ARG 55 -0.084 20.600 42.694 1.00 18.98 ATOM 501 O ARG 55 0.024 20.377 41.488 1.00 18.12 ATOM 502 N PHE 56 -0.499 19.692 43.567 1.00 17.36 ATOM 503 H PHE 56 -0.588 19.942 44.514 1.00 0.00 ATOM 504 CA PHE 56 -0.854 18.341 43.164 1.00 15.57 ATOM 505 CB PHE 56 -0.498 17.347 44.270 1.00 14.98 ATOM 506 CG PHE 56 0.950 17.344 44.634 1.00 12.04 ATOM 507 CDl PHE 56 : 1.371 17.844 45.862 1.00 11.96 ATOM 508 CD2 PHE 56 1.897 16.847 43.749 1.00 13.48 ATOM 509 CEl PHE 56 2.714 17.852 46.203 1.00 13.52 ATOM 510 CE2 PHE 56 3.245 16.850 44.079 1.00 12.78 ATOM 511 CZ PHE 56 3.654 17.353 45.310 1.00 14.92 ATOM 512 C PHE 56 -2.320 18.183 42.824 1.00 14.57 ATOM 513 O PHE 56 -3.192 18.802 43.439 1.00 16.84 ATOM 514 N HIS 57 -2.586 17.340 41.838 1.00 12.74 ATOM 515 H HIS 57 -1.838 16.904 41.364 1.00 0.00 ATOM 516 CA HIS 57 -3.942 17.049 41.412 1.00 13.90 ATOM 517 CB HIS 57 -4.248 17.741 40.080 1.00 17.35 ATOM 518CG HIS 57 -4.144 19.235 40.145 1.00 22.06 ATOM 519 CD2 HIS 57 -3.097 20.066 39.924 1.00 21.97 ATOM 520 NDl HIS 57 -5.198 20.041 40.523 1.00 23.17 ATOM 521 HDl HIS 57 -6.107 19.754 40.750 1.00 0.00 ATOM 522 CEl HIS 57 -4.802 21.303 40.536 1.00 23.20 ATOM 523NE2 HIS 57 -3.532 21.344 40.178 1.00 22.64 ATOM 524 HE2 HIS 57 -2.966 22.151 40.144 1.00 0.00 ATOM 525 C HIS57 -4.014 15.533 41.294 1.00 11.98 ATOM 526 O HIS57 -3.099 14.901 40.765 1.00 11.55 ATOM 527 N HIS58 -5.058 14.944 41.867 1.00 10.33 ATOM 528H HIS 58 -5.780 15.455 42.288 1.00 0.00 ATOM 529 CA HIS 58 -5.217 13.499 41.848 1.00 8.93 ATOM 530 CB HIS 58 -5.063 12.945 43.266 1.00 5.64 ATOM 531 CG HIS 58 -3.765 13.316 43.913 1.00 8.00 ATOM 532 CD2 HIS 58 -3.449 14.312 44.772 1.00 5.61 ATOM 533NDl HIS 58 -2.591 12.636 43.667 1.00 6.85 ATOM 534 HDl HIS 58 -2.468 11.854 43.085 1.00 0.00 ATOM 535 CEl HIS 58 -1.609 13.197 44.349 1.00 6.57 ATOM 536 NE2 HIS 58 -2.102 14.217 45.024 1.00 6.83 ATOM 537 HE2 HIS 58 -1.588 14.836 45.576 1.00 0.00 SUBST~TUTE ~}tEE~ ~RULE ~

CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATOM 538 C HIS58-6.570 13.158 41.267 1.00 9.13 ATOM 539 o HIS58-7.603 13.507 41.831 1.00 12.23 ATOM 540 N PHE59-6.551 12.519 40.107 1.00 9.S7 ATOM 541 H PHE59-5.709 12.287 39.679 1.00 0.00 ATOM 542 CAPHE 59 -7.769 12.150 39.408 1.00 12.32 ATOM 543 CB PHE59-7.703 12.621 37.948 1.00 11.96 ATOM 544 CG PHE59-7.623 14.109 37.789 1.00 13.50 ATOM 545 CDl PHE 59 -6.397 14.762 37.851 1.00 12.51 ATOM 546 CD2 PHE 59 -8.777 14.861 37.599 1.00 13.89 ATOM 547CEl PHE 59 -6.318 16.146 37.731 1.00 17.22 ATOM 548 CE2 PHE 59 -8.713 16.248 37.478 1.00 17.22 ATOM 549 CZ PHE59-7.481 16.893 37.544 1.00 17.16 ATOM 550 C PHE59-8.021 10.650 39.427 1.00 13.06 ATOM 551 O PHE59-7.232 9.868 38.893 1.00 12.71 1~ ATOM 552 N PRO 60 -9.108 10.220 40.075 1.00 14.37 ATOM 553 CD PRO60-10.034 10.958 40.953 i.00 13.14 ATOM 554 CA PRO60-9.374 8.782 40.094 1.00 15.39 ATOM 555 CB PRO60-10.420 8.640 41.206 1.00 15.06 ATOM 556 CG PRO60-11.125 9.952 41.195 1.00 16.60 ATOM 557 C PRO 60 -9.881 8.310 38.719 1.00 15.44 ATOM 558 O PRO60-10.659 9.000 38.051 1.00 16.09 ATOM 559 N ILE61-9.355 7.180 38.267 1.00 15.98 ATOM 560 H ILE61-8.723 6.742 38.838 1.00 0.00 ATOM 561 CA ILE61-9.724 6.582 36.986 1.00 15.23 2~ ATOM 562 CBILE 61 -8.472 6.222 36.164 1.00 14.68 ATOM 563 CG2 ILE 61 -8.868 5.536 34.856 1.00 15.39 ATOM 564 CGl ILE 61 -7.655 7.482 35.886 1.00 13.45 ATOM 565 CD ILE61-6.296 7.211 35 307 1.00 12.44 ATOM 566 C ILE61-10.497 5.309 37.308 1.00 17.07 ATOM 567 O ILE 61 -9-978 4.413 37.984 1.00 16.51 ATOM 568 N GLU62-11.739 5.240 36.845 1.00 19.22 ATOM 569 H GLU62-12.099 5.968 36.290 1.00 0.00 ATOM 570 CA GLU62-12.582 4.084 37.112 1.00 23.18 ATOM 571 CB GLU62-13.981 4.541 37.538 1.00 30.15 3~ ATOM 572 CGGLU 62 -14.906 3.407 37.975 1.00 39.45 ATOM 573 CD GLU62-16.305 3.882 38.332 1 00 44.10 ATOM 574 OEl GLU 62 -16.458 4.548 39.381 1.00 48.25 ATOM 57S OE2 GLU 62 -17.251 3.579 37.569 1.00 44.87 ATOM 576 C GLU 62 -12.688 3.162 35.910 1.00 23.10 SUBST~TUTE ~ (RULE 2~i) -W O 97/08300 PCT~US96/13918 ATOM 577 G GLU62-12.709 3.619 34.766 1.00 21.60 ATOM 578 N ARG63-12.721 1.862 36.180 1.00 24.50 ATOM 579 H ARG63-12.684 1.558 37.114 1.00 0.00 ATOM 580 CA ARG 63-12.848 0.861 35.135 1.00 28.70 ATOM 581 CB ARG 63 -12.152 -0.437 35.547 1.00 31.42 ATOM 582 CG ARG 63 -12.177 -1.521 34 477 1.00 36.91 ATOM 583 CD ARG 63 -11.909 -2.885 35.079 1.00 40.57 ATOM 584 NE ARG 63 -12.927 -3.223 36.072 1.00 46.47 ATOM 585 HE ARG 63 -13.820 -2.825 35.972 1.00 0.00 ATOM 586CZ ARG63 -12.730 -4.030 37.111 1.00 47.98 ATOM 587 NHl ARG 63 -11.546 -4.600 37.306 1.00 48.36 ATOM 588 HHll ARG63-10.792 -4.431 36.671 1.00 0.00 ATOM 589 HH12 ARG63-11.407 -5.204 38.089 1.00 0.00 ATOM 590 NH2 ARG 63-13.714 -4.247 37.975 1.00 47.23 ATOM 591 HH21 ARG 63 :-14.605 -3.810 37.847 1.00 0.00 ATOM 592 HH22 ARG63-13.559 -4.855 38.754 1.00 0.00 ATOM 593 C ARG63-14.332 0.590 34.944 1.00 28.52 ATOM 594 O ARG63-15.002 0.123 35.867 1.00 29.96 ATOM 595 N GLN64-14.851 0.931 33.771 1.00 29.71 ATOM 596 H GLN 64 -14.266 1.330 33.103 1.00 0.00 ATOM 597 CA GLN64-16.257 0.706 33.464 1.00 33.43 ATOM 5g8 CB GLN64-16.672 1.454 32.196 1.00 36.64 ATOM 599 CG GLN64-17.287 2.819 32.432 1.00 39.67 ATOM 600 CD GLN64-16.263 3.870 32.775 1.00 40.97 ATOM 601OEl GLN 64 -16.145 4.290 33.929 1.00 42.60 ATOM 602 NE2 GLN 64 -15.511 4.307 31.774 1.00 41.46 ATOM 603 HE21 GLN64-15.640 3.928 30.878 1.00 0.00 ATOM 604 HE22 GLN64-14.861 4.992 32.008 1.00 0.00 ATOM 605 C GLN64-16.545 -0.778 33.279 1.00 35.62 ATOM 606 O GLN 64 -15.648 -1.570 32.982 1.00 35.48 ATOM 607 N LEU65-17.816 -1.133 33.412 1.00 38.38 ATOM 608 H LEU65-18.450 -0.436 33.661 1.00 0.00 ATOM 609 CA LEU65-18.268 -2.510 33.264 1.00 42.81 ATOM 610 CB LEU65-19.792 -2.583 33.418 1.00 47.54 ATOM 611 CG LEU 65 -20.691 -1.926 32.359 1.00 51.72 ATOM 612 CDl LEU 65 -22.145 -2.279 32 653 1.00 54.58 ATOM 613 CD2 LEU 65 -20.501 -0.410 32.318 1.00 51.28 ATOM 614 C LEU 65 -17.849 -3.137 31.934 1.00 43.23 ATOM 615 O LEU 65 -17.547 -4.327 31.873 1.00 44.38 SUB5mUTE S~E~ ~RULE 2~;) CA 02226963 l998-02-l2 W 0 97/08300 PCT~US96/13918 ATOM 616 N ASN 66 -17.801 -2.329 30.879 1.00 42.92 ATOM 617 H ASN 66 -18.004 -1.382 30.987 1.00 0.00 ATOM 618 CA ASN 66 -17.421 -2.825 29.559 1.00 42.31 ATOM 619 CB ASN 66 -18.052 -1.973 28.456 1.00 45.73 ATOM 620 CG ASN 66 -17.404 -0.612 28.327 1.00 48.82 ATOM 621 ODl ASN 66 -16.998 -0.009 29.321 1.00 52.33 ATOM 622 ND2 ASN 66 -17.292 -0.124 27.100 1.00 52.00 ATOM 623 HD21 ASN66-17.611 -0.677 26.357 1.00 0.00 ATOM 624 HD22 ASN66-16.904 0.765 26.986 1.00 0.00 ATOM 625 C ASN 66 -15.909 -2.916 29.346 1.00 41.37 ATOM 626 O ASN 66 -15.444 -3.072 28.215 1.00 42.54 ATOM 627 N GLY 67 -15.144 -2.788 30.425 1.00 39.06 ATOM 628 H GLY 67 -15.525 -2.652 31.316 1.00 0.00 ATOM 629 CA GLY 67 -13.700 -2.884 30.321 1.00 35.20 ATOM 630 CGLY 67 -12.924 -1.642 29.927 1.00 31.27 ATOM 631 OGLY 67 -11.718 -1.728 29.706 1.00 32.16 ATOM 632 NTHR 68 -13.594 -0.501 29.801 1.00 28.74 ATOM 633 HTHR 68 -14.552 -0.492 29.964 1.00 0.00 ATOM 634 CATHR 68 -12.897 0.732 29.450 1.00 26.00 ATOM 635 CBTHR 68 -13.738 1.639 28.531 1.00 26.73 ATOM 636 OGl THR 68 -14.997 1.940 29.149 1.00 28.49 ATOM 637 HGl THR 68 -15.528 1.140 29.220 1.00 0.00 ATOM 638 CG2 THR 68 -13.962 0.970 27.186 1.00 27.12 ATOM 639 CTHR 68 -12.536 1.480 30.731 1.00 24.27 ATOM 640 OTHR 68 -12.941 1.075 31.821 1.00 23.18 ATOM 641 NTYR 69 -11.769 2.558 30.600 1.00 22.13 ATOM 642 HTYR 69 -11.499 2.867 29.726 1.00 0.00 ATOM 643 CATYR 69 -11.345 3.355 31.744 1.00 20.20 ATOM 644 CBTYR 69 -9.845 3.184 31.984 1.00 17.55 ATOM 645 CGTYR 69 -9.452 1.783 32.360 1.00 15.74 ATOM 646 CDl TYR69 -9.286 0.801 31.386 1.00 16.67 ATOM 647 CEl TYR69 -8.936 -0.501 31.731 1.00 18.61 ATOM 648 CD2 TYR69 -9.256 1.433 33.693 1.00 15.77 ATOM 649 CE2 TYR69 -8.905 0.138 34.050 1.00 17.24 ATOM 650 CZ TYR 69 -8.745 -0.824 33.065 1.00 18.54 ATOM 651 OH TYR 69 -8.389 -2.102 33.417 1.00 19.33 ATOM 652 HH TYR69-8.332 -2.618 32.605 1.00 0.00 9 ATOM 653 C TYR69-11.646 4.818 31.489 1.00 20.07 ATOM 654 O TYR69-11.509 5.296 30.360 1.00 19.19 SUBSTITUTE ~j~F~ tRULE 2fi~

CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 655 N ALA 70 -12.038 5 538 32.534 1.00 20 74 ATOM 656 H ALA 70 -12.144 5.122 33.421 1.00 0.00 ATOM 657 CA ALA 70 -12.346 6.951 32.380 1.00 22.43 ATOM 658 CB ALA70 -13.703 7.123 31.701 1.00 20.46 5 ATOM 659 C ALA70 -12.333 7.727 33.683 1.00 23.77 ATOM 660 O ALA70 -12.569 7.169 34.760 1.00 23.69 ATOM 661 N ILE71 -11.975 9.001 33.573 1.00 24.06 ATOM 662 H ILE71 -11.708 9.364 32.704 1.00 0.00 ATOM 663 CA ILE71 -11.982 9.909 34.704 1.00 24.49 ATOM 664 CBILE 71 -11.079 11.134 34.450 1.00 23.76 ATOM 665 CG2 ILE 71 -11.206 12.132 35.593 1.00 23.11 ATON 666 CGl ILE 71 -9.623 10.691 34.285 1.00 22.21 ATOM 667 CD ILE71 -8.669 11.832 34.009 1.00 18.51 ATOM 668 C ILE71 -13.445 10.346 34.719 1.00 26.14 ATOM 669 O ILE 71 -14.057 10.481 33.659 1.00 23.83 ATOM 670 N ALA72 -14.016 10.525 35.904 1.00 29.31 ATOM 671 H ALA72 -13.481 10.391 36.712 1.00 0.00 ATOM 672 CA ALA72 -15.417 10.922 36.026 1.00 33.39 ATOM 673 CB ALA72 -15.759 11.228 37.480 1.00 33.93 ATOM 674 C ALA 72 -15.764 12.113 35.138 1.00 34.98 ATOM 675 O ALA72 -15.242 13.212 35.324 1.00 34.89 ATOM 676 N GLY73 -16.628 11.874 34.158 1.00 36.34 ATOM 677 H GLY73 -16.960 10.963 34.030 1 00 0.00 ATOM 678 CA GLY73 -17.044 12.932 33.254 1.00 36.52 ATOM 679 C GLY 73 -16.171 13.105 32.025 1.00 35.63 ATOM 680 O GLY73 -16.375 14.032 31.239 1.00 37.15 ATOM 681 N GLY74 -15.201 12.215 31.852 1.00 33.13 ATOM 682 H GLY74 -15.099 11.459 32.459 1.00 0.00 ATOM 683 CA GLY 74 -14.320 12.301 30.706 1.00 32.37 ATOM 684 C GLY 74 -14.561 11.132 29.782 1.00 34.04 ATOM 685 O GLY74 -15.276 10.191 30.131 1.00 34.17 ATOM 686 N LYS75 -13.954 11.178 28.604 1.00 34.83 ATOM 687 H LYS75 -13.391 11.953 28.407 1.00 0.00 ATOM 688 CA LYS75 -14.112 10.109 27.630 1.00 35.85 ATOM 689 CBLYS 75 -13.575 10.550 26.266 1.00 40.25 ATOM 690 CG LYS75 -14.604 11.333 25.454 1 00 48 14 ATOM 691 CD LYS75 -13.992 12.101 24.290 1.00 53.33 ATOM 692 CE LYS75 -13.261 13.349 24 773 1.00 57.38 ATOM 693 NZ LYS75 -12.808 14.218 23.647 1.00 59.74 SUBSTITUTE ~HE}~ (RULE 26~

CA 02226963 l998-02-l2 WO 97/~8300 PCTAUS96/13918 ATOM 694 HZl LYS 75 -13.632 14.560 23.114 1.00 0.00 ATOM 695 HZ2 LYS 75 -12.192 13.677 23.006 i.00 0.00 ATOM 696 HZ3 LYS 75 -12.282 15.027 24.027 1.00 0.00 ATOM 697 C LYS 75 -13.461 8.807 28.082 1.00 34.24 5 ATOM 698 O LYS 75 -12.416 8.812 28.741 1.00 33.16 ATOM 699 N ALA 76 -14.114 7.695 27.767 '.00 31.87 ATOM 700 H ALA 76 -14.954 7.758 27.270 1.00 0.00 ATOM 701 CA ALA 76 -13.606 6.380 28.126 1.00 31.22 ATOM 702 CB ALA76-14.719 5.342 28.061 1.00 30.23 1 0 ATOM 703 CALA 76 -12.479 6.005 27.179 1.00 28.77 ATOM 704 O A ~A 76 -12.464 6.419 26.022 '.00 30.26 ATOM 705 N HIS77-11.525 5.237 27.683 '.00 27.21 ATOM 706 H HIS77-11.587 4.898 28.592 1.00 o oo ATOM 707 CA HIS77-10.389 4.800 26.893 ; 00 27.71 1 5 ATOM 708 CBHIS 77 -9.130 5.559 27.313 1.00 27.15 ATOM 709 CG HIS77-9.230 7.040 27.123 1.00 28.63 ATOM 710 CD2 HIS 77 -8.946 7.826 26.057 1.00 27.68 ATOM 711 NDl HIS 77 -9.699 7.888 28.105 1.00 29.85 ATOM 712 HDl HIS 77 -10.027 7.624 28.994 1.00 0.00 2 0 ATOM 713CEl HIS 77 -9.699 9.130 27.652 1.00 28.48 ATOM 714 NE2 HIS 77 -9.248 9.118 26.412 1.00 29.23 ATOM 715 HE2 HIS 77 -9.158 9.891 25.818 1.00 0.00 ATOM 716 C HIS77-10.236 3.302 27.118 1.00 28.88 ATOM 717 O HIS77-10.611 2.786 28.169 ;.00 27.46 25 ATOM 718 N CYS78-9.703 2.599 26.128 1 00 29.61 ATOM 719 H CYS78-9.406 3.050 25.306 1.00 0.00 ATOM 720 CA CYS78-9.542 1.153 26.224 1.00 30.03 ATOM 721 CB CYS78-9.278 0.566 24.841 I.00 34.14 ATOM 722 SG CYS78-8.119 1.534 23.883 1.00 44.93 30 ATOM 723 C CYS78-8.489 0.668 27.211 1.00 25.84 ATOM 724 O CYS78-8.370 -0.530 27.443 1.00 26.98 ATOM 725 N GLY79-7.733 1.590 27.797 1.00 23.67 ATOM 726 H GLY79-7.837 2.542 27.613 1.00 0.00 ATOM 727 CA GLY79-6.714 1.202 28.754 1.00 18.52 35 ATOM 728 C GLY79-6.019 2.397 29.371 1.00 18.97 ATOM 729 O GLY79-6.128 3.513 28.854 1.00 18.14 ATOM 730 N PRO80-5.281 2.194 30.473 1.00 18.06 ATOM 731 CD PRO80-5.090 0.904 31.157 1.00 18.29 ATOM 732 CA PRO80-4.559 3.264 31.165 1.00 17.93 SUBSTITUTE !i~E}~ tRULE 2~i) -ATOM 733 CB PRO80 -3.9312.536 32.357 1.00 20.63 ATOM 734 CG PRO80 -3.7911.121 31.873 1.00 19.63 ATOM 735 C PRO80 -3.5103.963 30.289 1.00 17.24 ATOM 736 O PRO80 -3.4085.190 30.300 1.00 14.92 ATOM 737 N ALA81 -2.7573.192 29.510 1.00 15.32 ATOM 738 H ALA81 -2.8642.214 29.533 1.00 0.00 ATOM 739 CA ALA81 -1.7423.776 28.635 1.00 15.99 ATOM 740 CB ALA81 -0.9g52.682 27.941 1.00 15.92 ATOM 741 C ALA81 --2.3674.713 27.600 1.00 16.17 1 0 ATOM 742 O ALA81 -1.8625.810 27.363 1.00 15.48 ATOM 743 N GLU82 -3.4814.284 27.009 1.00 18.46 ATOM 744 H GLU82 -3.8473.436 27.305 1.00 0.00 ATOM 745 CA GLU82 --4.1885.066 25.994 1.00 18.23 ATOM 746 CB GLU82 -5.2984.238 25.334 1.00 20.10 1 5 ATOM 747 CG GLU82 -4.8083.159 24.372 1.00 25.98 ATOM 748 CD GLU82 -4.4891.824 25.043 1.00 30.34 ATOM 749 OEl GLU 82 --4.351 0.817 24.317 1.00 35.16 ATOM 750 OE2 GLU 82 --4.382 1.763 26.284 1.00 30.98 ATOM 751 C GLU82 -4.7806.333 26.591 1.00 17.53 20 ATOM 752 O GLU82 --4.8557.368 25.928 1.00 15.66 ATOM 753 N LEU83 -5.1996.244 27.846 1.00 16.88 ATOM 754 H LEU83 -5.1365.386 28.316 1.00 0.00 ATOM 755 CA LEU83 -5.7697.383 28.548 1.00 17.11 ATOM 756 CB LEU83 -6.3596.929 29.888 1.00 17.19 25 ATOM 757 CG LEU83 -6.9737.966 30.825 1.00 16.72 ATOM 758 CDl LEU 83 -8.124 7.338 31.597 1.00 16.47 ATOM 759 CD2 LEU 83 -5.907 8.526 31.766 1.00 15.85 ATOM 760 C LEU83 -4.6948.454 28.742 1.00 17.05 ATOM 761 O LEU83 -4.9279.632 28.462 1.00 17.29 30 ATOM 762 N CYS84 -3.5068.039 29.167 1.00 16.35 ATOM 763 H CYS84 -3.3727.082 29.354 1.00 0.00 ATOM 764 CA CYS84 --2.4128.979 29.377 1.00 17.56 ATOM 765 CB CYS84 -1.2658.308 30.129 1.00 16.45 ATOM 766 SG CYS84 --1.6637.902 31.846 1.00 14.67 35 ATOM 767 C CYS84 --1.9259.578 28.060 1.00 20.60 ATOM 768 O CYS84 -1.58610.761 27.999 1.00 20.51 ATOM 769 N GLU85 -1.9118.766 27.005 1.00 22.93 ATOM 770 H GLU85 -2.1907.833 27.119 1.00 0.00 ATOM 771 CA GLU85 -1.4869.218 25.680 1.00 23.75 SU8STIT~TE S}~E~ (RULE 2~i) CA 02226963 l998-02-l2 ATOM 772 CB GLU85-1.420 8.034 24.703 1.00 27.58 ATOM 773 CG GLU8S-0.364 6.990 25.079 1.00 36.56 ATOM 774 CD GLU8S-0.28S S.806 24.11S 1.00 40.46 ATOM 775 OEl GLU 8S -1.16S 4.919 24.169 1.00 38.44 ATOM 776GE2 GLU 85 0.681 5.7S1 23.319 1.00 46.1S
ATOM 777 C GLU85-2.439 10.298 2S.164 1.00 23.S2 ATOM 778 O GLU8S-2.002 11.304 24.602 1.00 23.99 ATOM 779 N PHE86-3.73S 10.109 25.404 1 00 23.07 ATOM 780 H PHE86-4.026 9.296 2S.868 1.00 0.00 ATOM 781 CAPHE 86 -4.7S8 11.063 24.981 1.00 22.06 ATOM 782 CB PHE86-6.1S8 10.499 2S.24S 1.00 23.30 ATOM 783 CG PHE86-7.265 11.504 2S.064 1.00 2S.88 ATOM 784 CDl PHE 86 -7.693 11.867 23.795 1.00 28.1S
ATOM 785 CD2 PHE 86 -7.874 12.093 26.169 1.00 27.77 ATOM 786CEl PHE 86 -8.713 12.803 23.628 1.00 30.93 ATOM 787 CE2 PHE 86 -8.892 13.029 26.015 1.00 27.23 ATOM 788 CZ PHE86-9.314 13.385 24.742 1.00 30.08 ATOM 789 C PHE86-4.609 12.408 25.679 1.00 22.18 ATOM 790 O PHE86-4.657 13.457 25.032 1.00 22.09 ATOM 791 N TYR 87 -4.438 12.378 26.998 1.00 20.74 ATOM 792 H TYR87-4.421 ll.S16 27.464 1.00 0.00 ATOM 793 CA TYR87-4.291 13.604 27.776 1.00 20.26 ATOM 794 CB TYR87-4.S62 13.340 29.250 1.00 17.6S
ATOM 795 CG TYR87-6.021 13.088 29.531 1.00 19.72 ATOM 796CDl TYR 87 -6.4S5 11.844 29.967 1.00 20.21 ATOM 797 CEl TYR 87 -7.798 11.603 30 242 1.00 25.37 ATOM 798 CD2 TYR 87 -6.970 14.099 29.371 1.00 19.83 ATOM 799 CE2 TYR 87 -8.320 13.873 29.644 1.00 21.99 ATOM 800 CZ TYR87-8.727 12.618 30.081 1.00 25.65 ATOM 801 OHTYR 87 -10.052 12.356 30.364 1.00 25.64 ATOM 802 HH TYR87-10.057 11.542 30.886 1.00 0.00 ATOM 803 c TYR87-2.967 14.337 27.578 1.00 20.79 ATOM 804 O TYR87-2.795 15.458 28.061 1.00 20.79 ATOM 805 N SER88-2.026 13.691 26.895 1.00 24.94 ATOM 806 H SER 88 -2.190 12.769 26.608 1.00 0.00 ATOM 807 CA SER88-0.737 14.305 26.584 1.00 28.11 ATOM 808 CB SER880.268 13.249 26.112 1.00 27.90 ATOM 809 OG SER880.S65 12.303 27.124 1.00 35.96 ATOM 810 HG SER88-0.251 11.986 27.522 1.00 0.00 SUBSTiTUTE S~E~ ~RULE ;~fi) CA 02226963 l998-02-l2 ATOM 811 C SER88 -0.989 15.288 2S.443 1.00 29.72 ATOM 812 O SER88 -0.360 16.344 25.361 1.00 30.51 ATOM 813 N ARG89 -1.917 14.924 24.563 1.00 31.17 ATOM 814 H ARG89 -2.399 14.082 24.692 1.00 0.00 5 ATOM 815 CA ARG 89 -2.265 15.750 23.418 1.00 35.74 ATOM 816 CB ARG 89 -2 712 14.874 22.243 1 00 40.10 ATOM 817 CG ARG 89 -1 582 14 360 21 356 1.00 47 31 ATOM 818 CD ARG 89 -0 637 13.443 22.108 1.00 51 57 ATOM 819 NE ARG 89 0.489 13 018 21 281 1 00 54 95 ATOM 820HE ARG 89 0 313 12.782 20 344 1.00 0.00 ATOM 821 CZ ARG 89 1.742 12.918 21.719 1.00 56.98 ATOM 822 NHl ARG 89 2.039 13.215 22.980 1.00 56.68 ATOM 823 HHll ARG89 1.325 13.519 23.611 1.00 0.00 ATOM 824 HH12 ARG89 2.982 13.141 23.303 1.00 0.00 ATOM 825 NH2 ARG 89 2.700 12.511 20.897 1.00 57.57 ATOM 826 HH21 ARG89 2.477 12.279 19.950 1.00 0.00 ATOM 827 HH22 ARG89 3.642 12.430 21.228 1.00 0.00 ATOM 828 C ARG 89 -3.352 16.762 23.734 1.00 35.85 ATOM 829 ~ ARG89 -3.263 17.924 23.334 1.00 36.15 ATOM 830N ASP 90 -4.375 16.327 24.457 1.00 37.16 ATOM 831 H ASP 90 -4.418 15.403 24.786 1.00 0.00 ATOM 832 CA ASP 90 -5.484 17.206 24.793 1.00 38.14 ATOM 833 CB ASP 90 -6.696 16.820 23.935 1.00 41.72 ATOM 834 CG ASP 90 -7.849 17.796 24.064 1.00 45.64 ATOM 835ODl ASP 90 -9.005 17.364 23.872 1.00 49.81 ATOM 836 OD2 ASP 90 -7.608 18.992 24.342 1.00 47.83 ATOM 837 C ASP90 -5.841 17.147 26.278 1.00 35.95 ATOM 838 O ASP90 -6.216 16.094 26.786 1.00 35.57 ATOM 839 N PRO91 -5.724 18.285 26.992 1.00 35.06 ATOM 840 CDPRO 91 -5.220 19.578 26.497 1.00 34.31 ATOM 841 CA PRO91 -6.040 18.368 28.424 1.00 34.83 ATOM 842 CB PRO91 -5.934 19.865 28.705 1.00 33.84 ATOM 843 CG PRO91 -4.858 20.296 27.778 1.00 35.60 ATOM 844 C PRO91 -7.453 17.855 28.705 1.00 34.95 ATOM 845 O PRO 91 -7.685 17.165 29.695 1.00 34.91 ATOM 846 N ASP92 -8.393 18.245 27.844 1.00 34.68 ATOM 847 H ASP92 -8.121 18.822 27.107 1.00 0.00 ATOM 848 CA ASP 92 -9.796 17.837 27.934 1.00 34.83 ATOM 849 CB ASP 92 -9.980 16.465 27.261 1.00 38.56 SUBSTiTUTE S~EE~ ~RULE 26~

CA 02226963 l998-02-l2 W O 97/~8300 PCTrUS96/13918 ATOM 850 CGASP 92 -11.44116.132 26.973 1.00 43.08 ATOM 851 ODl ASP 92 -11.864 14.990 27.264 1.00 46.42 ATOM 852 oD2 ASP 92 -12.165 17.008 26.452 1.00 46.09 ATOM 853 CASP 92 -10.38017.841 29.358 1.00 33.28 5 ATOM 854 OASP 92 -11.02116.879 29.789 1.00 32.13 ATOM 855 NGLY 93 -10.16518.939 30.078 1 00 32.19 ATOM 856 HGLY 93 -9.64819.684 29.719 1.00 0.00 ATOM 857 CAGLY 93 -10.69119.042 31.428 1.00 30.80 ATOM 858 CGLY 93 -9.64719.125 32.523 1.00 28.16 1 0 ATOM 859 OGLY 93 -9.93219.620 33.614 1.00 29.26 ATOM 860 NLEU 94 -8.45618.600 32.262 1.00 25.58 ATOM 861 HLEU 94 -8.29218.164 31.399 1.00 0.00 ATOM 862 CALEU 94 -7.38018.642 33.244 1.00 25.19 ATOM 863 CBLEU 94 -6.26617.654 32.867 1.00 23.59 1 5 ATOM 864 CGLEU 94 -6.57816.165 32.692 1.00 21.25 ATOM 865 CDl LEU 94 -5.31415.463 32.246 1.00 20.19 ATOM 866 CD2 LEU 94 -7.09715.552 33.978 1.00 20.15 ATOM 867 CLEU 94 --6.81320.064 33.290 1.00 27.14 ATOM 868 OLEU 94 -6.95620.826 32.329 1.00 26.74 ATOM 869 NPRO 95 -6.16020.439 34.407 1.00 27.36 ATOM 870 CDPRO 95 -5.99119.647 35.637 1.00 27.79 ATOM 871 CAPRO 95 -5.57121.774 34.568 1.00 27.68 ATOM 872 CBPRO 95 -5.02521.736 35.999 1.00 28.71 ATOM 873 CGPRO 95 -4.77220.274 36.244 1.00 28.16 2 5 ATOM 874 CPRO 95 -4.47522.088 33.544 1.00 27.92 ATOM 875 OPRO 95 -4.07423.245 33.386 1.00 28.39 ATOM 876 NCYS 96 -3.95321.041 32.912 1.00 28.28 ATOM 877 HCYS 96 -4.24120.128 33.129 1.00 0.00 ATOM 878 CACYS 96 -2.91721.145 31.884 1.00 27.50 ATOM 879 CBCYS 96 -1.59621.666 32.467 1.00 27.76 ATOM 880 SGCYS 96 -0.77520.589 33.668 1.00 30.21 ATOM 881 CCYS 96 -2.72119.754 31.295 1.00 27.05 ATOM 882 OCYS 96 -3.13318.762 31.899 1.00 28.24 ATOM 883 NASN 97 -2.13719.678 30.106 1.00 24.88 ATOM 884 HASN 97 --1.80720.482 29.650 1 00 0.00 ATOM 885 CAASN 97 -1.90318.386 29.473 1.00 24.53 ATOM 886 CBASN 97 -1.60218.556 27.980 1.00 26.26 ATOM 887 CGASN 97 -0.32119.321 27.727 1.00 27.29 ATOM 888 ODl ASN 97 -0.14220.430 28.230 1.00 33.19 SUBSTITUTE ~i{EE~ tRULE 26) CA 02226963 l998-02-l2 WO 97/083~0 PCT~US96/~3918 ATOM 889 ND2 ASN 97 0.577 18.737 26.950 1.00 29.41 ATOM 890 HD21 ASN97 0.365 17.861 26.558 1.00 0.00 ATOM 891 HD22 ASN97 1.409 19.221 26.806 1.00 0.00 ATOM 892 CASN 97 -0.746 17.667 30.165 1.00 23.01 5 ATOM 893 OASN 97 0.075 18.291 30.847 1.00 21.65 ATOM 894 NLEU 98 -0.691 16.353 29.992 1.00 21.64 ATOM 895 HLEU 98 -1.373 15.929 29.433 1.00 0.00 ATOM 896 CALEU 98 0.359 15.546 30.594 1.00 21.20 ATOM 897 CBLEU 98 -0.034 14.069 30.570 1.00 17.06 ATOM 8g8CG LEU 98 -1.357 13.699 31.251 1.00 16.71 ATOM 899CDl LEU 98 -1.549 12.185 31.223 1.00 12.58 ATOM 900CD2 LEU 98 -1.370 14.216 32.684 1.00 14.60 ATOM 901 CLEU 98 1.684 15.754 29.867 1.00 23.86 ATOM 902 OLEU 98 1.835 15.360 28.708 1.00 26.15 ATOM 903N ARG 99 2.630 16.392 30.549 1.00 26.16 ATOM 904 HARG 99 2.455 16.653 31.475 1.00 0.00 ATOM 905 CAARG 99 3.951 16.674 29.994 1.00 28.30 ATOM 906 CBARG 99 4.241 18.177 30.025 1.00 26.96 ATOM 907CG ARG 99 3.171 19.070 29.447 1.00 30.41 ATOM 908CD ARG 99 3.508 20.526 29.734 1.00 34.41 ATOM 909NE ARG 99 2.427 21.433 29.355 1.00 38.66 ATOM 910HE ARG 99 1.995 21.299 28.487 1.00 0.00 ATOM 911CZ ARG 99 1.982 22.430 30.116 1.00 41.42 ATOM 912NHl ARG 99 2.521 22.659 31.307 1.00 44.31 2~ ATOM913 HHll ARG 99 3.261 22.076 31.642 1.00 0.00 ATOM 914 HH12 ARG99 2.176 23.402 31.880 1.00 0.00 ATOM 915 NH2 ARG 99 0.991 23.199 29.685 1.00 42.74 ATOM 916 HH21 ARG99 0.582 23.034 28.788 1.00 0.00 ATOM 917 HH22 ARG99 0.656 23.950 30.253 1.00 0.00 ATOM 918C ARG 99 5.022 15.981 30.827 1.00 30.19 ATOM 919 OARG 99 5.260 16.353 31.973 1.00 35.13 ATOM 920 NLYS 100 5.682 14.992 30.245 1.00 29.39 ATOM 921 HLYS 100 5.435 14.728 29.337 1.00 0.00 ATOM 922 CALYS 100 6.746 14.275 30.935 1.00 27.27 ATOM 923CB LYS 100 7.818 15.244 31.451 1.00 28.94 ATOM 924 CGLYS 100 9.056 14.548 31.998 1.00 38.33 ATOM 925 CDLYS 100 10.106 15.539 32.483 1.00 43.68 ATOM 926 CELYS 100 11.359 14.824 32.989 1.00 45.64 ATOM 927 NZLYS 100 11.077 13.949 34.166 1.00 47.84 -SUBSTITUTE ~EET (RUl E 2~i) CA 02226963 l998-02-l2 W O 97/083~0 PCTruS96rl3918 ATOM 928 HZl LYS100 10.401 13.212 33.886 1.00 0.00 ATOM 929 ~Z2 LYS100 10.658 14.516 34.932 1.00 0.00 ATOM 930 HZ3 LYS100 11.961 13.513 34.494 1.00 0.00 ATOM 931 C LYS1006.306 13.355 32.070 1.00 23.90 5 ATOM 932 O L'~S1005.879 13.802 33.136 1.00 21.73 ATOM 933 N PRO1016.365 12.043 31.827 1.00 20.62 ATOM 934 CD PRO1016.598 11.395 30.525 1.00 19.79 ATOM 935 CA PRO1015.985 11.063 32.840 1.00 18.73 ATOM 936 CB PRO1015.909 9.762 32.040 1.00 20.97 ATOM 937 CGPRO 101 6.897 9.978 30.934 1.00 22.39 ATOM 938 C PRO1017.058 10.992 33.923 1.00 17.30 ATOM 939 O PRO1018.252 11.122 33.644 1.00 16.81 ATOM 940 N CYS1026.633 10.823 35.165 1.00 15.53 ATOM 941 H CYS1025.688 10.683 35.322 1.00 0.00 ATOM 942 CAC'~S 102 7.563 10.720 36.268 1.00 13.89 ATOM 943 CB C~'S1026.898 11.178 37.557 1.00 13.31 ATOM 944 SG CYS1027.994 11.195 38.960 1.00 16.63 ATOM 945 C CYS1027.929 9.245 36.344 1.00 14.55 ATOM 946 O CYS1027.358 8.488 37.130 1.00 15.10 ATOM 947 N ASN 103 8.853 8.834 35.485 1.00 14.85 ATOM 948 H ASN1039.232 9.505 34.875 1.00 0.00 ATOM 949 CA ASN 103 9.283 7.440 35.421 1.00 15.80 ATOM 950 CB ASN 103 10.196 7.218 34.212 1.00 16.28 ATOM 951 CG ASN 103 9,503 7.509 32.896 1.00 15.02 ATOM 952ODl AS'N 103 8.353 7.121 32.679 1.00 16 41 ATOM 953 ND2 ASN103 10.196 8.205 32.013 1 00 20.99 ATOM 954 HD21 ASN10311.100 8.507 32.225 1.00 0.00 ATOM 955 HD22 AS'~1039.759 8.409 31.149 1.00 0 00 ATOM 956 C ASN 103 9.966 6.941 36.688 1.00 17.75 ATOM 957~ ASN103 10.709 7.676 37.341 1.00 17.16 ATOM 958 N A.-~G 104 9.699 5.684 37.027 1.00 16.96 ATOM 959 H ARG 104 9.110 5.152 36.460 1.00 0.00 ATOM 960 CA A~G 104 10.274 5.054 38.207 1.00 19.38 ATOM 961 CB A~G 104 9.781 3.610 38.330 1.00 19.40 ATOM 962CG A~G104 8.431 3.450 38.999 1.00 17.82 ATOM 963 CD AFG 104 8.002 1.999 39.007 1.00 17.65 ATOM 964 NE A.~G104 7.520 1.576 37.696 1.00 26.48 ATOM 965 HE A~G 104 6.667 1.930 37.380 1.00 0.00 ATOM 966 CZ A-~G 104 8.170 0.759 36.874 1.00 25.18 - 97 .

SUBSTITUTE SI~F}~ (RULE 2~i) W O 97/08300 PCT~US96/13918 ATOM 967 NHl ARG 104 9 350 0.260 37.213 1.00 29.12 ATOM g68 HHll ARG 104 9.760 0 484 38.095 1.00 0.00 ATOM 969 HH12 ARG 104 9.829 -0.357 36.586 1.00 0.00 ATOM 970 NH2 ARG 104 7.628 0.429 35.712 1.00 30.66 ATOM 971 HH21 ARG 104 6.735 0.803 35.464 1.00 0.00 ATOM 972 HH22 ARG 104 8.101 -0.194 35.088 1.00 0.00 ATOM 973 C ARG 10411.796 5.059 38.163 1.00 23.50 ATOM 974 O ARG 10412.395 4.746 37.133 1.00 23.54 ATOM 975 N PRO 10512.440 5.453 39.273 1.00 27.13 0 ATOM 976 CD PRO 10511.847 5.983 40.512 1.00 29.49 ATOM 977 CA PRO 10513.902 5.487 39.341 1.00 29.70 ATOM 978 CB PRO 10514.160 5.980 40.760 1.00 30.41 ATOM 979 CG PRO 10512.960 6.824 41.053 1.00 31.24 ATOM 980 C PRO 10514.429 4.070 39.163 1.00 32.78 ATOM 981 O PRO 105 13.750 3.103 39.517 1.00 33.65 ATOM 982 N SER 10615.631 3.946 38.613 1.00 36.54 ATOM 983 H SER 10616.143 4.736 38.342 1.00 0.00 ATOM 984 CA SER 10616.241 2.638 38.393 1.00 37.78 ATOM 985 CB SER 10617.652 2.810 37.829 1.00 40.86 ATOM 986 OGSER 106 17.637 3.643 36.680 1.00 45.12 ATOM 987 HG SER 10617.148 3.214 35.971 1.00 0.00 ATOM 988 C SER 10616.282 1.840 39.697 1.00 37.20 ATOM 989 O SER 10616.701 2.350 40.741 1.00 37.55 ATOM 990 N GLY 10715.808 0.601 39.636 1.00 36.08 2~ ATOM 991 H GLY 107 15.421 0.264 38.806 1 00 0 00 ATOM 992 CA GLY 10715.794 -0.239 40.817 1.00 35.61 ATOM 993 C GLY 10714.462 -0.209 41.544 1.00 34.68 ATOM 994 O GLY 10714.281 -0.921 42.532 1.00 37.59 ATOM 995 N LEU 10813.536 0.621 41.071 1.00 31.21 ATOM 996 H LEU 108 13.708 1.194 40.292 1.00 0.00 ATOM 997 CA LEU 10812.219 0.719 41.683 1.00 29.48 ATOM 998 CB LEU 10811.828 2.184 41.901 1.00 31.06 ATOM 999 CG LEU 10810.439 2.415 42.506 1.00 33.10 ATOM 1000 CDl LEU108 10.341 1.718 43.849 1.00 35.40 ATOM 1001 CD2 LEU 108 10.173 3.897 42.660 1.00 34.68 ATOM 1002 C LEU 10811.201 0.036 40.786 1.00 28.12 ATOM 1003 O LEU 10811.107 0.337 39.600 1.00 27.81 ATOM 1004 N GLU 10910.463 -0.908 41.353 1.00 27.83 ATOM 1005 H GLU 10910.572 -1.085 42.309 1.00 0.00 SUBSTITUTE Si~E~ ~RULE 21!i~

CA 02226963 l998-02-l2 WO 97/083~0 PCTAUS96/13918 ATOM 1006 CA GLU109 9.448 -1.644 40.612 1.00 26.64 ATOM 1007 CB GLU109 9.663 -3.151 40.801 1.00 33.21 ATOM 1008 CG GLU109 11.066 -3.653 40.433 1.00 42.25 ATOM 1009 CD GLU109 11.373 -3.558 38.940 1.00 48.40 ATOM 1010OEl GLU 109 11.182 -4.568 38.228 1.00 52.92 ATOM 1011 OE2 GLU 109 11.821 -2.485 38.479 1.00 51.82 ATOM 1012 C GLU109 8.080 -1.236 41.156 1.00 23.58 ATOM 1013 O GLU109 7.989 -0.648 42.241 1.00 23.49 ATOM 1014 N PRO110 7.002 -1.480 40.389 1.00 19.24 ATOM 1015 CD PRO 110 6.918 -1.981 39.007 1.00 16.22 ATOM 1016 CA PRO110 5.678 -1.103 40.896 1.00 16.34 ATOM 1017 CB PRO110 4.753 -1.406 39.715 1.00 14.78 ATOM 1018 CG PRO110 5.496 -2.439 38.930 1.00 18.83 ATOM 1019 C PRO110 5.337 -1.920 42.144 1.00 16.63 ATOM 1020 O PRO 110 5.600 -3.119 42.202 1 00 16.68 ATOM 1021 N GLNlll 4.803 -1.245 43.155 1.00 16.60 ATOM 1022 H GLN111 4.634 -0.287 43.041 1.00 0.00 ATOM 1023 CA GLN111 4.447 -1.869 44 425 1.00 16.91 ATOM 1024 CB GLNlll 4.206 -0.774 45.469 1.00 21.09 ATOM 1025 CG GLN 111 3.892 -1.263 46.873 1.00 29.38 ATOM 1026 CD GLN111 5.096 -1.852 47.581 1.00 35.11 ATOM 1027 OEl GLN 111 6.224 -1.390 47.404 1.00 39.80 ATOM 1028 NE2 GLN 111 4.863 -2.881 48.389 1.00 39.14 ATOM 1029 HE21 GLN111 3.934 -3.187 48.464 1.00 0.00 ATOM 1030 HE22 GLN 111 5.625 -3.267 48.862 1.00 0.00 ATOM 1031 C GLN111 3.220 -2.778 44.329 1.00 15.31 ATOM 1032 O GLN111 2.161 -2.358 43.856 1.00 12.08 ATOM 1033 N PRO112 3.356 -4.052 44.738 1.00 16.34 ATOM 1034 CD PRO112 4.563 -4.760 45.201 1.00 15.65 ATOM 1035 CA PRO 112 2.207 -4.961 44.676 1.00 16.29 ATOM 1036 CB PRO112 2.831 -6.322 44.999 1.00 17.56 ATOM 1037 CG PRO112 3.981 -5.966 45.896 1.00 18.96 ATOM 1038 C PRO112 1.162 -4.553 45.716 1.00 13.47 ATOM 1039 O PRO112 1.510 -4.094 46.810 1.00 12.01 ATOM 1040 N GLY 113 -0.110 -4.671 45.348 1.00 14.46 ATOM 1041 H GLY113 -0.338 -5.036 44.467 1.00 0.00 ATOM 1042 CA GLY113 -1.184 -4.317 46.256 1.00 14.99 ATOM 1043 C GLY113 -1.504 -5.450 47.212 1.00 15.75 ATOM 1044 O GLY113 -1.523 -6.625 46.827 1.00 15.37 _ 99 _ SUBST~TUTE ~ tRULE 2~i) W O 97108300 PCT~US96/13918 ATOM 1045 N VAL 114 -1.735 -5.107 48.471 1.00 13.61 ATOM 1046 H VAL 114 -1.698 -4.160 48.725 1.00 0.00 ATOM 1047 CA VAL 114 -2.060 -6.104 49.472 1.00 12.01 ATOM 1048 CB VAL 114 -2.103 -5.481 50.884 1.00 11.85 ATOM 1049 CGl VAL 114 -2.511 -6.519 51.915 1.00 11.29ATOM 1050 CG2 VAL 114 -0.738 -4.914 51.236 1.00 11.92 ATOM 1051 C VAL114 -3.386 -6.787 49.134 1.00 11.03 ATOM 1052 O VAL114 -3.474 -8.014 49.197 1.00 11.50 ATOM 1053 N PHE115 -4.389 -6.012 48.721 1.00 10.78 ATOM 1054 H PHE 115 -4.259 -5.036 48.674 1.00 0.00 ATOM 1055 CA PHE115 -5.698 -6.580 48.382 1.00 11.16 ATOM 1056 CB PHE115 -6.701 -5.485 48.003 1.00 9.84 ATOM 1057 CG PHE115 -8.145 -5.914 48.109 1.00 10.03 ATOM 1058 CDl PHE 115 -8.517 -6.981 48.927 1.00 7.64 ATOM 1059 CD2 PHE 115 -9.136 -5.237 47.409 1.00 11.26ATOM 1060 CEl PHE llS -9.852 -7.364 49.044 1 00 9.24 ATOM 1061 CE2 PHE 115 -10.475 -5.615 47.520 1.00 10.69 ATOM 1062 CZ PHE115 -10.830 -6.676 48.338 1.00 9.26 ATOM 1063 C PHE115 -5.598 -7.604 47.255 1.00 11.82 ATOM 1064 O PHE 115 -6.187 -8.678 47.338 1.00 12.23 ATOM 1065 N ASP116 -4.853 -7.262 46.207 1.00 12.76 ATOM 1066 H ASP116 -4.437 -6.379 46.194 1.00 0.00 ATOM 1067 CA ASP116 -4.649 -8.154 45.062 1.00 13.21 ATOM 1068 CB ASP116 -3.735 -7 493 44.019 1.00 15.79 ATOM 1069 CG ASP 116 -4.448 -6.435 43.187 1.00 18.80 ATOM 1070 ODl ASP 116 -5.617 -6.109 43.476 1.00 22.22 ATOM 1071 OD2 ASP 116 -3.831 -5.933 42.227 1.00 23.70 ATOM 1072 C ASP116 -4.001 -9.448 45.534 1.00 12.02 ATOM 1073 O ASP116 -4.399 -10.547 45.137 1.00 12.26 ATOM 1074 N CLE 117 -3.004 -9.295 46.395 1.00 12.55 ATOM 1075 H CLE117 -2.749 -8.387 46.652 1.00 0.00 ATOM 1076 CA CLE117 -2.267 -10.413 46.952 1.00 15.65 ATOM 1077 CB CLE117 -1.156 -9.892 47.847 1.00 16.88 ATOM 1078 SG CLE117 0.032 -11.145 48.309 1.00 24.55 ATOM 1079 B CLE 117 1.502 -9.640 49.805 1.20 27.84 ATOM 1080 C CLE117 -3.171 -11.348 47.746 1.00 17.48 ATOM 1081 O CLE117 -3.040 -12.573 47.655 1.00 18.50 ATOM 1082 N LEU118 -4.077 -10.772 48.533 1.00 16.22 ATOM 1083 ~ LEU118 -4.145 -9.793 48.594 1.00 0.00 SlJ85 ~ ~ I UTE ~E~ tRuLE 2~i) CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATOM 1084 CA LE'J 118 -5.004 -11.564 49.333 1.00 15.66 ATOM 1085 CB LE~J 118 -5.621 -10.727 50.458 1.00 15.67 ATOM 1086 CG LEU 118 -4.653 -10.113 51.472 1.00 20.69 ATOM 1087 CDl LE~ 118 -5.420 -9.697 52.717 1.00 25.46 5 ATOM 1088 CD2 LE~- 118 -3.561 -11.107 51.840 1.00 26.35 ATOM 1089 C LEU 118 -6.107 -12.191 48.484 i 00 15.77 ATOM 1090 O LEU 118 -6.496 -13.339 48.718 1.00 15.49 ATOM 1091 N ARG 119 -6.603 -11.452 47,495 1.00 14.72 ATOM 1092 H ARG 119 -6.276 -10.543 47.372 1.00 0.00 ATOM 1093 CA ARG 119 -7.654 -11.971 46.624 1.00 16.75 ATOM 1094 CB ARG 119 -8.187 -10.900 45.672 1.00 14.68 ATOM 1095 CG ARG 119 -8.923 -9.767 46.355 1.00 17.93 ATOM 1096 CD ARG 119 -9.927 -9.104 45.426 1 00 20.84 ATOM 1097 NE ARG 119 -9.383 -8 767 44.11Q 1.00 26.76 ATOM 1098 HE ARG 119 -9.540 -9.392 43.371 1 00 0.00 ATOM 1099 CZ ARG 119 -8.678 -7.672 43.837 1.00 29.78 ATOM 1100 NHl ARG 119 -8.412 -6.790 44.789 1.00 31.04 ATOM 1101 HHll ARG 119 -8.728 -6.943 45.724 1.00 0.00 ATOM 1102 HHl2 ARG 119 -7.872 -5.976 44.576 1.00 0.00 ATOM 1103 NH2 ARG 119 -8.256 -7.447 42.600 1.00 32.50 ATOM 1104 HH21 ARG 119 -8.466 -8.097 41.867 1.00 0.00 ATOM 1105 HH22 ARG 119 -7.723 -6.624 42.397 1.00 0.00 ATOM 1106 C ARG 119 -7.161 -13.164 45.823 1.00 18.07 ATOM 1107 O ARG 119 -7.940 -14.053 45.491 ~ 00 21.21 ATOM 1108 N AS? 120 -5.870 -13.188 45.514 1.00 17.45 ATOM 1109 H AS? 120 -5.289 -12.442 45.768 1 00 0.00 ATOM 1110 CA AS 120 -5.294 -14.298 44.766 1.00 17.83 ATOM 1111 CB ASr 120 -3.790 -14.087 44.576 1.00 22.04 ATOM 1112 CG AS? 120 -3.118 -15.265 43.903 1.00 23.22 ATOM 1113 ODl AS? 120 -3.371 -15.490 42.702 1.00 26.00 ATOM 1114 OD2 AS? 120 -2.341 -15.969 44.581 1.00 27.30 ATOM 1115 C ASP 120 -5.544 -15.602 45.515 1.00 16.21 ATOM 1116 O AS? 120 -6.080 -16.554 44.953 1.00 14.21 ATOM 1117 N AL~ 121 -5.192 -15.614 46.798 1.00 13.03 ATOM 1118 H AL~ 121 -4.782 -14.809 47.181 1.00 0.00 ATOM 1119 CA AL.'. 121 -5.366 -16.787 47.647 1.00 13.21 ATOM 1120 CB AL' 121 -4.778 -16.523 49.029 1.00 11.07 ATOM li21 C ALA 121 -6.825 -17.220 47.773 1.00 11.40 ATOM 1122 O A~' 121 -7.132 -18.415 47.772 1.00 11.87 ~ 101 -SUBSTITUTE S~tEE~ ~RULE 2fi~

CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 1123 N SEM122 -7.7Zl -16.248 47.885 1.00 9.79 ATOM 1124 H SEM122 -7.400 -15.319 47.872 1.00 0.00 ATOM 1125 CA SEM122 -9.141 -16.521 48.025 1.00 9.76 ATOM 1126 CB SEM122 -g.884 -15.251 48.433 1.00 12.08 5 ATOM 1127 CG SEM122 -9.471 -14.699 49.790 1.00 17.34 ATOM 1128 A SEM122 -10.315 -12.991 50.177 1.00 20.79 ATOM 1129 CE SEM122 -9.148 -12.427 51.564 1.00 22.20 ATOM 1130 C SEM122 -9.752 -17.115 46.762 1.00 10.01 ATOM 1131 O SEM122 -10.609 -17.995 46.844 1.00 11.95 ATOM 1132 N VAL 123 -9.329 -16.627 45.600 1.00 10.94 ATOM 1133 H VAL123 -8.673 -15.894 45.592 1.00 0.00 ATOM 1134 CA VAL123 -9.836 -17.140 44.333 1.00 12.22 ATOM 1135 CB VAL123 -9.371 -16.272 43.134 1.00 13.58 ATOM 1136 CGl VAL 123 -9 759 -16.926 41.810 1.00 15.25 ATOM 1137CG2 VAL 123 -10.003 -14.894 43.220 1.00 13.81 ATOM 1138 C VAL123 -9.367 -18.583 44.165 1.00 11.57 ATOM 1139 O VAL123 -10.145 -19.454 43.786 1.00 15.13 ATOM 1140 N ARG124 -8.105 -18.843 44.489 1.00 13.03 ATOM 1141 H ARG124 -7.519 -18.104 44.781 1.00 0.00 ATOM 1142 CA ARG 124 -7.559 -20.192 44.384 1.00 15.09 ATOM 1143 CB ARG124 -6.089 -20.219 44.804 1.00 19.47 ATOM 1144 CG ARG 124 -5.177 -19.326 43.978 1.00 29.40 ATOM 1145 CD ARG 124 -3.720 -19.503 44.389 1.00 34.8S
ATOM 1146 NE ARG 124 -3.238 -20.849 44.085 1.00 39.82 ATOM 1147HE ARG 124 -3.340 -21.538 44.777 1.00 0.00 ATOM 1148 CZ ARG 124 -2.669 -21.201 42.934 1.00 40.38 ATOM 1149 NHl ARG 124 -2.497 -20.304 41.967 1.00 40.47 ATOM 1150 HHll ARG124 -2.791 -19.357 42.092 1.00 0.00 ATOM 1151 HH12 ARG124 -2.060 -20.584 41.111 1.00 0.00 ATOM 1152 NH2 ARG 124 -2.295 -22.461 42.740 1.00 39.07 ATOM 1153 HH21 ARG124 -2.439 -23.141 43.460 1.00 0.00 ATOM 1154 HH22 ARG124 -1.862 -22.734 41.883 1.00 0.00 ATOM 1155 C ARG 124 -8.356 -21.143 45.271 1.00 13.87 ATOM 1156 O ARG 124 -8.776 -22.210 44.829 1.00 11.56 ATOM 1157N ASP 125 -8.581 -20.738 46.517 1.00 13.96 ATOM 1158 ~ ASP 125 -8.214 -19.874 46.802 1.00 0.00 ATOM 1159 CA ASP 125 -9.333 -21.554 47.464 1.00 14.81 ATOM 1160 CB ASP 125 -9.308 -20.925 48.861 1.00 18.19 ATOM 1161 CG ASP 125 -9.967 -21.807 49.908 1.00 20.88 SUE~STITUTE ~E~ (RULE 2~) W 097/08300 PCT~US96/139l8 ATOM 1162 OD1 ASP 125 -10.978 -21.373 50.496 1.00 26.61 ATOM 1163 OD2 ASP 125 -9.482 -22.937 50.135 1.00 20.43 ATOM 1164 C ASP125 -10.770 -21.783 46.996 1.00 13.18 ATOM 1165 O ASP125 -11.287 -22.894 47.097 1.00 14.12 ATOM 1166 N TYR 126 -11'.407 -20.747 46.463 1.00 12.S1 ATOM 1167 H TYR126 -10.954 -19.881 46.429 1.00 0.00 ATOM 1168 CA TYR126 -12.773 -20.879 45.958 1.00 14.80 ATOM 1169 CB TYR126 -13.310 -19.525 45.483 1.00 16.19 ATOM 1170 CG TYR126 -14.764 -19.552 45.050 1.00 19.94 ATOM 1171CD1 TYR 126 -15.789 -19.431 45.984 1.00 22.56 ATOM 1172 CE1 TYR 126 -17.129 -19.440 45.595 1.00 25.33 ATOM 1173 CD2 TYR 126 -15.115 -19.687 43.705 1.00 21.52 ATOM 1174 CE2 TYR 126 -16.453 -19.699 43.304 1.00 22.94 ATOM 1175 CZ TYR126 -17.456 -19.573 44.256 1.00 24.54 ATOM 1176 OH TYR 126 -18.781 -19.560 43.871 1 00 25.75 ATOM 1177 HH TYR126 -19.331 -19.523 44.667 1.00 0.00 ATOM 1178 C TYR126 -lZ.825 -21.880 44.799 1.00 14.74 ATOM 1179 O TYR126 -13.666 -22.779 44.779 1.00 12.46 ATOM 1180 N VAL127 -11.917 -21.723 43.838 1.00 14.94 ATOM 1181 H VAL 127 -11.265 -21.000 43.917 1.00 0.00 ATOM 1182 CA VAL 127 -11.865 -22.608 42.679 1.00 15.31 ATOM 1183 CB VAL 127 -10.846 -22.100 41.628 1.00 16.12 ATOM 1184 CG1 VAL 127 -10.675 -23.120 40.506 1.00 14.89 ATOM 1185 CG2 VAL 127 -11.320 -20.766 41.050 1.00 14.29 ATOM 1186 C VAL 127 -11.554 -24.049 43.086 1.00 15.31 ATOM 1187 O VAL127 -12.166 -24.991 42.577 1.00 14.57 ATOM 1188 N ARG128 -10.640 -24.213 44.036 1.00 15.60 ATOM 1189 H ARG128 -10.202 -23.424 44.413 1.00 0.00 ATOM 1190 CA ARG128 -10.265 -25.536 44.519 1.00 18.18 ATOM 1191 CB ARG 128 -9.071 -25.435 45.464 1.00 20.53 ATOM 1192 CG ARG128 -8.535 -26.774 45.921 1.00 26.43 ATOM 1193 CD ARG128 -7.466 -26.610 46.986 1.00 31.14 ATOM 1194 NE ARG128 -6.274 -25.919 46.494 1.00 32.88 ATOM 1195 HE ARG128 -5.736 -26.363 45.803 1.00 0.00 ATOM 1196 CZ ARG 128 -5.882 -24.719 46.911 1.00 33.15 ATOM 1197 NH1 ARG 128 -6.592 -24.062 47.822 1.00 33.64 ATOM 1198 HH11 ARG128 -7.423 -24.475 48.195 1.00 0.00 ATOM 1199 HH12 ARG128 -6.310 -23.161 48.136 1.00 0.00 ATOM 1200 NH2 ARG128 -4.754 -24.197 46.451 1.00 31.81 SUBSTITUTE S}iEE~ tRULE 2fi~

CA 02226963 l998-02-l2 WO 97~08300 PCT~US96/l3918 ATOM 1201 HH21 ARG 128 -4.207 -24.708 45.789 1.00 0.00 ATOM 1202 HH22 ARG 128 -4.451 -23.298 46.770 1.00 0.00 ATOM 1203 C ARG 128 -11.439 -26.220 45.228 1.00 19.96 ATOM 1204 O ARG 128 -11.724 -27.386 44.980 1.00 20.08 5 ATOM 1205 N GLN 129 -12.136 -25.485 46.087 1.00 21.86 ATOM 1206 H GLN 129 -11.861 -24.558 46.234 1.00 0.00 ATOM 1207 CA GLN 129 -13.278 -26.040 46.812 1.00 24.92 ATOM 1208 CB GLN 129 -13.783 -25.056 47.875 1.00 27.32 ATOM 1209 CG GLN 129 -12.763 -24.641 48.919 1.00 38.13 ATOM 1210 CD GLN 129 -12.195 -25.806 49.700 1.00 43.53 ATOM 1211 OEl GLN 129 -10.983 -25.900 49.895 1.00 49.52 ATOM 1212 NE2 GLN 129 -13.066 -26.693 50.167 1.00 46.67 ATOM 1213 HE21 GLN 129 -14.022 -26.565 50.000 1.00 0.00 ATOM 1214 HE22 GLN 129 -12.673 -27.439 50.665 1 00 0.00 5 ATOM 1215 C GLN 129 -14.444 -26.388 45.887 1.00 22.91 ATOM 1216 O GLN 129 -15.075 -27.427 46.040 1.00 25.98 ATOM 1217 N THR 130 -14.745 -25.500 44.950 1.00 21.09 ATOM 1218 H THR 130 -14.243 -24.663 44.875 1.00 0.00 ATOM 1219 CA THR 130 -15.858 -25.700 44.036 1.00 20.03 ATOM 1220 CB THR 130 -16.267 -24.365 43.386 1.00 21.01 ATOM 1221 OGl THR 130 -16.598 -23.426 44.415 1.00 24.86 ATOM 1222 HGl THR 130 -17.447 -23.676 44.803 1.00 0.00 ATOM 1223 CG2 THR 130 -17.471 -24.545 42.470 1.00 18.89 ATOM 1224 C THR 130 -15.639 -26.749 42.951 1.00 20.64 ATOM 1225 O THR 130 -16.476 -27.634 42.771 1.00 21.45 ATOM 1226 N TRP 131 -14.524 -26.660 42.234 1.00 18.24 ATOM 1227 H TRP 131 -13.871 -25.958 42.438 1.00 0.00 ATOM 1228 CA TRP 131 -14.248 -27.599 41.147 1.00 18.29 ATOM 1229 CB TRP 131 -13.573 -26.873 39.976 1.00 17.75 ATOM 1230 CG TRP 131 -14.368 -25.715 39.462 1.00 18.23 ATOM 1231 CD2 TRP 131 -15.316 -25.731 38.385 1.00 20.51 ATOM 1232 CE2 TRP 131 -15.833 -24.419 38.265 1.00 19.78 ATOM 1233 CE3 TRP 131 -15.781 -26.722 37.510 1.00 20.37 ATOM 1234 CDl TRP 131 -14.349 -24.433 39.935 1.00 18.07 ATOM 1235 NEl TRP 131 -15.225 -23.651 39.223 1.00 19.62 ATOM 1236 HEl TRP 131 -15.376 -22.692 39.377 1.00 0.00 ATOM 1237 CZ2 TRP 131 -16.793 -24.073 37.305 1.00 18.47 ATOM 1238 CZ3 TRP 131 -16.737 -26.376 36.553 1.00 19.44 ATOM 1239 CH2 TRP 131 -17.230 -25.062 36.460 1.00 19.54 SU8STITUTE ~H~ tR~JLE 26) CA 02226963 l998-02-l2 WO 97/0830~ PCT~US96/13918 ATOM 1240 C TRP131 -13.434 -28.831 41.539 1.00 17.51 ATOM 1241 O TRP131 -13.250 -29.734 40.718 1.00 17.01 ATOM 1242 N LYS132 -12.956 -28.863 42.783 1.00 17.08 ATOM 1243 ~ LYS132 -13.131 -28.128 43.405 1.00 0.00 5 ATOM 1244 CA L'fS132 -12.155 -29.977 43.300 1.00 21.35 ATOM 1245 CB L~S132 -13.010 -31.246 43.476 1.00 22.55 ATOM 1246 CG LYS132 -13.864 -31.290 44.741 1.00 27.05 ATOM 1247 CD LYS132 -15.049 -30.351 44.661 1.00 28.94 ATOM 1248 CE LYS132 -15.917 -30.429 45.909 1.00 27.71 ATOM 1249 NZ LYS 132 -15.176 -30.035 47.1~1 1.00 28.94 ATOM 1250 HZl LYS 132 -14.777 -29.086 47.010 1.00 0.00 ATOM 1251 HZ2 LYS 132 -14.398 -30.705 47.3'2 1.00 0.00 ATOM 1252 HZ3 LYS 132 -15.821 -30.030 47.956 1.00 0.00 ATOM 1253 C LYS132 -10.952 -30.279 42.4 0 1.00 21.09 ATOM 1254 O LYS 132 -10.616 -31.441 42.177 1.00 22.12 ATOM 1255 N LEU133 -10.311 -29.227 41.915 1.00 22.01 ATOM 1256 H LEU133 -10.601 -28.334 42.179 1.00 0.00 ATOM 1257 CA LEU133 -9.152 -29.376 41.044 1.00 24.78 ATOM 1258 C8 LEU133 -9.266 -28.439 39.841 1.00 24.76 ATOM 1259 CG LEU 133 -10.384 -28.729 38.840 1.00 23.74 ATOM 1260 CDl LEU 133 -10.423 -27.640 37.792 1.00 18.82 ATOM 1261 CD2 LEU 133 -10.168 -30.093 38.197 1.00 20.87 ATOM 1262 C LEU133 -7.851 -29.107 41.782 1.00 26.48 ATOM 1263 O LEU133 -7.844 -28.489 42.843 1.00 26.77 ATOM 1264 N GLU 134 -6.745 -29.561 41.204 1.00 31.08 ATOM 1265 H GLrJ134 -6.783 -30.056 40.359 1.00 0.00 ATOM 1266 CA GLU134 -5.436 -29.365 41.810 1.00 36.68 ATOM 1267 CB GLU134 -5.146 -30.478 42.821 1.00 42.39 ATOM 1268 CG GLU134 -4.135 -30.097 43.901 1.00 50.47 ATOM 1269 CD GLU 134 -4.605 -28.933 44.762 1.00 54.00 ATOM 1270 OEl GLU 134 -3.922 -27.885 44.772 1.00 56.35 ATOM 1271 OE2 GLU 134 -5.658 -29.065 45.426 1.00 55.94 ATOM 1272 C GLU134 -4.369 -29.349 40.720 1.00 36.98 ATOM 1273 O GLU134 -4.655 -29.660 39.559 1.00 37.05 ATOM 1274 N GLY 135 -3.156 -28.946 41.087 1.00 37.39 ATOM 1275 H GLY135 -3.008 -28.662 42.009 1.00 0.00 ATOM 1276 CA GLY135 -2.062 -28.894 40.133 1.00 38.80 ATOM 1277 C GLY135 -2.340 -27.998 38.941 1.00 39.61 ATOM 1278 O GLY135 -3.038 -26.986 39.062 1.00 40.95 - 10~ -SlJBSTtTUTE S}~E~ ~RULE 2~;) CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 1279 N GLU136 -1.816 -28.385 37.781 1.00 38.99 ATOM 1280 H GLU136 -1.290 -29.209 37.748 1.00 0.00 ATOM 1281 CA GLU136 -1.999 -27.616 36.553 1.00 38.69 ATOM 1282 CB GLU136 -1.244 -28.259 35.386 1.00 43.51 ATOM 1283 CG GLU 136 0.134 -27.652 35.129 1.00 51.02 ATOM 1284 CD GLU136 0.073 -26.157 34.827 1.00 5g.54 ATOM 1285 OEl GLU 136 0.533 -25.357 35.672 1.00 54.76 ATOM 1286 OE2 GLU 136 -0.437 -25.783 33.746 1.00 57.49 ATOM 1287 C GLU 136 -3.454 -27.403 36.172 1.00 35.47 ATOM 1288O GLU 136 -3.795 -26.386 35.564 1.00 33.83 ATOM 1289 N ALA 137 -4.304 -28.367 36.514 1.00 32.94 ATOM 1290 H ALA 137 -3.975 -29.157 36.985 1.00 0.00 ATOM 1291 CA ALA 137 -5.729 -28.268 36.215 1.00 31.07 ATOM 1292 CB ALA137 -6.440 -29.556 36.605 1.00 31.83 ATOM 1293 C ALA 137 -6.314 -27.079 36.976 1.00 27.50 ATOM 1294 ~ ALA137 -7.031 -26.257 36.405 1.00 29.33 ATOM 1295 N LEU138 -5.963 -26.973 38.254 1.00 24.80 ATOM 1296 H LEU138 -5.350 -27.643 38.627 1.00 0.00 ATOM 1297 CA LEU138 -6.435 -25.884 39.097 1.00 23.90 ATOM 1298 CB LEU 138 -5.909 -26.053 40.520 1.00 21.92 ATOM 1299 CG LEU138 -6.161 -24.920 41.514 1.00 21.33 ATOM 1300 CDl LEU 138 -7.648 -24.709 41.716 1.00 22.45 ATOM 1301 CD2 LEU 138 -5.493 -25.252 42.830 1.00 21.62 ATOM 1302 C LEU 138 -5.932 -24.573 38.527 1.00 26.43 2~ ATOM 1303O LEU 138 -6.686 -23.611 38.401 1.00 25.96 ATOM 1304 N GLU 139 -4.649 -24.550 38.179 1 00 30 25 ATOM 1305 H GLU 139 -4.110 -25.355 38.336 1.00 0.00 ATOM 1306 CA GLU 139 -4.003 -23.373 37.610 1.00 32.41 ATOM 1307 CB GLU 139 -2.546 -23.690 37.274 1.00 34.88 ATOM 1308CG GLU 139 -1.524 -22.848 38.024 1.00 40.02 ATOM 1309 CD GLU 139 -1.489 -23.111 39.524 1.00 42.46 ATOM 1310 OEl GLU 139 -2.188 -24.025 40.014 1.00 46.36 ATOM 1311 OE2 GLU 139 -0.743 -22.394 40.220 1.00 44.75 ATOM 1312 C GLU139 -4.726 -22.880 36.363 1.00 33.95 ATOM 1313 O GLU 139 -4.906 -21.679 36.181 1.00 33.01 ATOM 1314 N GLN140 -5.130 -23.808 35.500 1.00 36.05 ATOM 1315 H GLN140 -4.957 -24.758 35.685 1.00 0.00 ATOM 1316 CA GLN140 -5.845 -23.446 34.280 1.00 38.93 ATOM 1317 CB GLN140 -6.008 -24.560 33.356 1.00 43.55 .

SUBSTITUTE ~F~ tRULE 2fi) CA 02226963 l998-02-l2 ATOM 1318 CG GLN 140 -4.703 -25.2g5 32.911 1.00 50.09 ATOM 1319 CD GLN 140 -3.702 -24.272 32.420 1.00 54.44 ATOM 1320 OEl GLN 140 -3.865 -23.688 31.347 1.00 57.43 ATOM 1321 NE2 GLN 140 -2.662 -24.039 33.212 1.00 54.84 ATOM 1322 HE21 GLN 140 -2.611 -24.543 34.051 1.00 0.00 ATOM 1323 HE22 GLN140 -2.010 -23.377 32.911 1 00 0.00 ATOM 1324 C GLN140 -7.220 -22.895 34.633 1.00 37.85 ATOM 1325 O GLN140 -7.643 -21.865 34.106 1.00 38.61 ATOM 1326 N ALA141 -7.904 -23.581 35.543 1.00 35.28 ATOM 1327 H ALA 141 -7.494 -24.378 35.939 1.00 0.00 ATOM 1328 CA ALA141 -9.238 -23.188 35.974 1.00 33.81 ATOM 1329 CB ALA141 -9.806 -24.218 36.930 1.00 33.21 ATOM 1330 C ALA141 -9.297 -21.796 36.598 1.00 33.71 ATOM 1331 O ALA141 -10.220 -21.034 36.308 1.00 33.79 ATOM 1332 N ILE 142 -8.321 -21.452 37.436 1.00 34.36 ATOM 1333 H ILE142 -7.602 -22.089 37.625 1.00 0.00 ATOM 1334 CA ILE142 -8.324 -20.137 38.069 1.00 35.58 ATOM 1335 CB ILE142 -7.237 -19.979 39.178 1.00 37.48 ATOM 1336 CG2 ILE 142 -7.376 -21.080 40.221 1.00 36.69 ATOM 1337CGl ILE 142 -5.833 -19.991 38.580 1.00 40.54 ATOM 1338 CD ILE142 -4.736 -19.774 39.600 1.00 41.71 ATOM 1339 C ILE142 -8.189 -19.035 37.027 1.00 35.75 ATOM 1340 O ILE142 -8.807 -17.985 37.156 1.00 36.45 ATOM 1341 N ILE143 -7.421 -19.288 35.974 1.00 36.98 ATOM 1342 H ILE 143 -6.962 -20.154 35.905 1.00 0.00 ATOM 1343 CA ILE143 -7 244 -18.299 34.917 1.00 39.87 ATOM 1344 CB ILE143 -6.211 -18.782 33.846 1.00 40.93 ATOM 1345 CG2 ILE 143 -6.582 -18.283 32.451 1 00 39.88 ATOM 1346 CGl ILE 143 -4.804 -18.288 34.195 1.00 41.89 ATOM 1347 CD ILE 143 -4.260 -18.790 35.509 1.00 44.53 ATOM 1348 C ILE143 -8.592 -17.996 34.266 1.00 41.03 ATOM 1349 O ILE143 -8.953 -16.835 34.073 1.00 43.88 ATOM 1350 N SER144 -9.349 -19.046 33.977 1.00 41.09 ATOM 1351 H SER144 -9.002 -19.948 34.145 1.00 0.00 ATOM 1352 CA SER 144 -10.652 -18.908 33_345 1.00 42.72 ATOM 1353 CB SER144 -11.084 -20.261 32.786 1.00 43.70 ATOM 1354 OG SER144 -10.009 -20.876 32.098 1.00 48.58 ATOM 1355 HG SER144 -10.277 -21.685 31.660 1.00 0.00 ATOM 1356 C SER144 -11.740 -18 364 34.274 1.00 42.64 SUBSTITUTE ~E~ tRULE 2~) CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 1357 O SER144 -12.612 -17.606 33.845 1.00 43.71 ATOM 1358 N GLN145 -11.692 -18 756 35.543 1.00 42.82 ATOM 1359 H GLN145 -10.944 -19.324 35.823 1.00 0.00 ATOM 1360 CA GLN 145 -12.691 -18.335 36.520 1.00 42.48 ATOM 1361CB GLN 145 -12.879 -19.419 37.585 1.00 43.50 ATOM 1362 CG GLN 145 -13.600 -20.664 37.092 1.00 46.68 ATOM 1363 CD GLN 145 -15.042 -20.391 36.708 1.00 49.02 ATOM 1364 OEl GLN 145 -15.882 -20.086 37.562 1.00 49.76 ATOM 1365 NE2 GLN 145 -15.341 -20.506 35.419 1.00 48.88 ATOM 1366 HE21 GLN 145 -14.639 -20.764 34.792 1 00 0.00 ATOM 1367 HE22 GLN145 -16.274 -20.325 35.164 1.00 0.00 ATOM 1368 C GLN 145 -12.442 -16.996 37.204 1.00 41.52 ATOM 1369 O GLN 145 -13.393 -16.275 37.503 1.00 42.42 ATOM 1370 N ALA 146 -11.175 -16.657 37.423 1.00 41.08 ATOM 1371H ALA 146 -10.480 -17.248 37.094 1.00 0.00 ATOM 1372 CA ALA 146 -10.786 -15.418 38.102 1.00 42.09 ATOM 1373 CB ALA146 -9.305 -15.113 37.861 1.00 43.64 ATOM 1374 C ALA146 -11.638 -14.178 37.818 1.00 42.22 ATOM 1375 O ALA146 -12.169 -13.570 38.748 1.00 40.36 ATOM 1376 N PRO 147 -11.807 -13.801 36.535 1.00 42.75 ATOM 1377 CD PRO147 -11.279 -14.419 35.303 1.00 42.03 ATOM 1378 CA PRO147 -12.614 -12.617 36.213 1.00 42.24 ATOM 1379 CB PRO147 -12.433 -12.486 34.699 1.00 42.92 ATOM 1380 CG PRO147 -12.233 -13.908 34.258 1.00 42.35 ATOM 1381 C PRO 147 -14.092 -12.720 36.595 1.00 41.91 ATOM 1382 O PRO147 -14.694 -11.741 37.039 1.00 43.04 ATOM 1383 N GLN148 -14.656 -13.915 36.452 1.00 42.14 ATOM 1384 H GLN148 -14.092 -14.663 36.166 1.00 0.00 ATOM 1385 CA GLN 148 -16.065 -14.164 36.753 1.00 41.99 ATOM 1386CB GLN 148 -16.476 -15.527 36.191 1.00 46.02 ATOM 1387 CG GLN 148 -16.113 -15.735 34.728 1.00 52.36 ATOM 1388 CD GLN 148 -16.424 -17.140 34.245 1.00 56.58 ATOM 1389 OEl GLN 148 -17.548 -17.624 34.391 1.00 60.22 ATOM 1390 NE2 GLN 148 -15.426 -17.805 33.673 1.00 57.78 ATOM 1391 HE21 GLN 148 -14.538 -17.383 33.597 1.00 0.00 ATOM 1392 HE22 GLN148 -15.637 -18.697 33.339 1.00 0.00 ATOM 1393 C GLN148 -16.403 -14.109 38.246 1.00 40.35 ATOM 1394 O GLN148 -17.445 -13.576 38.643 1.00 42.32 ATOM 1395 N VAL149 -15.530 -14.677 39.070 1 00 35.77 SUBSTlTUTE SH~ tRULE 26) CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 1396 H VAL 149 -14.725 -15.083 38.684 1.00 0.00 ATOM 1397 CA VAL 149 -15.747 -14.705 40.512 1.00 30.92 ATOM 1398 CB VAL 149 -15.297 -16.056 41.116 1.00 29 67 ATOM 1399 CGl VAL 149 -16.047 -17.195 40.452 1.00 31.16 5ATOM 1400 CG2 VAL 149 -13.798 -16.245 40.942 1.00 27.34 ATOM 1401 C VAL 149 -15.034 -13.569 41.242 1.00 29.41 ATOM 1402 O VAL 149 -15.112 -13.469 42.466 1.00 25.93 ATOM 1403 N GLU 150 -14.375 -12.697 40.485 1.00 29.98 ATOM 1404 H GLU 150 -14.357 -12.827 39.513 1.00 0.00 ATOM 1405CA GLU 150 -13.627 -11.574 41.049 1.00 32.17 ATOM 1406 CB GLU 150 -13 075 -10.693 39.922 1 00 38.43 ATOM 1407 CG GLU 150 -11 690 -10 097 40.191 1.00 47.19 ATOM 1408 CD GLU 150 -10.566 -11.124 40.092 1.00 51.56 ATOM 1409 OEl GLU 150 -9.728 -10.999 39.171 1 00 53.66 ~5 ATOM 1410OE2 GLU 150 -10.512 -12.052 40.930 1.00 54.50 ATOM 1411 C GLU150 -14.431 -10.720 42.038 1.00 29.05 ATOM 1412 O GLU150 -14.033 -10.555 43.192 1.00 25.94 ATOM 1413 N LYS151 -15.565 -10.195 41.582 l.Q0 27.58 ATOM 1414 H LYS151 -15 817 -10 387 40.655 1.00 0.00 ATOM 1415 CA LYS 151 -16.432 -9.358 42.406 1.00 25.61 ATOM 1416 CB LYS 151 -17.655 -8.926 41.590 1.00 29.92 ATOM 1417 CG LYS 151 -18.689 -8.102 42.352 1.00 36.35 ATOM 1418 CD LYS 151 -18.247 -6.660 42.574 1.00 42 81 ATOM 1419 CE LYS 151 -18 173 -5.880 41.266 1.00 47 01 ATOM 1420 NZ LYS 151 -17.791 -4.452 41.481 1 00 51 50 ATOM 1421 HZl LYS 151 -16 880 -4.410 41.984 1.00 0.00 ATOM 1422 HZ2 LYS 151 -18.521 -3.974 42.046 1.00 0.00 ATOM 1423 HZ3 LYS 151 -17.696 -3.973 40.563 1.00 0.00 ATOM 1424 C LYS 151 -16 886 -10.100 43.656 1.00 23.86 ATOM 1425 O LYS 151 -16 864 -9.553 44.761 1.00 21.86 ATOM 1426 N LEU 152 -17.288 -11.352 43.468 1.00 22.21 ATOM 1427 H LEU 152 -17.238 -11.726 42.566 1.00 0.00 ATOM 1428 CA LEU 152 -17.768 -12.195 44.556 1.00 20.16 ATOM 1429 CB LEU 152 -18.151 -13.579 44.008 1.00 24.21 ATOM 1430 CG LEU 152 -18.970 -14.587 44.830 1.00 28.31 ATOM 1431 CDl LEU 152 -18.079 -15.648 45.449 1 00 30.35 ATOM 1432 CD2 LEU 152 -19.813 -13.875 45.883 1.00 31.40 ~ATOM 1433 C LEU 152 -16.736 -12.305 45.681 1.00 18.41 ATOM 1434 O LEU 152 -17.049 -12.034 46.839 1.00 17.53 SU85TlTUTE S~tE~ ~RULE 2~;) W O 97/08300 PCTrUS96/13918 ATOM lg35 N ILE 153 -15.501 -12.650 45.333 1.00 15.66 ATOM 1436 H ILE 153 -15.300 -12.822 44.388 1.00 0.00 ATOM 1437 CA ILE 153 -14.445 -12.782 46.327 1.00 14.50 ATOM 1438 CB ILE 153 -13.169 -13.439 45.728 1.00 14.50 ATOM 1439 CG2 ILE 153 -11.944 -13.093 46.556 1.0Q 13.04 ATOM 1440 CGl ILE 153 -13.311 -14.966 45.702 1.00 18.16 ATOM 1441 CD ILE 153 -14.378 -15.489 44.791 1.00 18.78 ATOM 1442 C ILE 153 -14.102 -11.446 46.986 1.00 14.37 ATOM 1443 O ILE 153 -13.967 -11.377 48.209 1.00 13.54 0 ATOM 1444 N ALA 154 -14.018 -10.386 46.187 1.00 13.14 ATOM 1445 H ALA 154 -14.184 -10.504 45.232 1.00 0.00 ATOM 1446 CA ALA 154 -13.681 -9.052 46.693 1.00 15.23 ATOM 1447 CB ALA 154 -13.464 -8.088 45.530 1.00 12.01 ATOM 1448 C ALA 154 -14.690 -8.462 47.685 1.00 14.41 ~5 ATOM 1449 O ALA 154 -14.309 -7.939 48.740 1.00 12.98 ATOM 1450 N THR 155 -15.973 -8.553 47.366 1.00 14.48 ATOM 1451 :~ THR 155 -16.254 -8.987 46.535 1.00 0.00 ATOM 1452 CA THR 155 -16.989 -7.997 48.250 1.00 16.73 ATOM 1453 CB THR 155 -18.355 -7.861 47.542 1.00 18.64 2~ ATOM 1454 OGl THR 155 -18.794 -9.139 47.073 1.00 18.35 ATOM 1455 HGl THR 155 -18.242 -9.431 46.333 1.00 0.00 ATOM 1456 CG2 THR 155 -18.239 -6.912 46.361 1.00 21.11 ATOM 1457 C THR 155 -17.152 -8.754 49.567 1.00 18.25 ATOM 1458 O THR 155 -17.628 -8.191 50.556 1.00 19.74 ATOM 1459 N THR 156 -16.690 -10.000 49.608 1.0û 16.51 ATOM 1460 :-- THR 156 -16.290 -10.405 48.811 1.00 0.00 ATOM 1461 CA THR 156 -16.816 -10.803 50.816 1.00 16.53 ATOM 1462 CB THR 156 -17.514 -12.151 50.491 1.00 18.06 ATOM 1463 OGl THR 156 -17.884 -12.806 51.710 1.00 29.31 ATOM 1464 HGl THR 156 -17.083 -13.066 52.183 1.00 0.00 ATOM 1465 CG2 THR 156 -16.601 -13.057 49.683 1.00 11.43 ATOM 1466 C THR 156 -15.502 -11.024 51.584 1.00 15.34 ATOM 1467 O THR 156 -15.498 -11.642 52.653 1.00 13.11 ATOM 1468 N ALA 157 -14.406 -10.461 51.076 1.00 13.94 ATOM 1469 H ALA 157 -14.471 -9.981 50.225 1.00 0.00 ATOM 1470 CA ALA 157 -13.086 -10.594 51.696 1.00 13.07 ATOM 1471 CB ALA 157 -12.043 -9.841 50.878 1.00 9.00 ATOM 1472 C ALA 157 -13.006 -10.169 53.163 1.00 13.45 ATOM 1473 O ALA 157 -12.221 -10.725 53.930 1.00 13.99 SU8STIT~TE ~}~E~ tRULE ~fi~

CA 02226963 l998-02-l2 WO 97/08300 P~T~US96/13918 ATOM 1474 N HIS 158 -13.805 -9.180 53.549 1.00 12.36 ATOM 1475 H HIS 158 -14.354 -8.762 52.857 1.00 0.00 ATOM 1476 CA HIS 158 -13.809 -8.685 54.925 1.00 13.60 ATOM 1477 CB HIS 158 -14.763 -7.495 55.061 1.00 13.48 ATOM 1478 CG HIS 158 -16.195 -7.824 54.759 1.00 12.57 ATOM 1479 CD2 HIS 158 -17.222 -8.159 55.574 1.00 7.29 ATOM 1480 NDl HIS 158 -16.705 -7.830 53.479 1.00 12.96 ATOM 1481 HDl HIS 158 -16.243 -7.591 52.643 1.00 0.00 ATOM 1482 CEl HIS 158 -17.984 -8.158 53.516 1.00 9.68 ATOM 14a3 NE2 HIS 158 -18.321 -8.364 54.776 1.00 10.23 ATOM 1484 HE2 HIS 158 -19.222 -8.640 55.059 1.00 0.00 ATOM 1485 C HIS 158 -14.173 -9.752 55.957 1.00 13.56 ATOM 1486 O HIS 158 -13.696 -9.718 57.085 1.00 12.70 ATOM 1487 N GLU 159 -14.999 -10.709 55.551 1.00 16.31 1~ ATOM 1488 H GLU 159 -15.284 -10.757 54.616 1 00 0.00 ATOM 1489 CA GLU 159 -15.451 -11.779 56.434 1.00 21.01 ATOM 1490 CB GLU 159 -16.550 -12.589 55.749 1.00 21.32 ATOM 1491 CG GLU 159 -17.756 -11.749 55.365 1.00 26.36 ATOM 1492 CD GLU 159 -18.864 -12.541 54.710 1.00 30.62 ATOM 1493 OEl GLU 159 -18.718 -13.769 54.541 1.00 36.67 ATOM 1494 OE2 GLU 159 -19.892 -11.925 54.360 1.00 36.45 ATOM 1495 C GLU 159 -14.354 -12.715 56.930 1.00 23.45 ATOM 1496 O GLU 159 -14.571 -13.489 57.868 1.00 26.52 ATOM 1497 N ARG 160 -13.178 -12.631 56.316 1.00 23.94 2~ ATOM 1498 H ARG 160 -13.026 -11.977 55.608 1.00 0.00 ATOM 1499 CA ARG 160 -12.052 -13.481 56.682 1.00 24.21 ATOM 1500 CB ARG 160 -11.340 -13.972 55.419 1.00 26.28 ATOM 1501 CG ARG 160 -12.276 -14.488 54.342 1.00 29.92 ATOM 1502 CD ARG 160 -11.522 -15.319 53.331 1.00 35.32 ATOM 1503 NL ARG 160 -10.957 -16.502 53.971 1.00 38.70 ATOM 1504 HE ARG 160 -10.355 -16.364 54.730 1.00 0.00 ATOM 1505 CZ ARG 160 -11.186 -17.749 53.578 1.00 41.35 ATOM 1506 NHl ARG 160 -11.965 -17.989 52.530 1.00 41.68 ATOM 1507 HHll ARG 160 -12.388 -17.232 52.035 1.00 0.00 3~ ATOM 1508 HH12 ARG 160 -12.144 -18.927 52.235 1.00 0.00 ATOM 1509 NH2 ARG 160 -10.669 -18.759 54.266 1.00 43.07 ATOM 1510 HH21 ARG 160 -10.108 -18.586 55.074 1.00 0.00 ATOM 1511 HH22 ARG 160 -10.839 -19.698 53.968 1.00 0.00 ATOM 1512 C ARG 160 -11.046 -12.749 57.562 1.00 23.53 SUBSTtTUTE S~tE~ ~RULE 2~;) CA 02226963 l998-02-l2 WO 97/083p0 PCT~US96/13918 ATOM 1513 O ARG160 -10.110 -13.355 58.090 1.00 23.47 ATOM 1514 N SEM161 -11.239 -11.444 57.716 1.00 21 32 ATOM 1515 H SEM161 -12.039 -11.020 57.353 1.00 0.00 ATOM 1516 CA SEM161 -10.329 -10.623 58.501 1.00 18.41 5 ATOM 1517 CB SEM161 -10.334 -9.192 57.963 1.00 18.20 ATOM 1518 CG SEM161 -10.002 -9.089 56.474 1.00 17.50 ATOM 1519 A SEM161 -8.302 -9.909 56.033 1.00 19.57 ATOM 1520 CE SEM161 -7.032 -8.759 56.813 1.00 18.11 ATOM 1521 C SEM161 -10,665 -10.643 59.990 1.00 16.60 ATOM 1522 O SEM 161 -11.834 -10.647 60.370 1.00 17.62 ATOM 1523 N PRO162 -*** -10.613 60.850 1.00 16.11 ATOM 1524 CD PRO162 -8 216 -10.576 60.459 1.00 17.97 ATOM 1525 CA PRO162 -9.766 -10.629 62.314 1.00 17.72 ATOM 1526 CB PRO162 -8.326 -10.423 62.779 1.00 17.28 ATOM 1527 CG PRO 162 -7.530 -11.077 61.704 1.00 19.86 ATOM 1528 C PRO162 -10.669 -9.526 62.867 1.00 18.86 ATOM 1529 O PRO162 -11.363 -9.716 63.869 1.00 17.42 ATOM 1530 N TRP163 -10.633 -8.368 62.215 1.00 18.22 ATOM 1531 H TRP163 -10.058 -8.304 61.429 1.00 0.00 ATOM 1532 CA TRP 163 -11.419 -7.214 62.634 1.00 14.35 ATOM 1533 CB TRP163 -10.816 -5.914 62.076 1.00 12.07 ATOM 1534 CG TRP163 -10.401 -5.950 60.614 1.00 11.68 ATOM 1535 CD2 TRP 163 -11.256 -5.810 59.471 1.00 10.99 ATOM 1536 CE2 TRP 163 -10.426 -5.805 58.326 1.00 11.80 ATOM 1537CE3 TRP 163 -12.641 -5.682 59 303 1.00 12.54 ATOM 1538 CDl TRP 163 -9.124 -6.034 60.126 1.00 10.94 ATOM 1539 NEl TRP 163 -9.133 -5.941 58.754 1.00 12.98 ATOM 1540 HEl TRP 163 -8.326 -5.895 58.178 1.00 0.00 ATOM 1541 CZ2 TRP 163 -10.938 -5.674 57.030 1.00 11.75 ATOM 1542CZ3 TRP 163 -13.151 -5.550 58.012 1.00 15.49 ATOM 1543 CH2 TRP 163 -12.299 -5.548 56.894 1.00 11.88 ATOM 1544 C TRP163 -12.915 -7.278 62.354 1.00 13.04 ATOM 1545 O TRP163 -13.662 -6.417 62.816 1.00 14.42 ATOM 1546 N TYR164 -13.363 -8.280 61.607 1.00 13.04 ATOM 1547 H TYR 164 -12.770 -8.981 61.266 1.00 0.00 ATOM 1548 CA TYR164 -14.783 -8.400 61.317 1.00 14.03 ATOM 1549 CB TYR164 -15.034 -8.901 59.893 1.00 11.45 ATOM 1550 CG TYR164 -16.502 -8.909 59.522 1.00 10.45 ATOM 1551 CDl TYR 164 -17.209 -7.717 59.384 1.00 11.63 SUE~STiTUTE ~HFE~ tRuLE 26) W O 97/08300 PCT~US96/13918 ATOM 1552 CEl TYB~ 164 -18.568 -7.714 59.062 1.00 11.94 ATOM 1553 CD2 TYR 164 -17.189 -10.107 59.326 1.00 11.28 ATOM 1554 CE2 TYR 164 -18.543 -10.114 59.002 1.00 12.61 ATOM 1555 CZ TYR 164 -19.225 -8.917 58.873 1.00 13.23 ~ 5 ATOM 1556 OH TYR 164 -20.563 -8.923 58.556 1.00 18.84 ATOM 1557 HH TYR 164 -20.907 -8.037 58.691 1.00 0,00 ATOM 1558 C TYR 164 -15.466 -9.327 62.311 1.00 14.87 ATOM 1559 O TYR 164 -15.013 -10.447 62.538 1.00 15.57 ATOM 1560 N HIS 165 -16.552 -8.846 62.908 1.00 15.89 10 ATOM 1561 H HIS 165 -16.875 -7.950 62.663 1.00 0.00 ATOM 1562 CA HIS 165 -17.315 -9.622 63.878 1.00 17.82 ATOM 1563 CB HIS 165 -17.376 -8.902 65.231 1.00 18.47 ATOM 1564 CG HIS 165 -16.045 -8.762 65.910 1.00 16.54 ATOM 1565 CD2 HIS 165 -14.915 -8.114 65.538 1.00 14.16 15 ATOM 1566 NDl HIS 165 -15.776 -9.320 67.142 1.00 14.58 ATOM 1567 HDl HIS 165 -16.276 -9.959 67.702 1.00 0.00 ATOM 1568 CEl HIS 165 -14.541 -9.018 67.500 1.00 15.81 ATOM 1569 NE2 HIS 165 -13.997 -8.289 66.543 1.00 15.66 ATOM 1570 HE2 HIS 165 -13.064 -8.031 66.556 1.00 0.00 20 ATOM 1571 C HIS 165 -18.713 -9.820 63.321 1.00 18.44 ATOM 1572 ~ HIS 165 -19.497 -8.876 63.238 1.00 19.84 ATOM 1573 N SER 166 -19.007 -11.056 62.925 1.00 21.85 ATOM 1574 H SER 166 -18.316 -11.751 62.997 1.00 0.00 ATOM 1575 CA SER 166 -20.296 -11.434 62 345 1 00 24 63 25 ATOM 1576 CB SER 166 -20 289 -12.922 61.981 1.00 25.45 ATOM 1577 OG SER 166 -19.253 -13.209 61.056 1.00 36.62 ATOM 1578 HG SER 166 -18.382 -13.082 61.448 1.00 0.00 ATOM 1579 C SER 166 -21.521 -11.138 63.203 1.00 24.57 ATOM 1580 O SER 166 -22.593 -10.850 62.672 1.00 24.97 30 ATOM 1581 N SER 167 -21.382 -11.261 64.518 1.00 25.49 ATOM 1582 H SER 167 -20.541 -11.538 64.921 1.00 0.00 ATOM 1583 CA SER 167 -22.504 -11.000 65.408 1.00 30.48 ATOM 1584 CB SER 167 -23.222 -12.301 65.777 1.00 31.09 ATOM 1585 OG SER 167 -23.709 -12.957 64.618 1.00 36.91 35 ATOM 1586 HG SER 167 -24.177 -12.308 64.074 1.00 0.00 ATOM 1587 C SER 167 -22.069 -10.265 66.662 1.00 30.67 ATOM 1588 O SER 167 -21.564 -10.863 67.617 1.00 34.44 ATOM 1589 N LEU 168 -22.237 -8.952 66.629 1.00 27.52 ATOM 1590 H LEU 168 -22.633 -8.515 65.836 1.00 0.00 SUE~STITUTE ~F~ ~RULE 26~

CA 02226963 l998-02-l2 W O 97/0830~ PCTAUS96113918 ATOM 1591 CA LEU168 -21.894 -8.096 67.747 1.00 23.85 ATOM 1592 CB LEU 168-20.504 -7.487 67.587 1.00 23.06 ATOM 1593 CG LEU 168-19.283 -8.162 68.190 1.00 22.81 ATOM 1594 CDl LEU168 -18.189 -7.116 68.286 1.00 20.60 ATOM 1595 CD2 LEU 168 -19.596 -8.715 69.558 1.00 22.00 ATOM 1596 C LEU 168-22.886 -6.969 67.769 1.00 22.39 ATOM 1597 O LEU 168-23.127 -6.325 66.747 1.00 23.43 ATOM 1598 N THR 169-23.498 -6.751 68.920 1.00 20.11 ATOM 1599 H THR 169-23.297 -7.292 69.704 1.00 0.00 ATOM 1600 CATHR 169 -24.431 -5.655 69.047 1.00 18.64 ATOM 1601 CB THR 169-25.503 -5.944 70.120 1.00 20.52 ATOM 1602 OGl THR169 -24.876 -6.164 71.390 1.00 21.40 ATOM 1603 HGl THR169 -25.601 -6.350 72.002 1.00 0.00 ATOM 1604 CG2 THR169 -26.313 -7.180 69.738 1.00 22.55 ATOM 1605 C THR 169 -23.547 -4.494 69.485 1.00 16.14 ATOM 1606 O THR 169 -22.355 -4.682 69.759 1.00 14.33 ATOM 1607 N ARG 170 -24.125 -3.304 69.557 1.00 17.90 ATOM 1608 H ARG 170 -25.076 -3.202 69.314 1.00 0.00 ATOM 1609 CA ARG 170 -23.383 -2.125 69.975 1.00 16.65 ATOM 1610 CB ARG 170 -24.302 -0.907 69.956 1.00 15.78 ATOM 1611 CG ARG 170 -23.645 0.392 70.358 1.00 16.09 ATOM 1612 CD ARG 170 -24.672 1.495 70.345 1.00 17.74 ATOM 1613 NE ARG 170 -24.099 2.796 70.649 1.00 17.11 ATOM 1614 HE ARG 170 -23.788 2.980 71.549 1.00 0.00 ATOM 1615 CZ ARG 170 -23.966 3.775 69.762 1.00 16.57 ATOM 1616 NHl ARG170 -23.442 4.933 70.132 1.00 15.48 ATOM 1617 HHll ARG 170-23.176 5.091 71.081 1.00 0.00 ATOM 1618 HH12 ARG 170-23.372 5.687 69.486 1.00 0.00 ATOM 1619 NH2 ARG 170-24.327 3.589 68.501 1.00 15.05 ATOM 1620 HH21 ARG 170 -24.701 2.709 68.207 1.00 0.00 ATOM 1621 HH22 ARG 170-24.185 4.334 67.852 1.00 0.00 ATOM 1622 C ARG 170-22.799 -2.329 71.375 1.00 16.82 ATOM 1623 O ARG 170-21.631 -2.013 71.616 1.00 16.43 ATOM 1624 N GLU 171-23.603 -2.877 72.284 1.00 16.19 ATOM 1625 H GLU 171 -24.524 -3.101 72.035 1.00 0.00 ATOM 1626 CA GLU 171-23.157 -3.114 73.654 1.00 17.65 ATOM 1627 CB GLU 171-24.296 -3.656 74.521 1.00 20.42 ATOM 1628 CG GLU 171-23.890 -3.861 75.985 1.00 28.15 ATOM 1629 CD GLU 171-24.931 -4.598 76.818 1.00 33.50 SUBST~TUTE S~tEE~ ~RULE 2~) CA 02226963 l998-02-l2 WO 97/083~0 PCTAUS96/13918 ATOM 1630 OEl GLU171 -24.529 -5.400 77.688 1.00 35.78 ATOM 1631 OE2 GLU171 -26.144 -g.371 76.619 1.00 38.13 ATOM 1632 C GLU171 -21.980 -4.075 73.721 1.00 15.35 ATOM 1633 ~ GLU171 -20.990 -3.816 74.418 1.00 13.06 ~ 5 ATOM 1634 N GLU172 -22.095 -5.187 73.001 1.00 16.60 ATOM 1635 H GLU172 -22.905 -5.331 72.465 1.00 0.00 ATOM 1636 CA GLU172 -21.041 -6.193 72.977 1.00 16.42 ATOM 1637 CB GLU172 -21.497 -7.427 72.206 1.00 18.60 ATOM 1638 CG GLU172 -22.697 -8.119 72.818 1.00 24.77 10 ATOM 163g CD GLU172 -23.255 -9.223 71.940 1.00 30.30 ATOM 1640 OEl GLU172 -23.063 -9.176 70.706 1.00 30.79 ATOM 1641 OE2 GLU 172 -23.901 -10.141 72.486 1.00 35.30 ATOM 1642 C GLU172 -19.780 -5.617 72.357 1.00 15.63 ATOM 1643 o GLU172 -18.674 -5-933 72.790 1.00 18.34 ATOM 1644 N ALA173 -19.946 -4.763 71.351 1.00 16.15 ATOM 1645 H ALA173 -20.848 -4.556 71.029 1.00 0.00 ATOM 1646 CA ALA173 -18.805 -4.132 70.695 1.00 13.89 ATOM 1647 CB ALA173 -19.273 -3.292 69.520 1.00 14.91 ATOM 1648 C ALA173 -18.053 -3.266 71.703 1.00 11.93 ATOM 1649 ~ ALA173 -16.831 -3.338 71.806 1.00 12.06 ATOM 1650 N GLU174 -18.791 -2.471 72.471 1.00 13.97 ATOM 1651 H GLU174 -19.767 -2.481 72.349 1.00 0.00 ATOM 1652 CA GLU174 -18.178 -1.603 73.471 1.00 13.42 ATOM 1653 CB GLU174 -19.204 -0.636 74.064 1.00 12.52 ATOM 1654 CG GLU174 -19.696 0.413 73.072 1.00 13.96 ATOM 1655 CD GLU174 -20.406 1.582 73.734 1.00 16.34 ATOM 1656 OEl GLU174 -20.943 2.438 73.004 1.00 17.65 ATOM 1657 OE2 GLU174 -20.423 1.658 74.979 1.00 20.00 ATOM 1658 C GLU 174 -17.517 -2.418 74.574 1.00 14.72 ATOM 1659 ~ GLU 174 -16.446 -2.059 75.062 1.00 16.13 ATOM 1660 N ARG 175 -18.144 -3.S25 74.953 1.00 16.98 ATOM 1661 H ARG 175 -18.996 -3.758 74.523 1.00 0 00 ATOM 1662 CA ARG 175 -17.592 -4.387 75.987 1.00 17.73 ATOM 1663 CB ARG175 -18.566 -5.516 76.317 1.00 20.45 ATOM 1664 CG ARG175 -18.072 -6.491 77.373 1.00 27.83 ATOM 1665 CD ARG175 -19.238 -7.101 78.146 1.00 32.77 ATOM 1666 NE ARG175 -20.332 -7.531 77.274 1.00 38.89 ATOM 1667 HE ARG175 -20.118 -8.137 76.537 1.00 0.00 ATOM 1668 CZ ARG175 -21.602 -7.152 77.416 1.00 41.12 SUE~STlTUT} ~E~ tRULE 2f;) CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATOM 1669 NHl ARG 175-21.955 -6.333 78.400 1.00 40.50 ATOM 1670 HXll ARG 175-21.266 -5.992 79.041 1.00 0.00 ATOM 1671 HH12 ARG 175-22.906 -6.052 78.508 1.00 0.00 ATOM 1672 NX2 ARG 175-22.522 -7.585 76.563 1.00 42.19 ATOM 1673 HH21 ARG 175 -22.264 -8.200 75.819 1.00 0.00 ATOM 1674 HX22 ARG 175-23.475 -7.301 76.675 1.00 0.00 ATOM 1675 C ARG 175-16.245 -4.944 75.542 1.00 18.13 ATOM 1676 O ARG 175-15.305 -4.989 76.330 1.00 17.99 ATOM 1677 N LYS 176-16.133 -5.319 74.270 1.00 19.22 ATOM 1678 H LYS 176 -16.906 -5.249 73.671 1.00 0.00 ATOM 1679 CA LYS 176-14.872 -5.853 73.757 1.00 19.25 ATOM 1680 CB LYS 176-15.070 -6.569 72.420 1.00 20.57 ATOM 1681 CG LYS 176-15.907 -7.827 72.531 1.00 24.61 ATOM 1682 CD LYS 176-15.949 -8.609 71.230 1.00 31.16 ATOM 1683 CELYS 176 -14.759 -9.547 71.088 1.00 36.55 ATOM 1684 NZ LYS 176-13.455 -8.837 70.995 1.00 41.60 ATOM 1685 HZl LYS176 -13.289 -8.308 71.876 1.00 0.00 ATOM 1686 HZ2 LYS176 -13.483 -8.179 70.192 1.00 0.00 ATOM 1687 HZ3 LYS176 -12.687 -9.525 70.849 1.00 0.00 ATOM 1688 C LYS 176 -13.806 -4.776 73.622 1.00 19.16 ATOM 1689 O LYS 176-12.645 -5.006 73.952 1.00 20.81 ATOM 1690 N LEU 177-14.199 -3.597 73.150 1.00 18.33 ATOM 1691 H LEU 177-15.133 -3.466 72.878 1.00 0.00 ATOM 1692 CA LEU 177-13.251 -2.499 72.994 1.00 18.62 ATOM 1693 CBLEU 177 -13.857 -1.375 72.153 1 00 14.79 ATOM 1694 CG LEU 177-14.119 -1.701 70.681 1.00 14.52 ATOM 1695 CDl LEU177 -14.746 -0.502 70.016 1.00 14.81 ATOM 1696 CD2 LEU177 -12.833 -2.073 69.972 1.00 12.01 ATOM 1697 C LEU 177-12.742 -1.950 74.328 1.00 19.76 ATOM 1698 O LEU 177 -11.562 -1.628 74.456 1.00 20.72 ATOM 1699 N TYR 178-13.632 -1.839 75.312 1.00 20.07 ATOM 1700 H TYR 178-14.555 -2.105 75.139 1.00 0.00 ATOM 1701 CA TYR 178-13.263 -1.334 76.634 1.00 21.20 ATOM 1702 CB TYR 178-14.507 -0.935 77.425 1.00 18.72 ATOM 1703 CGTYR 178 -15.063 0.420 77.073 1.00 16.53 ATOM 1704 CDl TYR178 -14.238 1.543 77.029 1.00 17.03 ATOM 1705 CEl TYR178 -14.752 2.796 76.738 1.00 14.85 ATOM 1706 CD2 TYR178 -16.418 0.587 76.813 1.00 15.41 ATOM 1707 CE2 TYR178 -16.942 1.833 76.520 1.00 14.24 .

SUBSTiTUTE ~{E~ ~RULE 2~i) CA 02226963 l998-02-l2 ATOM 1708 CZ TYR178-16.105 2.935 76.485 1.00 15.80 ATOM 1709 OH TYR178-16.624 4.177 76.198 1.00 17.17 ATOM 1710 HH TYR178-17.593 4.110 76.183 1.00 0.00 ATOM 1711 C TYR178-12.471 -2.349 77.446 1.00 24.65 5 ATOM 1712 O TYR178-11.596 -1.986 78.233 1.00 26.95 ATOM 1713 N SER179-12.791 -3.622 77 266 1.00 31.05 ATOM 1714 H SER179-13.473 -3.885 76.617 1.00 0.00 ATOM 1715 CA SER179-12.116 -4.680 77.998 1.00 35.86 ATOM 1716 CB SER179-13.067 -5.861 78.220 1.00 37.01 ATOM 1717 OG SER 179 -14.265 -5.444 78.868 1.00 38.69 ATOM 1718 HG SER179-14.778 -5.012 78 177 1.00 0.00 ATOM 1719 C SER179-10.869 -5.126 77.251 1.00 39.08 ATOM 1720 O SER179-10.909 -6.065 76.456 1.00 42.60 ATOM 1721 N GLY180-9.765 -4.432 77.498 1.00 42.38 ATOM 1722 H GLY 180 -9 787 -3.665 78.115 1 00 0.00 ATOM 1723 CA GLY180-8.516 -4.773 76.846 1.00 45.79 ATOM 1724 C GLY180-7.445 -3.734 77.103 1.00 47.21 ATOM 1725 O GLY180-7.400 -3.126 78.171 1.00 47.24 ATOM 1726 N ALA181-6.590 -3.519 76.109 1.00 48.92 ATOM 1727 H ALA 181 -6.697 -4.028 75.282 1.00 0.00 ATOM 1728 CA ALA181-5.508 -2.549 76.222 1.00 50.24 ATOM 1729 CB ALA181-4 423 -2.857 75.197 1.00 49.84 ATOM 1730 C ALA181-6.006 -1.111 76 055 1.00 51.23 ATOM 1731 O ALA181-5.331 -0.165 76.465 1 00 54.12 ATOM 1732 N GLN 182 -7.179 -0.953 75.446 1.00 50.07 ATOM 1733 H GLN182-7.676 -1.742 75.154 1.00 0.00 ATOM 1734 CA GLN182-7.772 0.365 75.214 1.00 47.88 ATOM 1735 CB GLN182-8.274 0.993 76.521 1 00 49.86 ATOM 1736 CG GLN182-9 511 0.332 77.103 1.00 53.43 ATOM 1737 CD GLN 182 -10.189 1.192 78.152 1.00 57.83 ATOM 1738 OEl GLN182 -10.327 0.796 79.308 1~00 60.70 ATOM 1739 NE2 GLN182 -10.616 2.383 77.752 1.00 58.70 ATOM 1740 HE21 GLN 182 -10.461 2.650 76.828 1~00 0.00 ATOM 1741 HE22 GLN 182 -11.079 2.922 78.427 1.00 0.00 ATOM 1742 C GLN 182 -6.832 1.332 74.497 1.00 43.44 ATOM 1743 O GLN182-6.892 2.548 74.703 1.00 41.92 ATOM 1744 N THR183-5.972 0.789 73.643 1.00 39.92 ATOM 1745 H THR183-5.956 -0.170 73.460 1.00 0.00 ATOM 1746 CA THR183-5.036 1.606 72.891 1.00 36.35 SUBSTiTUTE ~ RULE 26~

CA 02226963 l998-02-l2 W O 97/08300 PCTrUS96113918 ATOM 1747 CB THR183 -3.864 0.758 72.357 1.~_ 38.51 ATOM 1748 OGl THR183 -4.351 -0.519 71.923 l C0 42.00 ATOM 1749 HGl THR183 -3.917 -0.732 71.092 1.00 0.00 ATOM 1750 CG2 THR183 -2.830 0.542 73.457 1.00 39.77 5 ATOM 1751 C THR 183 -5.758 2.321 71.749 1.30 32.35 ATOM 1752 O THR 183 -6.676 1.772 71.132 1.30 29.04 ATOM 1753 N ASP 184 -5.367 3.567 71.508 1.30 27.99 ATOM 1754 H ASP 184 -4.644 3.943 72.040 l.v0 0.00 ATOM 1755 CA ASP184 -5.975 4.376 70.460 1.30 27.05 ATOM 1756CB ASP 184 -5.285 5.742 70.374 1.00 27.76 ATOM 1757 CG ASP184 -5.617 6.647 71.553 1.00 29.09 ATOM 1758 ODl ASP184 -4.767 7.483 71.914 1.00 30.44 ATOM 1759 OD2 ASP184 -6.729 6.539 72.109 1.00 30.19 ATOM 1760 C ASP 184 -5.973 3.701 69.092 1.00 23.21 t5 ATOM 1761O ASP 184 -5.000 3.054 68.704 1.3û 22.81 ATOM 1762 N GLY 185 -7.088 3.826 68.385 1 _0 22.28 ATOM 1763 H GLY 185 -7.863 4.278 68.784 l.C0 0.00 ATOM 1764 CA GLY185 -7.200 3.235 67.068 1.00 20.98 ATOM 1765 C GLY185-7.690 1.800 67.065 1.00 20.58 ATOM 1766 o GLY 185 _7.879 1.223 65.994 l.C0 21.98 ATOM 1767 N LYS186-7.847 1.198 68.241 1.00 19.39 ATOM 1768 H LYS186-7.620 1.668 69.072 1.00 0.00 ATOM 1769 CA LYS186-8.343 -0.173 68.330 1.30 19.96 ATOM 1770 CB LYS186-8.385 -0.628 69.790 l.a0 24.49 ATOM 1771 CG LYS 186 -8.935 -2.022 69.996 l.u3 30.49 ATOM 1772 CD LYS186-8.020 -3.081 69.408 l.û3 39.02 ATOM 1773 CE LYS186-6.799 -3.343 70.288 1.30 47.08 ATOM 1774 NZ LYS186-5.832 -2.209 70.348 1.30 51.52 ATOM 1775 HZl LYS186 -6.284 -1.364 70.753 1.00 0.00 ATOM 1776HZ2 LYS 186 -5.492 -1.990 69.391 1.00 0.00 ATOM 1777 HZ3 LYS186 -5.026 -2.478 70.946 1.00 0.00 ATOM 1778 C LYS186-9.753 -0.153 67.742 1.00 17.33 ATOM 1779 O LYS186-10.603 0.617 68.198 1.00 17.32 ATOM 1780 N PHE187-10.008 -1~010 66.756 1.00 14.12 ATOM 1781 H PHE 187 -9.312 -1.637 66.467 1.00 0.00 ATOM 1782 CA PHE187-11.305 -1.032 66.092 1.00 10.45 ATOM 1783 CB PHE187-11.202 -0.237 64.786 1.00 11.01 ATOM 1784 CG PHE187-10.455 -0.967 63.697 1.00 12.30 ATOM 1785 CDl PHE187 -11.142 -1.525 62.618 1.00 11.77 SUBSTlTUTE S~tE~ (RULE 26) CA 02226963 l998-02-l2 WO 97/08300 PCTrUS96/139l8 ATOM 1786 CD2 PHE187 -9.073 -1.137 63.770 1.00 10.05 ATOM 1787 CEl PHE187 -10.461 -2.246 61 635 1.00 10.76 ATOM 1788 CE2 PHE187 -8.385 -1.857 62.788 1.00 10.66 ATOM 1789 CZ PHE187-g.081 -2.411 61.723 1.00 8.89 5 ATOM 1790 C PHE187-11.844 -2.421 65.754 1.00 11.49 ATOM 1791 O PHE187-11.157 -3.432 65 903 1.00 12.56 ATOM 1792 N LEU188-13.071 -2.437 65.243 1 00 11.03 ATOM 1793 H LEU188-13.567 -1.591 65.168 1.00 0.00 ATOM 1794 CA LEU188-13.752 -3.644 64.802 1.00 10.57 ATOM 1795 CB LEU 188 -14.276 -4.474 65.988 1.00 13.68 ATOM 1796 CG LEU188-15.280 -3.955 67.030 1.00 12.79 ATOM 1797 CDl LEU188 -16.689 -3.832 66.447 1.00 12.29 ATOM 1798 CD2 LEU188 -15.290 -4.941 68.190 1.00 10.52 ATOM 1799 C LEU188-14.888 -3.218 63.881 1_00 10.06 ATOM 1800 O LEU 188 -15.359 -2.082 63.956 1.00 11.34 ATOM 1801 N LEU189-15.286 -4.107 62.980 1.00 11.08 ATOM 1802 H LEU189-14.863 -4.989 62.944 1.00 0.00 ATOM 1803 CA LEU189-16.363 -3.830 62.039 1 00 11.26 ATOM 1804 CB LEU189-15.845 -3.967 60.597 1.00 14.05 ATOM 1805 CG LEU 189 -16.568 -3.364 59.379 1.00 18.08 ATOM 1806 CDl LEU189 -17.908 -4.020 59.126 1 00 20.55 ATOM 1807 CD2 LEU189 -16.725 -1.869 59.551 1 00 21.24 ATOM 1808 C LEU189-17.449 -4.858 62.332 1.00 10.17 ATOM 1809 o LEU189-17.160 -6.037 62.539 1.00 9,97 ATOM 1810 N ARG 190 -18.696 -4.416 62.364 1 00 8.42 ATOM 1811 H ARG190-18.893 -3.469 62.193 1.00 0.00 ATOM 1812 CA ARG190-19.803 -5.313 62.658 1.00 10.21 ATOM 1813 CB ARG190-20.199 -5.183 64.137 1.00 12.50 ATOM 1814 CG ARG190-20.586 -3.758 64.560 1.00 11.39 ATOM 1815 CD ARG 190 -20.747 -3.613 66.072 1.00 10.81 ATOM 1816 NE ARG190-20.865 -2.210 66.479 1.00 10.25 ATOM 1817 HE ARG190-20.054 -1.759 66.795 1.00 0.00 ATOM 1818 CZ ARG190-21.993 -1.501 66.454 1.00 8.67 ATOM 1819 NHl ARG190 -23.133 -2.044 66.050 1.00 8.01 ATOM 1820 HHll ARG 190 -23.143 -3.001 65.758 1.00 0.00 ATOM 1821 HH12 ARG190-23.970 -1.501 66.030 1.00 0.00 ATOM 1822 NH2 ARG190-21.975 -0.220 66.799 1.00 11.12 ATOM 1823 HH21 ARG190-21.118 0.212 67.080 1.00 0.00 ATOM 1824 HHZ2 ARG190-22.814 0.312 66.777 1.00 0.00 SUBST~TUTE ~tE~ (RULE 76~

CA 02226963 l998-02-l2 W O 97/08300 PCT~US96113918 ATOM 1825 C ARG 190-20.996 -4.977 61.789 1.00 12.50 ATOM 1826 O ARG 190-21.172 -3.826 61.380 1.00 14.16 ATOM 1827 N PRO 191-21.785 -5.991 61.416 1.00 14.16 ATOM 1828 CD PRO 191-21.581 -7.440 61.603 1.00 14.81 5 ATOM 1829 CA PRO 191-22.960 -5.721 60.587 1.00 14.23 ATOM 1830 CB PRO 191-23.281 -7.094 60.004 1.00 15.24 ATOM 1831 CG PRO 191-22.890 -8.023 61.119 1.00 16.17 ATOM 1832 C PRO 191-24.081 -5.222 61.500 1.00 14.24 ATOM 1833 O PRO 191-24.039 -5.444 62.712 1.00 15.68 ATOM 1834 N ARG 192 -25.036 -4.492 60.937 1.00 15.51 ATOM 1835 H ARG 192-25.006 -4.277 59.982 1.00 0.00 ATOM 1836 CA ARG 192-26.164 -3.988 61.712 1.00 18.28 ATOM 1837 CB ARG 192-26.369 -2.489 61.458 1.00 13.36 ATOM 1838 CG ARG 192-25.210 -1.623 61.914 1.00 11.77 ATOM 1839 CDARG 192 -25.445 -0.158 61.606 1.00 12.79 ATOM 1840 NE ARG 192-26.554 0.404 62.374 1.00 13.77 ATOM 1841 HE ARG 192-26.455 0.472 63.346 1.00 0.00 ATOM 1842 CZ ARG 192-27.707 0.809 61.849 1.00 15.28 ATOM 1843 NHl ARG192 -27.925 0.718 60.544 1.00 14.55 ATOM 1844 HHll ARG 192 -27.221 0.344 59.941 1.00 0.00 ATOM 1845 HH12 ARG 192-28.799 1.013 60.162 1.00 0.00 ATOM 1846 NH2 ARG 192-28.643 1.322 62.631 1.00 16.15 ATOM 1847 HH21 ARG 192-28.468 1.402 63.611 1.00 0.00 ATOM 1848 HH22 ARG 192-29.515 1.625 62.246 1.00 0.00 ATOM 1849 C ARG 192 -27.406 -4.779 61.311 1.00 20.44 ATOM 1850 O ARG 192-27.345 -5.612 60.404 1.00 21.80 ATOM 1851 N LYS 193-28.523 -4.532 61.988 1.00 26.86 ATOM 1852 H LYS 193-28.484 -3.869 62.709 1.00 0.00 ATOM 1853 CA LYS 193-29.773 -5.232 61.690 1.00 30.35 ATOM 1854 CBLYS 193 -30.876 -4.793 62.654 1.00 34.92 ATOM 1855 CG LYS 193-30.577 -5.067 64.117 1.00 42.06 ATOM 1856 CD LYS 193-31.765 -4.694 64.990 1.00 48.13 ATOM 1857 CE LYS 193-31.490 -4.992 66.457 1.00 52.32 ATOM 1858 NZ LYS 193-32.702 -4.794 67.307 1.00 53.88 ATOM 1859 HZl LYS 193 -33.436 -5.457 66.987 1.00 0.00 ATOM 1860 HZ2 LYS193 -33.047 -3.819 67.206 1.00 0.00 ATOM 1861 HZ3 LYS193 -32.473 -4.984 68.304 1.00 0.00 ATOM 1862 C LYS 193 -30.226 -5.004 60.246 1.00 32.33 ATOM 1863 O LYS 193 -30.611 -5.950 59.557 1.00 33.07 - 12~ -5138STITUTE ~EE~ tRul-E 2~-J

CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 1864 N GLU 194-30.176 -3.751 59.795 1.00 31.89 ATOM 1865 H GLU 194-29.824 -3.055 60.377 1.00 0.00 ATOM 1866 CA GLU 194-30.575 -3.401 58.430 1.00 31.91 ATOM 1867 CB GLU 194-30.744 -1.884 58.274 1.00 32.74 ATOM 1868 CGGLU 194 -32.021 -1.301 58.861 1.00 35.26 ATOM 1869 CD GLU 194-32.036 -1.294 60.376 1.00 36.36 ATOM 1870 OEl GLU194 -32.968 -1.885 60.956 1 00 40,45 ATOM 1871 oE2 GLU194 -31.128 -0.694 60.989 1.00 38.26 ATOM 1872 C GLU 194 -29.541 -3.882 57.424 1.00 30.11 ATOM 1873O GLU 194 -28.362 -3.556 57.536 1.00 31.42 ATOM 1874 N GLN 195 -29.986 -4.651 56.438 1.00 30.67 ATOM 1875 H GLN 195 -30.939 -4.860 56.409 1.00 0.Q0 ATOM 1876 CA GLN195 -29.097 -5.168 55.405 1.00 30.73 ATOM 1877 CB GLN195 -29.866 -6.090 54.460 1.00 37.53 1~ ATOM 1878CG GLN 195 -30.238 -7.431 55.070 1.00 48.32 ATOM 1879 CD GLN195 -Z9.120 -8.457 54.969 1.00 54.80 ATOM 1880 OEl GLN195 -29.252 -9.457 54.264 1.00 59.01 ATOM 1881 NE2 GLN195 -28.016 -8.216 55.669 1.00 57.50 ATOM 1882 HE21 GLN 195 -27.917 -7.416 56.226 1.00 0.00 ATOM 1883 HE22 GLN 195 -27.317 -8.894 55.589 1.00 0.00 ATOM 1884 C GLN 195-28.477 -4.024 54.617 1 00 27.43 ATOM 1885 O GLN 195-29.171 -3.094 54 209 1.00 26.89 ATOM 1886 N GLY 196-27.170 -4.095 54.410 1.00 24.53 ATOM 1887 H GLY 196-26.647 -4.854 54.751 1.00 0.00 ATOM 1888 CAGLY 196 -26.491 -3.050 53.672 1.00 23.48 ATOM 1889 C GLY 196-25.943 -1.969 54.579 1.00 22.43 ATOM 1890 O GLY 196-25.454 -0.946 54.094 1.00 21.55 ATOM 1891 N THR 197-26.067 -2.166 55.891 1.00 19.48 ATOM 1892 H THR 197-26.503 -2.975 56.238 1.00 0.00 ATOM 1893 CATHR 197 -25.548 -1.203 56.852 1.00 17.30 ATOM 1894 CB THR 197-26.665 -0.454 57.610 1.00 18.42 ATOM 1895 OGl THR197 -27.334 -1.352 58.501 1.00 18.98 ATOM 1896 HGl THR197 -27.449 -2.142 57.983 1.00 0.00 ATOM 1897 CG2 THR197 -27.667 0.147 56.635 1.00 17.56 ATOM 1898 C THR 197 -24.652 -1.933 57.841 1.00 16.36 ATOM 1899 ~ THR 197-24.952 -3.057 58.261 1.00 16.10 ATOM 1900 N TYR 198-23.539 -1.294 58.178 1.00 13.90 ATOM 1901 H TYR 198-23.392 -0.390 57.840 1.00 0.00 ATOM 1902 CA TYR 198-22.542 -1.834 59.092 1.00 13.70 SUBST~UTE ~ RULE ;~fi) CA 02226963 l998-02-l2 ATOM 1903 CB TYR 198 -21.324 -2.317 58.302 1.00 15.79 ATOM 1904 CG TYR 198 -21.644 -3.336 57.239 1.00 16.67 ATOM 1905 CDl TYR198 -22.117 -2.941 55.988 1.00 16.60 ATOM 1906 CEl TYR198 -22.441 -3.876 55.016 1.00 18.00 5 ATOM 1907 CD2 TYR198 -21.498 -4.699 5i.490 1.00 17.21 J
ATOM 1908 CE2 TYR198 -21.817 -5.643 56.525 1.00 20.80 ATOM 1909 CZ TYR198 -22.289 -5.226 55.290 1.00 20.28 ATOM 1910 OH TYR198 -22.612 -6.159 54.330 1.00 23.06 ATOM 1911 HH TYR198 -Z2.386 -7.044 54.647 1.00 0.00 1 0 ATOM 1912 C TYR 198 -22.101 -0.708 60.006 1.00 12.46 ATOM 1913 O TYR198 -22.450 0.448 59.783 1.00 15.43 ATOM 1914 N ALA199 -21.317 -1.033 61.019 1.00 12.73 ATOM 1915 H ALA199 -21.033 -1.954 61.164 1.00 0.00 ATOM 1916 CA ALA199 -20.833 -0.012 61.927 1.00 10.15 15 ATOM 1917 CB ALA199 -21.628 -0.023 63.221 1.00 11.67 ATOM 1918 C ALA199 -19.363 -0.225 62.210 1.00 11.06 ATOM 1919 O ALA199 -18.900 -1.361 62.357 1.00 11.49 ATOM 1920 N LEU200 -18.624 0.876 62.204 1.00 10.36 ATOM 1921 H LEU200 -19.053 1.732 62.000 1.00 0.00 20 ATOM 1922 CA LEU200 -17.206 0.870 62.492 1.00 9.26 ATOM 1923 CB LEU200 -16.483 1.830 61.550 1.00 12.13 ATOM 1924 CG LEU200 -15.092 1.470 61.028 1.00 17.52 ATOM 1925 CDl LEU200 -14.463 2.731 60.451 1.00 19.60 ATOM 1926 C32 LEU200 -14.204 0.905 62.129 1.00 20.00 2~ ATOM 1927 C LEU200 -17.122 1.389 63.927 1.00 10.58 ATOM 1928 O LEU200 -17.605 2.483 64.225 1.00 11.51 ATOM 1929 ~ SER201 -16.590 0.577 64.829 1.00 10.65 ATOM 1930 H SER201 -16.248 -0.304 64.561 1.00 0.00 ATOM 1931 CA SER201 -16.465 0.972 66.223 1.00 11.10 30 ATOM 1932 CB SER201 -17.216 -0.016 67.121 1.00 11.49 ATOM 1933 OG SER201 -18.576 -0.156 66.728 1.00 13.41 ATOM 1934 HG SER201 -18.554 -0.583 65.856 1.00 0.00 ATOM 1935 C SER201 -14.998 1.007 66.610 1.00 13.09 ATOM 1936 O SER201 -14.274 0.031 66.405 1.00 15.42 3~ ATOM 1937 N LEU202 -14.538 2.145 67.112 1.00 13.25 ATOM 1938 H LEU202 -15.116 2.931 67.224 1.00 0.00 ATOM 1939 CA LEU202 -13.155 2.258 67.535 1.00 14.15 ATOM 1940 CB LEU202 -12.259 2.865 66.439 1.00 16.72 ATOM 1941 CG LEU202 -12.277 4.272 65.816 1.00 18.51 SUBSTITUTE S~EE~ ~RULE 26) CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 1942 CDl LEU202 -13.589 4.533 65.121 1.00 18.26 ATOM 1943 CD2 LEU202 -11.956 5.347 66.840 1.00 21.05 ATOM 1944 CLEU 202 -13.054 3.024 68.843 1.00 15.33 ATOM 1945 OLEU 202 -13.968 3.753 69.224 1.00 14.20 5 ATOM 1946 NILE 203 -11.973 2.796 69.567 1.00 18.07 ATOM 1947 HILE 203 -11.290 2.170 69.241 1.00 0.00 ATOM 1948 CAILE 203 -11.777 3.470 70.835 1.00 19.49 ATOM 1949 C8ILE 203 -11.514 2.444 71.974 1.00 18.21 ATOM 1950 CG2 ILE203 -10.279 1.623 71.687 1.00 21.96 ATOM 1951CGl ILE 203 -11.419 3.146 73.326 1.00 21.52 ATOM 1952 CDILE 203 -11.46g 2.190 74.496 1.00 21.43 ATOM 1953 CILE 203 -10.669 4.517 70.703 1.00 20.13 ATOM 1954 OILE 203 -9.645 4.288 70.048 1.00 20.26 ATOM 1955 NTYR 204 -10.940 5.707 71.226 1.00 20.23 ATOM 1956 H TYR 204 -11.801 5.874 71.657 1.00 0.00 ATOM 1957 CATYR 204 -9.997 6.809 71.186 1.00 21.84 ATOM 1958 CBTYR 204 -10.257 7.691 69.960 1.00 23.09 ATOM 1959 CGTYR 204 _9,371 8.909 69.903 1.00 28.63 ATOM 1960 CDl TYR204 _7.983 8.783 69.891 1.00 31.65 ATOM 1961CEl TYR 204 -7.160 9,905 69.885 1.00 35.44 ATOM 1962 CD2 TYR204 _9.917 10.189 69.901 1.00 31.96 ATOM 1963 CE2 TYR204 -9.102 11.320 69.894 1.00 36.73 ATOM 1964 CZTYR 204 -7.726 11.171 69.887 1.00 37.11 ATOM 1965 OHTYR 204 -6.915 12.283 69.889 1.00 43.01 ATOM 1966 HH TYR 204 -7.453 13.075 69.817 1.00 0.00 ATOM 1967 CTYR 204 -10.164 7.618 72.465 1.00 21.93 ATOM 1968 OTYR 204 -11.271 8.048 72.792 1.00 20.87 ATOM 1969 NGLY 205 -9.069 7.796 73.199 1.00 22.69 ATOM 1970 HGLY 205 -8.223 7.424 72.920 1.00 0.00 ATOM 1971 CA GLY 205 -9.117 8.540 74.446 1.00 23.60 ATOM 1972 CGLY 205 -10.061 7.891 75.442 1.00 23.74 ATOM 1973 OGLY 205 -10.865 8.572 76.075 1.00 26.62 ATOM 1974 NLYS 206 -9.993 6.565 75.533 1.00 22.74 ATOM 1975 HLYS 206 -9.361 6.092 74.946 1.00 0.00 3~ ATOM 1976 CA LYS 206 -10.834 5.784 76.437 1 00 22.71 ~ ATOM 1977 CBLYS 206 -10.498 6.085 77.900 1.00 26.75 ATOM 1978 CGLYS 206 -9.177 5.500 78.359 1.00 34.97 ATOM 1979 CDLYS 206 -9.136 5.336 79.874 1.00 40.88 ATOM 1980 CELYS 206 -7.962 4.464 80.300 1.00 45.58 SUBST~TUTE S} }E~ tRUI E 26 CA 02226963 l998-02-l2 ATOM 1981 NZ LYS 206 -7.989 4 126 81.753 1.00 48.73 ATOM 1982 HZl LYS206 -8.863 3.613 81.978 1.00 0.00 ATOM 1983 HZ2 LYS206 -7.937 4~997 82.313 1.00 0.00 ATOM 1984 HZ3 LYS206 -7.170 3.524 81.979 1.00 0.00 5 ATOM 1985 C LYS 206-12.326 5.963 76.195 1.00 21.73 ATOM 1986 O LYS 206-13.132 5 757 77,093 1.00 21.98 ATOM 1987 N THR 207-12.685 6.330 74.972 1.00 20.32 ATOM 1988 H THR 207-12.028 6.508 74.270 1.00 0.00 ATOM 1989 CA TER 207-14.079 6.524 74.604 1.00 21.18 ATOM 1990 CBTHR 207 -14.401 8.020 74.393 1.00 23.74 ATOM 1991 OGl THR207 -13.997 8.769 75.547 1.00 30.73 ATOM 1992 HGl THR207 -13.029 8.728 75.573 1.00 0.00 ATOM 1993 CG2 THR207 -15.888 8.214 74.174 1.00 26.96 ATOM 1994 C THR 207 -14.309 5.776 73.296 1.00 17.81 ATOM 1995 O THR 207 -13.429 5.741 72.443 1.00 17.93 ATOM 1996 N VAL 208 -15.469 5.151 73.150 1 00 18.45 ATOM 1997 H VAL 208 -16.138 5.204 73.866 1.00 0.00 ATOM 1998 CA VAL 208 -15.776 4.406 71.935 1.00 17.67 ATOM 1999 CB VAL 208 -16.454 3.040 72.245 1.00 17.07 ATOM 2000 CGl VAL 208 -16.790 2.305 70.950 1.00 16.77 ATOM 2001 CG2 VAL208 -15.539 2.182 73.095 1.00 11.55 ATOM 2002 C VAL 208-16.656 5.205 70.983 1.00 18.54 ATOM 2003 O VAL 208-17.696 5.741 71.377 1.00 17.58 ATOM 2004 N TYR 209-16.216 5.276 69.730 1.00 18.01 ATOM 2005 H TYR 209 -15 380 4.834 69.510 1.00 0.00 ATOM 2006 CA TYR 209-16.923 5.978 68.666 1.00 16.80 ATOM 2007 CB TYR 209-15.953 6.871 67.888 1.00 15.72 ATOM 2008 CG TYR 209-15.356 7.983 68.715 1.00 19.87 ATOM 2009 CDl TYR209 -15.781 9.298 68.551 1.00 22.52 ATOM 2010 CEl TYR 209 -15.260 10.324 69.329 1.00 24.59 ATOM 2011 CD2 TYR209 -14.387 7.721 69.679 1.00 18.42 ATOM 2012 CE2 TYR209 -13.860 8.741 70.462 1.00 21.29 ATOM 2013 CZ TYR 209-14.302 10.037 70.282 1.00 23.10 ATOM 2014 OH TYR 209-13.798 11.052 71.058 1.00 27.37 ATOM 2015 HHTYR 209 -14.236 11.878 70.826 1.00 0.00 ATOM 2016 C TYR 209-17.522 4.945 67.719 1.00 14.63 ATOM 2017 O TYR 209-16.941 3.882 67.505 1.00 14.50 ATOM 2018 N EIS 210-18.706 5.238 67.195 1.00 13.02 ATOM 2019 H HIS 210-19.145 6.068 67.452 1.00 0.00 SU8ST~TUTE ~}EET (RULE 2~;~

W O 97/08300 PCT~US96/13918 ATOM 2020 CA HIS 210 -19.378 4.345 66.259 1.00 12.53 ATOM 2021 CB HIS 210 -20.662 3.786 66.864 1.00 12.65 ATOM 2022 CG HIS 210 -20.459 3.040 68.144 1.00 16.12 ATOM 2023 CD2 HIS 210 -20.531 3.447 69.432 1.00 14.44 ATOM 2024 NDl HIS 210 -20.151 1.697 68.182 1.00 14.83 ATOM 2025 HDl HIS 210 -19.968 1.099 67.418 1.00 0.00 ATOM 2026 CEl HIS 210 -20.047 1.309 69.440 1.00 15.80 ATOM 2027 NE2 HIS 210 -20.271 2.352 70.217 1.00 14.45 ATOM 2028 HE2 HIS 210 -20.186 2.357 71.186 1.00 0.00 ATOM 2029 C HIS 210 -19.734 5.160 65.031 1.00 13.68 ATOM 2030 O HIS 210 -20.289 6.249 65.161 1.00 15.52 ATOM 2031 N TYR 211 -19.363 4.664 63.853 l.D0 13.00 ATOM 2032 H TYR 211 -18.867 3.819 63.799 1.00 0.00 ATOM 2033 CA TYR 211 -lg.658 5.333 62.590 1 00 10.84 ATOM 2034 CB TYR 211 -18.379 5.684 61.835 1.00 10.80 ATOM 2035 CG TYR 211 -17.516 6.699 62.535 1.00 12.06 ATOM 2036 CDl TYR 211 -16.582 6.304 63.492 1.00 13.54 ATOM 2037 CEl TYR 211 -15.788 7.231 64.144 1.00 15.10 ATOM 2038 CD2 TYR 211 -17.631 8.056 62.247 1.00 13.72 ATOM 2039 CE2 TYR 211 -16.835 8.997 62.896 1.00 13.35 ATOM 2040 CZ TYR 211 -15.919 8.575 63.843 1.00 15.06 ATOM 2041 OH TYR 211 -15.127 9.487 64.494 1.00 16.21 ATOM 2042 HH TYR 211 -14.660 9,055 65.212 1.00 0.00 ATOM 2043 C TYR 211 -20.486 4 397 61.743 1.00 11.32 ATOM 2044 O TYR 211 -20.200 3.199 61.667 1.00 11.69 ATOM 2045 N LEU 212 -21.511 4.950 61.114 L.00 9.85 ATOM 2046 H LEU 212 -21.636 5.919 61.180 1.00 0.00 ATOM 2047 CA LEU 212 -22.415 4.194 60.266 1.00 11.52 ATOM 2048 CB LEU 212 -23.775 4.912 60.217 1.00 11.56 ATOM 2049 CG LEU 212 -25.035 4.391 59.503 1 00 15.30 ATOM 2050 CDl LEU 212 -25.117 4.895 58.086 1.00 16.57 ATOM 2051 CD2 LEU 212 -25.126 2.883 59.563 1.00 13.66 ATOM 2052 C LEU 212 -21.830 4.050 58.863 1.00 12.35 ATOM 2053 O LEU 212 -21.269 4.996 58.319 1.00 11.11 ATOM 2054 N ILE 213 -21.906 2.842 58.317 1.00 11.83 ATOM 2055 H ILE 213 -22.310 2.108 58.828 1.00 0.00 ATOM 2056 CA ILE 213 -21.431 2.564 56.968 1.00 11.63 ATOM 2057 CB ILE 213 -20.299 1.504 56.954 1.00 12.05 ATOM 2058 CG2 ILE 213 -19.934 1.142 55.505 1.00 9.05 SUBST~TUTE ~ii 3E~ tRULE 26~

CA 02226963 l998-02-l2 W O 97/~8300 PCT~US96/13918 ATOM 2059 CGl ILE213 -19-070 2.022 57.704 1.00 10.26 ATOM 2060 CD ILE 213-17.985 0.988 57.897 1.00 9.92 ATOM 2061 C ILE 213-22.626 1.997 56.209 1.00 12.13 ATOM 2062 O ILE 213-23.269 1.063 56.685 1.00 13.61 5 ATOM 2063 N SER 214-22.970 2.592 55.073 1.00 12.35 ATOM 2064 H SER 214-22.502 3 387 54.736 1.00 0.00 ATOM 2065 CA SER 214-24.084 2.091 54.279 1.00 16.58 ATOM 2066 CB SER 214-25.328 2.965 54.462 1.00 20.18 ATOM 2067 OG SER 214-25.052 4.321 54.167 1.00 28.58 ATOM 2068 HGSER 214 -25.884 4.781 54.279 1.00 0.00 ATOM 2069 C SER 214-23.683 2.063 52.817 1.00 17.82 ATOM 2070 O SE~ 214-22.747 2.753 52.413 1.00 17.93 ATOM 2071 N GLN 215-24.331 1.218 52.028 1.00 20.77 ATOM 2072 H GLN 215-25.045 0.650 52.395 l.G0 0.00 ATOM 2073 CAGLN 215 -23.995 1.175 50.620 l 00 25.66 ATOM 2074 CB GLN 215-23.692 -0.247 50.140 1.00 28.54 ATOM 2075 CG GLN 215-24.821 -1.247 50.204 1.00 32.61 ATOM 2076 CD GLN 215-24.390 -2.603 49 665 1 00 34.57 ATOM 2077 OEl GLN215 -24 663 -3.638 50.270 1 00 38 97 ATOM 2078NE2 GLN 215 -23.684 -2.599 48.539 1 00 32.79 ATOM 2079 HE21 GLN 215 -23.457 -1.751 48.109 1.00 0.00 ATOM 2080 HE22 GLN 215 -23.416 -3.468 48.179 1.00 0.00 ATOM 2081 C GLN 215-25.063 1.853 49.784 1.00 26.76 ATOM 2082 O GLN 215-26.257 1 704 50 042 1.00 27.55 ATOM 2083 N ASP 216 -24.621 2 676 48 840 1.00 27.69 ATOM 2084 H ASP 216-23 650 2.786 48.753 1 00 0.00 ATOM 2085 CA ASP 216-25.536 3.407 47.977 1 00 28.52 ATOM 2086 CB ASP 216-24.862 4.672 47.417 1.00 27.76 ATOM 2087 CG ASP216 -23.572 4.381 46.642 1.00 26.36 ATOM 2088ODl ASP 216 -23.455 3.317 46.003 1.00 26.80 ATOM 2089 OD2 ASP216 -22.670 5.242 46.654 1.00 26.55 ATOM 2090 C ASP 216-26.111 2.558 46.851 1.00 30.65 ATOM 2091 o ASP 216-25.818 1.367 46.745 1.00 29.83 ATOM 2092 N LYS 217-26.910 3.~96 46.001 1.00 35.42 ATOM 2093 H LYS 217 -27.102 4.124 46.214 1 00 0.00 ATOM 2094 CA LYS 217-27.538 2.543 44.857 1.00 38.73 ATOM 2095 CB LYS 217-28.406 3 540 44 074 1.00 42 89 ATOM 2096 CG LYS 217-27.645 4.721 43.478 1.00 48.87 ATOM 2097 CD LYS 217-27.269 5.752 44 537 1.00 53 40 SUBST~TUT~ ~ tRUI E 2~i) ATOM 2098 CE LYS 21i -26.291 6.785 43.996 1.00 58.3i ATOM 2099 NZ LYS 217 -24.979 6.187 43.601 1.00 59.73 ATOM 2100 HZl LYS217 -25.131 5.461 42.871 1.00 0.00 ATOM 2101 HZ2 LYS217 -24.529 5.743 44.426 1.00 0.00 5 ATOM 2102 HZ3 LYS217 -24.352 6.930 43.224 1.00 0.00 ATOM 2103 C LYS 217 -26.502 1.913 43.925 1.00 38.15 ATOM 2104 O LYS 217 -26.749 0.865 43.328 1.00 40.41 ATOM 2105 N ALA 218 -25.340 2.552 43.814 1.00 35.55 ATOM 2106 H ALA 218 -25.215 3.381 44.311 1.00 0.00 ATOM 2107 CA ALA 218 -24.265 2.052 42.959 1.00 33.42 ATOM 2108 CB ALA 218-23.274 3.168 42.659 1.00 33.11 ATOM 2109 C ALA 218-23.535 0.850 43.563 1.00 31.29 ATOM 2110 O ALA 218-22.651 0.274 42.928 1.00 32.67 ATOM 2111 N GLY 219-23.891 0.490 44.794 1.00 28.81 ATOM 2112 H GLY 219 -24.622 0.946 45.252 1.00 0.00 ATOM 2113 CA GLY 219-23.253 -0.633 45.461 1.00 25.16 ATOM 2114 C GLY 219-21.997 -0.266 46.235 1.00 21.96 ATOM 2115 O GLY 219-21.363 -1.132 46.841 1.00 21.31 ATOM 2116 N LYS 220-21.642 1.015 46.223 1.00 18.93 ATOM 2117 H LYS 220 -22.183 1.645 45.717 1.00 0.00 ATOM 2118 CA LYS 220-20.465 1.499 46.929 1.00 17.78 ATOM 2119 CB LYS 220-19.940 2.767 46.266 1.00 20.25 ATOM 2120 CG LYS 220-19.307 2.495 44.913 1.00 24.18 ATOM 2121 CD LYS 220-18.898 3.771 44.211 1.00 31.09 ATOM 2122 CELYS 220 -18.088 3.470 42.960 1.00 34.60 ATOM 2123 NZ LYS 220-18.821 2.569 42.026 1.00 37.47 ATOM 2124 HZl LYS220 -19.718 3.013 41.752 1.00 0.00 ATOM 2125 HZ2 LYS220 -19.017 1.663 42.495 1.00 0.00 ATOM 2126 HZ3 LYS220 -18.261 2.395 41.170 1.00 0.00 ATOM 2127 C LYS 220 -20.746 1.743 48.407 1.00 16.48 ATOM 2128 O LYS 220-21.865 2.094 48.780 1.00 17.93 ATOM 2129 N TYR 221-19.728 1.535 49.236 1.00 12.90 ATOM 2130 H TYR 221-18.873 1.259 48.858 1.00 0.00 ATOM 2131 CA TYR 221-19.837 1.709 50.680 1.00 13.00 ATOM 2132 CBTYR 221 -19.086 0.593 51.414 1.00 14.73 ATOM 2133 CG TYR 221-19.541 -0.805 51.080 1.00 14.94 ATOM 2134 CDl TYR221 -19.019 -1.481 49.982 1.00 14.31 ATOM 2135 CEl TYR221 -19.413 -2.779 49.682 1.00 17.85 ATOM 2136 CD2 TYR221 -20.479 -1.464 51.876 1.00 18.01 .

SUBST~TUTE ~i~E}~} ~RULE 2~i) CA 02226963 l998-02-l2 W 097/08300 PCTnUS96/l39l8 ATOM 2137 CE2 TYR221 -20.881 -2.769 51.583 1.00 19.06 ATOM 2138 CZ TYR 221-20.339 -3.418 50.483 1.00 18.46 ATOM 2139 OH TYR 221-20.710 -4.712 50.187 1.00 21.74 ATOM 2140 HH TYR 221-21.440 -4.960 50.769 1.00 0.00 ATOM 2141 C TYR 221 -19.239 3.026 51.127 1.00 13.74 ATOM 2142 O TYR 221-18.268 3.505 50.537 1.00 13.39 ATOM 2143 N CYS 222-19.792 3.588 52.196 1.00 12.18 ATOM 2144 H CYS 222-20.597 3.211 52.622 1.00 0.00 ATOM 2145 CA CYS 222 -19.270 4.832 52.738 1.00 12.71 ATOM 2146 CBCYS 222 -19.460 5.988 51.746 1.00 12.80 ATOM 2147 SG CYS 222-21.164 6.569 51.564 1.00 18.19 ATOM 2148 C CYS 222-19.924 5.225 54.042 1.00 11.87 ATOM 2149 ~ CYS 222-21.011 4.751 54.382 1.00 13.51 ATOM 2150 N ILE 223-19.194 6.019 54.814 1.00 11.88 ATOM 2151 H ILE 223 -18.278 6.244 54.535 1.00 ~-~~
ATOM 2152 CA ILE 223-19.709 6.588 56.049 1.00 11.29 ATOM 2153 CB ILE 223-18.542 7 030 56.971 1.00 10.12 ATOM 2154 CG2 ILE223 -19.073 7.735 58.217 1.00 9.33 ATOM 2155 CGl ILE223 -17.712 5.801 57.366 1.00 10.22 ATOM 2156 CDILE 223 -16.409 6.116 58.065 1.00 12.74 ATOM 2157 C ILE 223-20.409 7.805 55.418 1.00 13.19 ATOM 2158 O ILE 223-19.883 8.380 54.461 1.00 14.19 ATOM 2159 N PRO 224-21.627 8.158 55.864 1.00 13.86 ATOM 2160 CD PRO 224-22.436 7.580 56.951 1.00 15.81 ATOM 2161 CAPRO 224 -22.313 9.314 55.269 1.00 14.75 ATOM 2162 CB PRO 224-23.430 9.593 56.271 1.00 15 29 ATOM 2163 CG PRO 224-23.798 8.225 56.718 1.00 16.55 ATOM 2164 C PRO 224-21.418 10.538 55.052 1.00 13.87 ATOM 2165 O PRO 224-20.737 10.999 55.972 1.00 14.06 ATOM 2166 N GLU 225 -21.406 11.024 53.812 1.00 16.66 ATOM 2167 H GLU 225-21.973 10.588 53.143 1.00 0.00 ATOM 2168 CA GLU 225 -20.611 12.184 53.399 1.00 18.98 ATOM 2169 CB GLU 225 -20.880 13.377 54.321 1.00 23.00 ATOM 2170 CG GLU 225 -22.332 13.822 54.340 1.00 31.63 ATOM 2171 CD GLU 225 -22.586 14.925 55.345 1.00 38.26 ATOM 2172 OEl GLU225 -22.900 14.610 56.514 1.00 44.60 ATOM 2173 oE2 GLU225 -22.472 16.111 54.965 1.00 44.04 ATOM 2174 C GLU 225 -19.109 11.901 53.325 1.00 17.01 ATOM 2175 O GLU 225 -18.297 12.827 53.247 1.00 17.14 SU~STlTUTE Si~ tRlJLE 2~) CA 02226963 l998-02-l2 ATOM 2176 N GLY 226-18.745 10.623 53.308 1.00 14.45 ATOM 2177 H GLY 226-19.411 9.908 53.330 1.00 0.00 ATOM 2178 CA GLY 226-17.347 10.255 53.244 1.00 11.18 ATOM 2179 C GLY 226-16.950 9.659 51.910 1.00 10.31 ATOM 2180 O GLY 226 -17.741 9.618 50.969 1.00 9.78 ATOM 2181 N THR 227-15.713 9.189 51.843 1.00 12.43 ATOM 2182 H THR 227-15.132 9.231 52.635 1.00 0.00 ATOM 2183 CA THR 227-15.161 8.580 50.642 1.00 13.92 ATOM 2184 CB THR 227-13.660 8.259 50.845 1.00 13.92 ATOM 2185 OGl THR 227 -12.995 9.405 51.387 1.00 14.17 ATOM 2186 HGl ~HR227 -12.972 10.110 50.731 1.00 0.00 ATOM 2187 CG2 THR227 -13.004 7.903 49.531 1.00 13.18 ATOM 2188 C THR 227-15.907 7.288 50.339 1 00 13.19 ATOM 2189 O THR 227-16.348 6.600 51.256 1.00 15.61 ATOM 2190 N LYS 228 -16.064 6.968 49 061 1.00 12.19 ATOM 2191 H LYS 228-15.734 7.560 48.345 1.00 0.00 ATOM 2192 CA LYS 228-16.751 5.746 48.676 1.00 14.24 ATOM 2193 CB LYS 228-17.773 6.035 47.582 1 00 17.80 ATOM 2194 CG LYS 228-18.879 6.939 48.084 1.00 18.53 ATOM 2195 CDLYS 228 -19.925 7.208 47.046 1.00 24.24 ATOM 2196 CE LYS 228-21.091 7.919 47.693 1.00 25.57 ATOM 2197 NZ LYS 228-21.680 7.085 48.782 1.00 26.31 ATOM 2198 HZl LYS228 -20.949 6.908 49.499 1.00 0.00 ATOM 2199 HZ2 LYS228 -22.012 6.178 48.395 1.00 0.00 ATOM 2200 HZ3 LYS 228 -22.481 7.585 49.217 1.00 0.00 ATOM 2201 C LYS 228-15.765 4.663 48.258 1.00 14.50 ATOM 2202 O LYS 228-14.730 4.948 47.650 1.00 13.50 ATOM 2203 N PHE 229-16.093 3.424 48.612 1.00 11.73 ATOM 2204 H PHE 229-16.935 3.271 49.091 1.00 0.00 ATOM 2205 CAPHE 229 -15.256 2.266 48.331 1.00 11.12 ATOM 2206 CB PHE 229-14.666 1.726 49.633 1.00 10.16 ATOM 2207 CG PHE 229-13.962 2.761 50.453 1.00 10.70 ATOM 2208 CDl PHE229 -14.669 3.545 51.364 1.00 10.54 ATOM 2209 CD2 PHE229 -12 596 2.969 50.309 1.00 9.61 ATOM 2210 CEl PHE 229 -14.026 4.516 52.112 1.00 9.20 ATOM 2211 CE2 PHE229 -11.944 3.940 51.057 1.00 9.06 ATOM 2212 CZ PHE 229-12.657 4.715 51.959 1.00 9.11 ATOM 2213 C PHE 229-16.083 1.168 47.688 1.00 12.28 ATOM 2214 O PHE 229-17.298 1.086 47.908 1.00 10.19 SIJBSTITUTE S~tE~ (RULE 2~i) CA 02226963 l998-02-l2 WO 97/08300 PCTrUS96/13918 ATOM 2215 N ASP 230 -15.426 0.325 46.898 1.'0 10.90 ATOM 2216 H ASP 230 -14 463 0.469 46.747 l.C0 0.00 ATOM 2217 CA ASP230 -16.105 -0.786 46.233 1.00 12.50 ATOM 2218 CB ASP230 -15.298 -1.275 45.027 1.00 11.22 ATOM 2219CG ASP 230 -15.537 -0.441 43.784 1.30 14.98 ATOM 2220 ODl ASP230 -14.994 -0.805 42.725 1.30 16.87 ATOM 2221 OD2 ASP230 -16.267 0.569 43.852 1.50 18.88 ATOM 2222 C ASP 230-16.353 -1.947 47.185 1.00 10.65 ATO~ 2223 O ASP 230-17.276 -2.736 46.984 1.00 11.11 ATOM 2224 N THR 231 -15.529 -2.047 48.224 1.00 11.48 ATOM 2225 H THR 231-14.831 -1.374 48.373 1.00 0.00 ATOM 2226 CA THR 231-15.664 -3.120 49.197 1.00 7.69 ATOM 2227 CB THR 231-14.672 -4.283 48.916 1.00 7.51 ATOM 2228 OGl THR231 -13.326 -3.812 49.047 1.00 6.84 ATOM 2229HGl THR 231 -13.152 -3.283 48.249 1.20 0.00 ATOM 2230 CG2 THR231 -14.867 -4.851 47.514 1.20 9.18 ATOM 2231 C THR 231-15.383 -2.611 50.601 1.00 8.28 ATOM 2232 O THR 231-14.786 -1.549 50.787 1.00 6.01 ATOM 2233 N LEU 232-15.803 -3.394 51.587 1.00 11.12 ATOM 2234 H LEU 232 -16.301 -4.202 51.349 1.20 0.00 ATOM 2235 CA LEU 232-15.576 -3.069 52.991 1.00 11.15 ATOM 2236 CB LEU 232-16.452 -3.943 53.890 1.00 10.62 ATOM 2237 CG LEU 232-17.944 -3.612 53.890 1.00 10.59 ATOM 2238 CDl LEU232 -18.702 -4.656 54.692 1.00 9.60 ATOM 2239CD2 LEU 232 -18.163 -2.225 54.474 1.20 9.95 ATOM 2240 C LEU 232-14.106 -3.254 53.355 l.a0 10.18 ATOM 2241 O LEU 232-13.591 -2.556 54.224 1.00 10.71 ATOM 2242 N TRP 233-13.433 -4.188 52.682 1 00 7.94 ATOM 2243 H TRP 233-13.899 -4.714 52.004 1.00 0.00 ATOM 2244 CATRP 233 -12.019 -4.454 52.930 1.00 7.29 ATOM 2245 CB TRP 233-11.547 -5.644 52.082 1.00 6.24 ATOM 2246 CG TRP 233-10.206 -6.191 52.486 i.oo 8.76 ATOM 2247 CD2 TRP233 -8.918 -5.653 52.152 1.00 10.99 ATOM 2248 CE2 TRP233 -7.949 -6.473 52.772 1 00 8.57 ATOM 2249CE3 TRP 233 -8.487 -4.551 51.394 1.00 10.97 ATOM 2250 CDl TRP233 -9.971 -7.291 53.265 1.00 9.24 ATOM 2251 NEl TRP233 -8.619 -7.463 53.441 1.00 9.83 ATOM 2252 HEl TRP233 -8.218 -8.194 53.968 1.00 0.00 r ATOM 2253 CZ2 TRP233 -6.577 -6.229 52.658 1.00 9.97 -- 13~ -SUBSTITUT~ RULE 2fi) CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 2254 CZ3 TRP233 -7.120 -4 307 51.281 1.00 9.13 ATOM 2255 CH2 TRP233 -6.183 -5.144 51.913 1.00 11.33 ATOM 2256 C TRP233-11.197 -3.207 52.599 1.00 7.04 ATOM 2257 O TRP233-10.319 -2 799 53.370 1.00 7.78 ATOM 2258 N GLN 234 -11.503 -2.593 51.461 1.00 8.41 ATOM 2259 H GLN234-12.219 -2.958 50.896 1.00 0.00 ATOM 2260 CA GLN234-10.803 -1.388 51.014 1.00 9.39 ATOM 2261 CB GLN234-11.165 -1.071 49.562 1.00 8.16 ATOM 2262 CG GLN234-10.565 -2.062 48.559 1.00 10.01 ATOM 2263 CD GLN 234 -11.154 -1.939 47.158 1.00 12.43 ATOM 2264 OEl GLN234 -12.366 -2.054 46.969 1.00 11.45 ATOM 2265 NE2 GLN234 -10.292 -1.740 46.168 1.00 12.16 ATOM 2266 HE21 GLN234-9.333 -1.691 46.378 1.00 0.00 ATOM 2267 HE22 GLN234-10.642 -1.644 45.264 1.00 0.00 ~5 ATOM 2268 C GLN 234 -11.057 -0.179 51.916 1.00 8 34 ATOM 2269 O GLN234-10.160 0.632 52.140 1.00 11.19 ATOM 2270 N LEU235-12.275 -0.065 52.434 1.00 9.44 ATOM 2271 H LEU235-12.961 -0.717 52.193 1.00 0.00 ATOM 2272 CA LEU235-12.644 1.025 53.336 1.00 9.31 ATOM 2273 CB LEU 235 -14.137 0.914 53.705 1.00 10.64 ATOM 2274 CG LEU235-14.799 1.893 54.690 1.00 8.65 ATOM 2275 CDl LEU235 -16.276 2.014 54.359 1.00 12.30 ATOM 2276 CD2 LEU235 -14 606 1 444 56 139 1.00 8.88 ATOM 2277 C LEU 235 -11.768 0.979 54.592 1.00 10.98 ATOM 2278O LEU235 -11.118 1.964 54.949 1.00 10.19 ATOM 2279 N VAL 236 -11.726 -0.185 55.232 1.00 11.09 ATOM 2280 H VAL 236 -12.243 -0.941 54.873 1.00 0.00 ATOM 2281 CA VAL 236 -10.941 -0.372 56.446 1.00 13.11 ATOM 2282 CB VAL 236 -11.160 -1.792 57.035 1.00 13.64 ATOM 2283CGl VAL 236 -10.210 -2.052 58.198 1.00 9.34 ATOM 2284 CG2 VAL236 -12.606 -1.937 57.497 1.00 9.82 ATOM 2285 C VAL236-9.460 -0.122 56.202 1.00 12.74 ATOM 2286 O VAL236-8.814 0.617 56.947 1.00 12.87 ATOM 2287 N GLU237-8.936 -0.692 55.124 1.00 11.87 3~ ATOM 2288 H GLU 237 -9.506 -1.255 54.555 1.00 0.00 ATOM 2289 CA GLU237-7.526 -0.530 54.810 1.00 14.06 ATOM 2290 CB GLU237-7.131 -1.443 53.654 1.00 18.30 ATOM 2291 CG GLU237-6.010 -2.409 54.009 1.00 27.57 ATOM 2292 CD GLU237-6.318 -3.258 55.236 1.00 33.91 SUE~STITUTE S~tE~ ~RULE ~

WO 97/08300 PCTnUS96/13918 ATOM 2293 OEl GLU237 -5.411 -3.405 56.082 1.00 36.05 ATOM 2294 OE2 GLU237 -7.452 -3.781 55 356 1.00 36.98 ATOM 2295 C GLU237-7.140 0.911 54.513 1.00 11.41 ATOM 2296 O GLU237-6.046 1.347 54.862 1.00 13.53 ATOM 2297 N TYR 238 -8.048 1.651 53.887 1.00 10.99 ATOM 2298 H TYR238-8.918 1.250 53.660 1.00 0.00 ATOM 2299 CA TYR238-7.811 3.051 53,547 1.00 10.24 ATOM 2300 CB TYR238-8.917 3.539 52.616 1.00 8.37 ATOM 2301 CG TYR238-8.736 4.938 52.070 1.00 9.95 t0 ATOM 2302CDl TYR 238 -7.971 5.165 50.923 1.00 11.03 ATOM 2303 CEl TYR238 -7.866 6.436 50.371 1.00 11.61 ATOM 2304 CD2 TYR238 -9.385 6.023 52.655 1 00 9.61 ATOM 2305 CE2 TYR238 -9.286 7.295 52.109 1.00 13.06 ATOM 2306 CZ TYR238-8.530 7 494 50.969 1.00 12.38 ATOM 2307 OH TYR 238 -8.461 8.750 50.423 1.00 15.47 ATOM 2308 HH TYR238-7.934 8.739 49.623 1.00 0.00 ATOM 2309 C TYR238-7.787 3.898 54.819 1.00 12.10 ATOM 2310 O TYR238-6.896 4.730 55.014 1.00 10.77 ATOM 2311 N LEU239-8.739 3.636 55.709 1.00 12.47 ATOM 2312 H LEU 239 _9,406 2.937 55.527 1.00 0.00 ATOM 2313 CA LEU239-8.844 4.371 56.960 1.00 12.96 ATOM 2314 CB LEU239-10.225 4.161 57.581 1.00 11.26 ATOM 2315 CG LEU239-11.369 4.619 56.659 1.00 14.61 ATOM 2316 CDl LEU239 -12.723 4.368 57.306 1.00 11.36 ATOM 2317CD2 LEU 239 -11.208 6.100 56.303 1.00 15.59 ATOM 2318 C LEU239-7 713 4.045 57.938 1.00 15.09 ATOM 2319 O LEU239-7.609 4.644 59.014 1.00 15.00 ATOM 2320 N LYS240-6.881 3.073 57.572 1.00 15.14 ATOM 2321 H LYS240-7.069 2.565 56.760 1.00 0.00 ATOM 2322 CA LYS 240 -5.721 2.713 58.380 1 00 17.35 ATOM 2323 CB LYS240-5.258 1.284 58.095 1.00 15.90 ATOM 2324 CG LYS240-6.069 0.192 58.749 1.00 19.37 ATOM 2325 CD LYS240-5.352 -1.147 58.604 1.00 23.39 ATOM 2326 CE LYS240-6.141 -2.282 59.234 1.00 26.87 ATO~ 2327 NZ LYS 240 -5.449 -3.592 59.076 1.00 27.64 ATOM 2328 HZl LYS240 -4.528 -3.564 59.561 1.00 0.00 ATOM 2329 HZ2 LYS240 -5.303 -3.797 58.066 1.00 0.00 ATOM 2330 HZ3 LYS240 -6.056 -4.328 59.485 1.00 0.00 ATOM 2331 C LYS 240 -4.602 3.674 57.988 1.00 18.17 SUBSTITU~E ~}~E~ ~RULE 2h) W O 97/08300 PCT~US96/13918 ATOM 2332 O LYS240-3.741 4.005 58.797 1.00 20.88 ATOM 2333 N LEU241-4.624 4.119 56.737 1.00 19.69 ATOM 2334 H LEU241-5.346 3.850 56.132 1.00 0.00 ATOM 2335 CA LEU241-3.609 5.034 56.235 1.00 24.27 5 ATOM 2336 CB LEU241-3.499 4.927 54.708 1.00 27.48 ATOM 2337 CG LEU241-3.315 3.550 54.060 1.00 32.84 ATOM 2338 CDl LEU241 -3.353 3.698 52.541 1.00 33.90 ATOM 2339 CD2 LEU241 -2.008 2.909 54.505 1.00 33.04 ATOM 2340 C LEU241-3.906 6.483 56.615 1.00 23.86 0 ATOM 2341 O LEU241-2.997 7.237 56 962 1.00 25.78 ATOM 2342 N LYS242-5.176 6.870 56.544 1.00 23.81 ATOM 2343 H LYS242-5.879 6.232 56.282 1.00 0.00 ATOM 2344 CA LYS242-5.581 8.237 56.851 1.00 22.58 ATOM 2345 CB LYS242-5.570 g.074 55.565 1.00 25.37 ATOM 2346 CG LYS 242 -6.401 8 478 54.432 1.00 2i.76 ATOM 2347 CD LYS242-6.085 9.108 53.085 1.00 30.37 ATOM 2348 CE LYS242-4.720 8.701 52.554 1.00 28.46 ATOM 2349 NZ LYS242-4.450 9.342 51.238 1.00 27.65 ATOM 2350 HZl LYS242 -4.507 10.369 51.346 1.00 0.00 ATOM 2351HZ2 LYS 242 -5.152 9.021 50.544 1.00 0.00 ATOM 2352 HZ3 LYS242 -3.496 9.081 50.914 1.00 0.00 ATOM 2353 C LYS 242 -6.955 8.287 57.512 1.00 19.10 ATOM 2354 O LYS 242 -7.853 7.535 57.142 1.00 17.80 ATOM 2355 N ALA 243 -7.110 9.197 58.473 1.00 18.84 ATOM 2356H ALA243 -6.329 9.765 58.680 1.00 0.00 ATOM 2357 CA ALA 243 -8.362 9.362 59 214 1 00 17 03 ATOM 2358 CB ALA243-8.233 10.489 60.240 1.00 14.93 ATOM 2359 C ALA243-9.540 9.620 58.285 1.00 16.79 ATOM 2360 O ALA243-10.632 9.098 58.503 1 00 15.85 ATOM 2361 N ASP 244 -9.332 10.486 57.295 1.00 17.15 ATOM 2362 H ASP244-8.459 10.915 57.232 1.00 0.00 ATOM 2363 CA ASP 244 -10.359 10.796 56.304 ~.00 18.82 ATOM 2364 CB ASP 244 -10.481 9.599 55.347 1.00 18.91 ATOM 2365 CG ASP 244 -11.295 9.904 54.113 1.00 21.74 ATOM 2366ODl ASP 244 -12.087 9.030 53.712 1.00 23 51 ATOM 2367 OD2 ASP244 -11.139 10.998 53.533 1.00 25.93 ATOM 2368 C ASP244-11.723 11.169 56.923 1.00 19.28 ATOM 2369 O ASP244-12.786 10.734 56.461 1.00 17.04 ATOM 2370 N GLY245-11.687 11.994 57.963 1.00 18.87 .

SUBS~lTUTE ~}E~ ~RULE

ATOM 2371 HGLY 245 -10.837 12.330 58.306 l.Q0 0.00 ATOM 2372 CAGLY 245 -12.920 12.402 58.613 1.00 18.84 ATOM 2373 CGLY 245 -13.123 11.779 59.982 1.00 18.77 ATOM 2374 OGLY 245 -13.863 12.319 60.804 1.00 18.51 5 ATOM 2375 NLEU 246 -12.503 10.625 60.218 1.00 18.35 ATOM 2376 HLEU 246 -11.973 10.209 59.505 1.00 0.00 ATOM 2377 CALEU 246 -12.623 9.949 61.506 1.00 18.30 ATOM 2378 CBLEU 246 -12.066 8.519 61.442 1.00 17.23 ATOM 2379 CGLEU 246 -12.647 7.431 60.534 1.00 17.12 1 0 ATOM 2380CDl LEU 246 -11.849 6.151 60.746 1.00 18.63 ATOM 2381 CD2 LEU246 -14.104 7.186 60.834 1.00 15.56 ATOM 2382 CLEU 246 -11.866 10.707 62.591 1.00 18.47 ATOM 2383 OLEU 246 -10.921 11.448 62.307 1.00 17.84 ATOM 2384 NILE 247 -12.253 10.453 63.837 1.00 17.52 1 5 ATOM 2385 H ILE 247 -13.020 9.857 63.945 1.00 0.00 ATOM 2386 CAILE 247 -11.636 11.072 65.005 1.00 18.73 ATOM 2387 CBILE 247 -12.424 10.694 66.302 1.00 19.74 ATOM 2388 CG2 ILE247 -12.209 9.225 66.664 1.00 17.58 ATOM 2389 CGl ILE247 -12.020 11.599 67.463 1.00 22.31 20 ATOM 2390 CDILE 247 -12.501 13.023 67.320 1.00 25.66 ATOM 2391 CILE 247 -10.163 10.651 65.129 1.00 20.39 ATOM 2392 OILE 247 -9.340 11.381 65.680 1 00 20.44 ATOM 2393 NTYR 248 -9.840 9.475 64.598 1.00 20.63 ATOM 2394 HTYR 248 -10.512 8.919 64.159 1.00 0.00 2 5 ATOM 2395 CA TYR 248 -8.484 8.937 64.631 1.00 21.07 ATOM 2396 CBTYR 248 -8.174 8.391 66.030 1.00 20.66 ATOM 2397 CGTYR 248 -6.704 8.168 66.310 1.00 21.55 ATOM 2398 CDl TYR248 -6.212 6.894 66.590 1.00 23.90 ATOM 2399 CEl TYR248 -4.861 6.691 66.884 1.00 27.45 3 0 ATOM 2400CD2 TYR 248 -5.810 9.235 66.327 1.00 24.95 ATOM 2401 CE2 TYR248 -4.457 9-045 66.622 1.00 26.89 ATOM 2402 CZTYR 248 -3.992 7.773 66.900 1.00 27.31 ATOM 2403 OXTYR 248 -2.664 7.588 67.209 1.00 32.39 ATOM 2404 HHTYR 248 -2.203 8.432 67.197 1.00 0.00 35 ATOM 2405 CTYR 248 -8.463 7.806 63.602 1.00 21.64 ATOM 2406 OTYR 248 -9.506 7.223 63.307 1.00 22.45 4 ATOM 2407 NCYS 249 -7.304 7.510 63.025 1.00 21.61 ATOM 2408 HCYS 249 -6.477 7.958 63.280 1.00 0.00 ATOM 2409 CACYS 249 -7.252 6.444 62.035 1.00 22.88 SU8STITUTE S}t E~ ~RULE 26) CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATOM 2410 CB CYS 249 -6.102 6.649 61.042 1.00 25.15 ATOM 2411 SG CYS 249 -4.471 6.722 61.779 1.00 42.2S
ATOM 2412 C CYS 249 -7.189 5.068 62.692 1.00 21.47 ATOM 2413 O CYS 249 -6.787 4.929 63.853 1.00 20.61 ATOM 2414 N LEU 250 -7.642 4.065 61.952 1.00 20.77 ATOM 2415 H LEU 250 -7.945 4.257 61.037 1.00 0.00 ATOM 2416 CA LEU 250 -7.674 2.687 62.425 1.00 20.19 ATOM 2417 CB LEU 250 -8.416 1.820 61.405 1.00 18.49 ATOM 2418 CG LEU 250 -9.944 1.724 61.463 1.00 17.48 ATOM 2419 CDl LEU 250 -10.596 2.988 61.983 1.00 17.55 ATOM 2420 CD2 LEU 250 -10.467 1.353 60.095 1.00 11.95 ATOM 2421 C LEU 250 -6.274 2.142 62.662 1.00 21.59 ATOM 2422 O LEU 250 -5.389 2.319 61.829 1.00 22.32 ATOM 2423 N LYS 251 -6.077 1.480 63.797 1.00 23.42 ATOM 2424 H LYS 251 -6.834 1.343 64.404 1.00 0.00 ATOM 2425 CA LYS 251 -4.776 0.913 64.136 1.00 27.72 ATOM 2426 CB LYS 251 -4.191 1.594 65.381 1.00 27.91 ATOM 2427 CG LYS 251 -3.938 3.085 65.239 1.00 29.20 ATOM 2428 CD LYS 251 -2.882 3.372 64.197 1.00 30.93 ATOM 2429 CE LYS 251 -2.677 4.859 64.038 1.00 33.75 ATOM 2430 NZ LYS 251 -1.669 5.159 62.987 1.00 38.98 ATOM 2431 HZl LYS 251 -1.976 4.774 62.070 1.00 0.00 ATOM 2432 HZ2 LYS 251 -0.753 4.744 63.253 1.00 0.00 ATOM 2433 HZ3 LYS 251 -1.561 6.191 62.908 1.00 0.00 ATOM 2434 C LYS 251 -4.837 -0.603 64.353 1 00 31.01 ATOM 2435 O LYS 251 -4.768 -1.385 63.401 1.00 34.63 ATOM 2436 N GLU 252 -4.991 -1.013 65.606 1.00 31.53 ATOM 2437 H GLU 252 -5.146 -0,377 66.329 1.00 0.00 ATOM 2438 CA GLU 252 -5.036 -2.426 65.952 1.00 31.94 ATOM 2439 CB GLU 252 -4.535 -2.629 67.383 1.00 36.37 ATOM 2440 CG GLU 252 -3.113 -2.136 67.621 1.00 47.65 ATOM 2441 CD GLU 252 -2.878 -1.678 69.053 1.00 53.28 ATOM 2442 OEl GLU 252 -2.807 -0.447 69.277 1.00 56.81 ATOM 2443 OE2 GLU 252 -2.770 -2.542 69.952 1.00 56.39 ATOM 2444 C GLU 252 -6.440 -2.993 65.817 1.00 30.12 ATOM 2445 O GLU 252 -7.419 -2.361 66.213 1.00 29.12 ATOM 2446 N ALA 253 -6.527 -4.182 65.237 1.00 26.83 ATOM 2447 H ALA 253 -5.716 -4.627 64.930 1.00 0.00 ATOM 2448 CA ALA 253 -7.795 -4.853 65.063 1.00 26.20 .

SUBS ~ ITUTE S}~E~ ~RULE ~6) ATOM 2449 C8ALA253 --7.698--5.868 63.944 1.00 25.70 ATOM 2450 CALA 2S3 --8.149-5.554 66.361 1.00 28.42 ATOM 2451 OALA 253 -7.276-6.096 67.036 1.00 28.38 ATOM 2452 NCYS 254 -9.414-5.473 66.746 1.00 31.05 ATOM 2453 E~CYS254 -10.046-4.955 66.206 1.00 0.00 ATOM 2454 CACYS254 -9 907-6.143 67.941 1.00 32.95 ATOM 2455 CBCYS254 -11.087-5.361 68.533 1.00 34.98 ATOM 2456 SGCYS254 -11.787-6.015 70.077 1.00 32.47 ATOM 2457 CCYS 254 --10.372 -7.475 67.358 1.00 35.53 1 0 ATOM 2458 OCYS 254 -11.391-7.528 66.674 1.00 33.47 ATOM 2459 NPRO 255 --9.584-8.545 67.554 1.00 40.79 ATOM 2460 CDPRO255 -8.346-8.542 68.352 1.00 42.81 ATOM 2461 CAPRO255 -9.865-9.900 67.058 1.00 45.35 ATOM 2462 CBPRO255 -8.780-10.738 67.733 1.00 46.01 1 5 ATOM 2463 CGPRO255 -7.643-9.774 67.847 1.00 43.91 ATOM 2464 CPRO 255 -11.258-10.437 67.368 1 00 48.63 ATOM 2465 OPRO 255 -12.027-9.807 68.088 1.00 50.93 ATOM 2466 NASN 256 -11.549-11.612 66.813 1.00 52.77 ATOM 2467 HASN 256 -10.862-12.052 66.277 1.00 0.00 ATOM 2468 CAASN256 -12.825-12.314 66.965 1.00 56.77 ATOM 2469 CBASN256 --12.631 -13.804 66.654 1.00 56.87 ATOM 2470 CGASN256 --11.494 --14.430 67.455 1.00 58.22 ATOM 2471 ODl ASN 256 -10.354 -14.507 66.987 1.00 58.21 ATOM 2472 ND2 ASN 256 -11.798 -14.874 68.666 1.00 60.09 ATOM 2473 HD21 ASN 256 -12.721 -14.706 68 970 1.00 0.00 ATOM 2474 HD22 ASN 256 -11.107 -15.313 69.188 1.00 0.00 ATOM 2475 CASN 256 -13.545--12.159 68.308 1.00 59.22 ATOM 2476 OASN 256 -12.888-12.281 69.365 1.00 60.95 ATOM 2477 OTASN256 -14.776--11.934 68.282 1.00 62.08 ATOM 2478 CBASN301 -31.3655.229 63.299 1.00 56.01 ATOM 2479 CGASN301 -32.7065.204 64.007 1.00 56.26 ATOM 2480 ODlASN301 -33.3384.151 64.119 1.00 54.90 ATOM 2481 ND2ASN301 --33.146 6.360 64.490 1.00 56.88 ATOM 2482 HD21 ASN 301 --32.620 7.179 64.396 1.00 0.00 ATOM 2483 HD22 ASN 301 -34.026 6.336 64.926 1.00 0.00 ATOM 2484 CASN 301 -30.1464.272 65.265 1.00 56.46 ATOM 2485 OASN 301 -30.7673.599 66.093 1.00 57.32 ATOM 2486 HTlASN301 -31.9502.747 64.009 1.00 0.00 ATOM 2487 HT2ASN301 -30.3862.096 64.004 1.00 0.00 SUBSTITUT~ S~tEE~ tRuLE 21i) CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13gl8 ATOM 2488 N ASN 301 -31.028 2.767 63.S13 1.00 SS.62 ATOM 2489 HT3 ASN301 -31.104 2.517 62.501 1.00 0.00 T ATOM 2490 CA ASN 301 -30.427 4.112 63.774 1.00 56.70 c ATOM 2491 N GLN302 -29.220 S.167 6S.602 1.00 55.38 5 ATOM 2492 H GLN302 -28.777 S.736 64.93S 1.00 0.00 ATOM 2493 CA GLN302 -28.849 S.397 66.995 1.00 52.01 ATOM 2494 CB GLN302 -28.061 4.185 67.520 1.00 54.35 ATOM 2495 CG GLN302 -28.174 3.927 69.017 1.00 56.79 ATOM 2496 CD GLN302 -29.560 3.475 69.421 1 00 60.50 10 ATOM 2497 OEl GLN302 -30.386 4.280 69.859 1.00 63.09 ATOM 2498 NE2 GLN302 -29.825 2.182 69.280 1.00 60.40 ATOM 2499 HE21 GLN 302 -29.131 1.575 68.950 I.00 0.00 ATOM 2500 HE22 GLN 302 -30.732 1.904 69.512 1.00 0.00 ATOM 2501 C GLN302 -27.998 6.670 67.089 1.00 47.72 15 ATOM 2502 O GLN302 -28.185 7.614 66.311 1.00 46.40 ATOM 2503 N LEU303 -27.061 6.677 68.034 1.00 43.29 ATOM 2504 H LEU303 -26.909 5.925 68.633 1.00 0.00 ATOM 2505 CA LEU303 -26.165 7.802 68.260 1.00 36.89 ATOM 2506 CB LEU303 -25.966 7.986 69.764 1.00 38.96 20 ATOM 2507 CG LEU303 -27.251 7.951 70.594 1 00 42.01 ATOM 2508 CDl LEU303 -26.9S2 7.491 72.007 1.00 41.24 ATOM 2509 CD2 LEU303 -27.926 9.316 70.S72 1.00 43.88 ATOM 2510 C LEU303 -24.824 7.489 67.595 1.00 31.37 ATOM 2511 o LEU303 -23.917 6.942 68.228 1.00 31.51 25 ATOM 2512 N PTY304 -24.712 7.799 66.309 1.00 25.51 ATOM 2513 H PTY304 -25.443 8.263 65.853 1.00 0.00 ATOM 2514 CA PTY304 -23.481 7.545 65.572 1.00 22.04 ATOM 2515 CB PTY304 -23.774 6.882 64.224 1.00 18.08 ATOM 2516 CG PTY304 -24.310 5.478 64.358 1.00 16.80 30 ATOM 2517 CDl PTY304 -23.459 4.375 64.296 1.00 15.50 ATOM 2518 CEl PTY304 -23.950 3.078 64.462 1.00 17.12 ATOM 2519 CD2 PTY304 -2S.662 5.253 64.580 1.00 18.22 ATOM 2520 CE2 PTY304 -26.160 3.971 64.743 1.00 18.21 ATOM 2521 CZ PTY 304 -25.305 2.889 64.687 1.00 16.53 35 ATOM 2522 OH PTY 304 -25 840 1.637 64.857 1.00 15.66 ATOM 2523 ORl PTY304 -26.848 1.189 66.998 i.oo 17.78 ATOM 2524 oR2 PTY304 -24.474 1.199 66.960 1.00 13.33 ATOM 252S OR3 PTY304 -2S.836 -0.551 6S.882 1.00 19.12 ATOM 2526 PR PTY 304 -25.659 0.847 66.222 1.00 16.13 SUBST~TUTE Si~E~ ~RULE 2~i~
-CA 02226963 l998-02-l2 W 0 97/08300 PCT~US96/13918 ATOM 2527 C PTY 304-22.717 8.839 65.375 1.00 20.65 ATOM 2528 O PTY 304-23.313 9.909 65.272 1.00 23.13 ATOM 2529 N ASN 305-21.396 8.741 65.358 1.00 18.57 ATOM 2530 H ASN 305-21.009 7.863 65.445 1.00 0.00 ATOM 2531 CA ASN 305 -20.545 9.907 65.189 1.00 20.26 ATOM 2532 CB ASN 305 -19.157 9.625 65.164 1.00 19.11 ATOM 2533 CG ASN 305 -19.197 9.305 67.241 1.00 21.22 ATOM 2534 ODl ASN305 -19.003 10.180 68.084 1.00 24.78 ATOM 2535 ND2 ASN305 -19.481 8.054 67.567 1.00 20.41 ATOM 2536 HD21 ASN 305 -19.675 7.444 66.829 1.00 0.00 ATOM 2537 HD22 ASN 305-19.499 7.805 68.521 1.00 0.00 ATOM 2538 C ASN 305-20.452 10.333 63.725 1.00 20.42 ATOM 2539 O ASN 305-20.549 9.503 62.819 1.00 21.37 ATOM 2540 N GLU 306-20.295 11.635 63.506 1.00 21.58 ATOM 2541 H GLU 306 -20.232 12.234 64.271 1.00 0.00 ATOM 2542 CA GLU 306-20.191 12.203 62.165 1.00 22.52 ATOM 2543 CB GLU 306-20.911 13.556 62.093 1.00 28.56 ATOM 2544 CG GLU 306-22.411 13.510 62.344 1.00 37.30 ATOM 2545 CD GLU 306-23.053 14.889 62.283 1 00 41.64 ATOM 2546 OEl GLU 306 -22.761 15.719 63.169 1.00 43.36 ATOM 2547 OE2 GLU306 -23.846 15.143 61.349 1.00 45.10 ATOM 2548 C GLU 306-18.729 12.416 61.791 1.00 20.22 ATOM 2549 O GLU 306-17.859 12.502 62.665 1.00 20.01 ATOM 2550 N LEU 307-18.469 12.528 60.493 1.00 18.25 ATOM 2551 H LEU 307 -19 208 12.499 59.842 1 00 0.00 ATOM 2552 CA LEU 307-17.118 12.747 60.005 1.00 16.72 ATOM 2553 CB LEU 307-16.995 12.307 58.544 1.00 16.17 ATOM 2554 CG LEU 307-17.056 10.831 58.166 1.00 13 26 ATOM 2555 CDl LEU 307-16.950 10.720 56.658 1.00 14.79 ATOM 2556 CD2 LEU 307 -15.921 10.075 58.829 1.00 12.43 ATOM 2557 C LEU 307-16.778 14.223 60.080 1.00 18.93 ATOM 2558 O LEU 307-17.632 15.075 59.843 1.00 19.72 ATOM 2559 N ASN 308-15.544 14.529 60.455 1.00 18.95 ATOM 2560 H ASN 308-14.946 13.819 60.757 1.00 0.00 ATOM 2561 CA ASN 308 -15.108 15.913 60.479 1.00 22.39 ATOM 2562 CB ASN 308-13.848 16.076 61.324 1.00 22.65 ATOM 2563 CG ASN 308-13.325 17.502 61.322 1.00 24.93 ATOM 2564 ODl ASN 308-13.764 18.348 60.540 1.00 23.61 -~
ATOM 2565 ND2 ASN 308-12.363 17.769 62.186 1.00 29.91 SU8STITUTE ~E~ tRuLE 2~) CA 02226963 l998-02-l2 WO 97/~8300 PCT~US96/13918 ATOM 2566 HD21 ASN 308 -12.039 17.026 62.740 1.00 0.00 ATOM 2567 HD22 ASN 308 -12.030 18.689 62.233 1.00 0.00 ATOM 2568 CASN 308 -14.800 16.173 59.012 1.00 22.77 ATOM 2569 OASN 308 -13.728 15.821 58.519 1.00 22.81 6 ATOM 2570 NLEU 309 -15.770 16.733 58.305 1.00 25.79 ATOM 2571 HLEU 309 -16.614 16.937 58.764 1.00 0.00 ATOM 2572 CALEU 309 -15.624 17.002 56.884 1.00 29.56 ATOM 2573 CBLEU 309 -16.937 17.546 56.316 1.00 30.40 ATOM 2574 CGLEU 309 -18.120 16.573 56.465 1.00 31.06 ATOM 2575 CDl LEU 309 -19.365 17.171 55.845 1.00 29.69 ATOM 2576 CD2 LEU 309 -17.802 15.229 55.814 1.00 28.45 ATOM 2577 CLEU 309 -14.433 17.879 56.496 1.00 32.74 ATOM 2578 OLEU 309 -13.980 17.840 55.352 1.00 34.00 ATOM 2579 NGLY 310 -13.896 18.628 57.453 1.00 34.39 ATOM 2580 H GLY 310 -14 259 18.618 58.363 1.00 0.00 ATOM 2581 CAGLY 310 -12.749 19.471 57.166 1.00 37.43 ATOM 2582 CGLY 310 -11.451 18.694 56.967 1.00 40.37 ATOM 2583 OGLY 310 -10.494 19.212 56.382 1.00 42.20 ATOM 2584 NARG 311 -11.411 17.454 57.453 1.00 39.39 ATOM 2585 H ARG 311 -12.204 17.096 57.902 1.00 0.00 ATOM 2586 CAARG 311 -10.220 16.613 57.334 1.00 37.84 ATOM 2587 CBARG 311 -9.912 15.938 58.673 1.00 38.89 ATOM 2588 CGARG 311 -9.364 16.864 59.737 1.00 42.25 ATOM 2589 CDARG 311 -9.096 16.101 61.022 1.00 47.16 ATOM 2590 NE ARG 311 -10.323 15.546 61.587 1.00 51.46 ATOM 2591 HEARG 311 -11.178 15.829 61.204 1.00 0.00 ATOM 2592 CZARG 311 -10.364 14.671 62.588 1.00 53.11 ATOM 2593 NHl ARG 311 -9.242 14.231 63.145 1.00 54.45 ATOM 2594 HHll ARG 311 -8.350 14.554 62.828 1.00 0.00 ATOM 2595 HH12 ARG 311 -9.301 13.580 63.901 1.00 0.00 ATOM 2596 NH2 ARG 311 -11.535 14.255 63.054 1.00 54.64 ATOM 2597 HH21 ARG 311 -12.383 14.597 62.652 1.00 0.00 ATOM 2598 HH22 ARG 311 -11.568 13.601 63.810 1.00 0.00 ATOM 2599 CARG 311 -10.306 15.545 56.246 1.00 35.04 r! 35 ATOM 2600 O ARG 311 -9.479 14.632 56.201 1.00 35.34 ~ ATOM 2601 NARG 312 -11.315 15.639 55.389 1.00 34.68 ATOM 2602 HARG 312 -11.927 16.402 55.451 1.00 0.00 ATOM 2603 CAARG 312 -11.484 14.668 54.316 1.00 34.78 ATOM 2604 CBARG 312 -12.882 14.766 53.706 1.00 35.31 -SUBSTiTUTE SH~ RULE i~6) CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 2605 CG ARG 312 -13.947 13 942 54.403 1.00 36.14 ATOM 2606 CD ARG 312 -15.085 13.646 53.436 1.00 37.95 ATOM 2607 NE ARG 31Z -14.597 12.970 52.232 1.00 37.17 ATOM 2608 HE ARG 312 -13.715 12.542 52.265 1.00 0.00 ATOM 2609CZ ARG 312 -15.268 12.882 51.086 1.00 37.05 ATOM 2610 NHl ARG 312 -16.473 13.423 50.966 1.00 38.97 ATOM 2611 HHll ARG312 -16.899 13.908 51.731 1.00 0.00 ATOM 2612 HH12 ARG312 -16.956 13.348 50.094 1.00 0.00 ATOM 2613 NH2 ARG312 -14.721 12.271 50.044 1.00 36.61 ATOM 2614 HH21 ARG 312 -13.804 11.879 50.127 1.00 0.00 ATOM 2615 HH22 ARG312 -15.225 12.194 49.185 1.00 0.00 ATOM 2616 C ARG312 -10.449 14.829 53.209 1.00 36.45 ATOM 2617 O ARG312 -9.953 15.929 52.957 1.00 35.30 ATOM 2618 N GLU313 -10.121 13.715 52.560 1.00 37.25 ATOM 2619 H GLU 313 -10.548 12.871 52.795 1.00 0.00 ATOM 2620 CA GLU313 -9 169 13.713 51.459 1.00 37.51 ATOM 2621 CB GLU313 -8.586 12.317 51.249 1.00 39.21 ATOM 2622 CG GLU 313 -7.367 12.039 52.100 1 00 42.52 ATOM 2623 CD GLU 313 -6.114 12.722 51.576 1.00 43.09 ATOM 2624OEl GLU 313 -5.282 12.027 50.962 1.00 44.41 ATOM 2625 OE2 GLU 313 -5.954 13.945 51.778 1.00 44.79 ATOM 2626 C GLU313 -9.903 14.162 50.214 1.00 35.75 ATOM 2627 O GLU313 -10.973 13.639 49.894 1.00 37.66 ATOM 2628 N GLU314 -9.332 15.139 49.523 1.00 33.41 ATOM 2629 H GLU 314 -8.466 15.487 49.818 1.00 0.00 ATOM 2630 CA GLU314 -9.939 15.683 48.319 1.00 31.60 ATOM 2631 CB GLU314 -9.771 17.214 48.305 1.00 37.69 ATOM 2632 CG GLU314 -10.165 17.916 46.999 1.00 46.27 ATOM 2633 CD GLU 314 -8.965 18.483 46.233 1.00 51.86 ATOM 2634OEl GLU 314 -8.667 19.689 46.391 1.00 54.73 ATOM 2635 OE2 GLU 314 -8.322 17.728 45.468 1.00 53.64 ATOM 2636 C GLU314 -9.363 15.083 47.043 1.00 25.93 ATOM 2637 O GLU314 -8.152 14.916 46.918 1.00 24.72 ATOM 2638 N PTY315 -10.249 14.729 46.119 1.00 21.35 ATOM 2639 H PTY 315 -11.206 14.843 46.282 1.00 0.00 ATOM 2640 CA PTY315 -9.854 14.204 44.820 1.00 19.78 ATOM 2641 CB PTY315 -10.482 12.839 44.544 1.00 17.55 ATOM 2642 CG PTY315 -9.678 11.690 45.091 1.00 14.77 ATOM 2643 CDl PTY 315 -8.575 11.196 44.396 1.00 9.06 SUBSTITUTE ~ ~ tRULE ~6) CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 2644 CEl PTY315 -7.808 10.163 44.916 1 30 12.12 ATOM 2645 CD2 PTY315 -9.998 11.117 46.319 1.00 14.36 ATOM 2646 CE2 PTY315 -9.239 10.085 46.847 1.00 14.01 ; ATOM 2647 CZ PTY 315 -8.146 9.612 46.145 1.00 14.96 ATOM 2648OH PTY 315-7.408 8.580 46.682 1.00 15.26 ATOM 2649 ORl PTY315 -6.224 9.301 48.730 1.00 15.27 ATOM 2650 OR2 PTY315 -5.231 9.872 46.712 1.00 14.33 ATOM 2651 oR3 PTY315 -5.246 7.621 47,409 1.00 16.50 ATOM 2652 PRPTY 315 -6.018 8.864 47.331 1.00 14.86 ATOM 2653 C PTY 315-10.349 15.218 43.808 1.00 21.32 ATOM 2654 O PTY 315 -11.354 15.892 44.034 1.00 22.46 ATOM 2655 N ASP 316 -9.629 15.351 42.707 1.00 22.70 ATOM 2656 H ASP 316 -8.875 14.753 42.558 1.00 0.00 ATOM 2657 CA ASP 316 -10.009 16.306 41.684 1.00 24.09 ATOM 2658CB ASP 316-8.770 16.826 40.954 1.00 24.94 ATOM 2659 CG ASP 316 -7.853 17.622 41.860 1 00 28.90 ATOM 2660 ODl ASP316 -7.849 18.865 41.756 1.00 32.00 ATOM 2661 OD2 ASP316 -7.140 17.004 42.681 1.00 29.88 ATOM 2662 C ASP 316 -10.981 15.691 40.698 1.00 24.49 ATOM 2663O ASP316 -11.148 14.473 40.646 1.00 23.60 ATOM 2664 M VAL 317 -11.644 16.559 39.948 1.00 27.16 ATOM 2665 H VAL 317 -11.475 17.521 40.029 1.00 0.00 ATOM 2666 CA VAL 317 -12.605 16.155 38.934 1.00 32.09 ATOM 2667 CB VAL 317 -lg.069 16.266 39.437 1.00 35.09 ATOM 2668CGl VAL 317-14.375 15.156 40 434 .00 36.22 ATOM 2669 CG2 VAL317 -14.314 17.636 40.066 1~J3 36.89 ATOM 2670 C VAL '17 -12.410 17.095 37.757 1.00 30.78 ATOM 2671 O VAL 317 -11.807 18.159 37.906 1.00 28.67 ATOM 2672 N LEU 318 -12.871 16.684 36.583 1.00 33.70 3~ ATOM 2673 H LEU 318-13.315 15.816 36.543 1.00 0.00 ATOM 2674 CALEU 318 -12.745 17.513 35.395 1.00 36.88 ATOM 2675 CBLEU 318 -13.044 16.699 34.138 1.00 34.38 ATOM 2676 CGLEU 318 -12.133 15.505 33.854 1.00 32.08 ATO~ 2677 CDl LEU318 -12.560 14.864 32.553 1.00 33.40 ATO~ 2678CD2 LEU 318-10.678 15.939 33.775 1.00 30.49 ATOM 2679 C LEU 318 -13.698 18.700 35.492 ~ 00 41.41 ATOM 2680 O LEU 318 -14.768 18.604 36.108 1.00 41.34 4 ATOM 2681 N ASP 319 -13.282 19.821 34.911 1.00 46.71 ATOM 2682 H ASP 319 -12.447 19.843 34.406 1.00 0.00 SVBSTITU~E ~tE~ tRuLE 26~

CA 02226963 l998-02-l2 WO 97108300 PCTAJS96/13gl8 ATOM 2683 CA ASP319-14.072 21.048 34.913 1.00 51.29 ATOM 2684 CB ASP319-13.204 22.239 35.340 1.00 53.24 ATOM 2685 CG ASP319-11.958 22.400 34.479 1.00 55.43 ATOM 2686 ODl ASP319 -12.065 22.950 33.361 1.00 58.31 ATOM 2687 OD2 ASP319 -10.868 21.982 34.923 1.00 58.61 ATOM 2688 C ASP 319 -14.682 21.306 33.535 1.00 52.86 ATOM 2689 O ASP 319 -14.195 20.701 32.549 1.00 53.27 ATOM 2690 OT ASP 319 -15.634 22.114 33.459 1 00 54.58 ATOM 2691 OH2 H20501 -16.395 6.573 53.935 1.00 13.04 1 0 ATOM 2692Hl H20 501 -15.625 7.149 54.126 1.00 0.00 ATOM 2693 H2 H20 501 -16.189 6.220 53.062 1.00 0.00 ATOM 2694 OH2 H20502 -6.900 -1.703 48.53? 1.00 15.81 ATOM 2695 Hl H20 502 -6.073 -2.133 48.827 1.00 0.00 ATOM 2696 H2 H20 502 -7.012 -1.023 49.224 1.00 0 00 1 5 ATOM 2697OH2 H20 503 -7.775 0.446 50.612 1.00 12.12 ATOM 2698 Hl H20 503 -8.328 0.785 51.329 1.00 0.00 ATOM 2699 H2 H20 503 -8.364 0.608 49.869 1.00 0.00 ATOM 2700 OH2 H20504 -5.965 5.376 45.701 1.00 13.82 ATOM 2701 Hl H20 504 -5.838 6.191 46.188 1.00 0.00 2 0 ATOM 2702H2 H20 504 -5.040 5.192 45.431 1.00 0.00 ATOM 2703 OH2 H20505 -14.971 -6.776 51.457 1.00 11.75 ATOM 2704 Hl H20 505 -14.401 -7.005 50.693 1.00 0.00 ATOM 2705 H2 H20 505 -15.747 -6.411 50.986 1.00 0.00 ATOM 2706 OH2 H20506 -7.399 -1.565 45.723 1.00 20.80 25 ATOM 2707 Hl H20 506 -6.869 -0.820 45.388 1.00 0.00 ATOM 2708 H2 H20 506 -7.127 -1.603 46.669 1.00 0.00 ATOM 2709 OH2 H20507 -3.458 7.189 49.505 1.00 12.46 ATOM 2710 Hl H20 507 -3.854 6.375 49.171 1.00 0.00 ATOM 2711 H2 H20 507 -4.035 7.857 49.121 1.00 0.00 30 ATOM 2712 OH2 H20508 -19.524 4.162 75.938 1.00 31.54 ATOM 2713 Hl H20 508 -20.107 4.703 76.513 1.00 0.00 ATOM 2714 H2 H20 508 -19.510 4.732 75.158 1.00 0.00 ATOM 2715 OH2 H20509 11.153 11.020 41.619 1.00 23.22 ATOM 2716 Hl H20 509 10.658 10.668 40.869 1.00 0.00 3~ ATOM 2717 H2 H20 509 10.757 11.895 41.712 1.00 0.00 6 ATOM 2718 OH2 H20510 -17.729 -5.463 50.658 1.00 8.16 ATOM 2719 Hl H20 510 -18.166 -5.105 49.866 1.00 0.00 ATOM 2720 H2 H20 510 -18.454 -6.018 50.978 1.00 0.00 ATOM 2721 oH2 H20511 -2.939 4.711 45.111 1.00 12.99 SUBSTl rUTF S~EET ~RULE 2~i) CA 02226963 l998-02-l2 W O 97/08300 P ~ AUS96/13918 ATOM 2722 Hl H20 511 -2.168 4.703 45.673 1.00 0.00 ATOM 2723 H2 H20 511 -2 789 3.917 44.596 1.00 0.00 ATOM 2724 OH2 H20512 -14.697 8.482 54.840 1.00 28.53 ATOM 2725 Hl H20 512 -15.286 8.807 55.530 1.00 0.00 ATOM 27Z6 H2 H20 512 -13.856 8.877 55.112 1.00 0.00 ATOM 2727 OH2 H20513 -4.301 -4.082 45.672 1.00 22.83 ATOM 2728 Hl H20 513 -3.747 -3.518 45.097 1.00 0.00 ATOM 2729 H2 H20 513 -5.176 -3.940 45.269 1.00 0.00 ATOM 2730 OH2 H20514 -21.713 7.798 61.095 1.00 18.35 ATOM 2731Hl H20 514 -21.035 8.271 61.588 1.00 0.00 ATOM 2732 H2 H20 514 -22.251 8.537 60.778 1.00 0.00 ATOM 2733 OH2 H20515 -10.843 5.000 40.733 1.00 28.99 ATOM 2734 Hl H20 SlS -10.540 4.529 41.519 1.00 0.00 ATOM 2735 H2 H20 515 -10.110 4.889 40.111 1.00 0.00 1~ ATOM 2736OH2 H20 516 1.069 6.001 27.806 1.00 27.31 ATOM 2737 Hl H20 516 1.435 6.888 27.776 1.00 0.00 ATOM 2738 H2 H20 516 0.143 6.122 27.559 1 00 0.00 ATOM 2739 OH2 H20517 -4.403 -3.111 48.506 1.00 19.12 ATOM 2740 Hl H20 517 -4.371 -3.215 47.537 l.OQ 0.00 ATOM 2741H2 H20 517 -3.595 -2.596 48.690 1.00 0.00 ATOM 2742 OH2 H20518 -20.848 12.059 58.636 1.00 30.17 ATOM 2743 Hl H20 518 -20.732 12.086 57.675 1.00 0.00 ATOM 2744 H2 H20 518 -21.337 11.237 58.756 1.00 0.00 ATOM 2745 OH2 H20519 -7.330 -4.001 44.530 1.00 20.45 ATOM 2746Hl H20 519 -7.479 -3.098 44.898 1.00 0.00 ATOM 2747 H2 H20 519 -7.935 -4.524 45.062 1.00 0.00 ATOM 2748 OH2 H20520 -12.664 0.989 38.964 1.00 15.59 ATOM 2749 Hl H20 520 -12.180 0.157 39.070 1.00 0.00 ATOM 2750 H2 H20 520 -13.550 0.682 39.238 1.00 0.00 ATOM 2751OH2 H20 521 -11.379 10.139 30.946 1.00 26.07 ATOM 2752 Hl H20 521 -11.624 10.977 30.530 1.00 0.00 ATOM 2753 H2 H20 521 -11.994 9.525 30.519 i.oo o.oo ATOM 2754 OH2 H20522 -15.662 9.282 47.198 1.00 17.30 ATOM 2755 Hl H20 522 -15.240 9.703 46.450 1.00 0.00 3~ ATOM 2756H2 H20 522 -16.316 9.967 47.478 1.00 0.00 ATOM 2757 OH2 H20 523 -11.947 -18.788 49.297 1.00 31.49 ATOM 2758 Hl H20 523 -11.710 -18.432 48.437 1.00 0.00 ATOM 2759 H2 H20 523 -12.293 -17.992 49.754 1.00 0.00 ATOM 2760 OH2 H20 524 6.740 2.001 42.957 1.00 21.38 SU85TITUTE S}~ tRuL~ 26~

W O 97/~8300 PCTnUS96/13918 ATOM 2761 Hl H20 524 5.847 2.141 43.289 1.00 0.00 ATOM 2762 H2 H20 524 6.864 1.047 42.981 1.00 0.00 ATOM 2763 OH2 H20525 -8.682 6.518 44.398 1.00 27.19 ATOM 2764 Hl H20 525 -7.791 6.155 44.453 1.00 0.00 ATOM 2765H2 H20 525 -8.649 7.215 45.061 1.00 0.00 ATOM 2766 OH2 H20526 -14.840 3.578 44.839 1.00 22.05 ATOM 2767 Hl H20 526 -15.718 3.347 45.149 l.OO 0.00 ATOM 2768 H2 H20 526 -14.551 4.227 45.498 1.00 0.00 ATOM 2769 OH2 H20527 4.492 23.057 38.874 1.00 25.33 0 ATOM 2770Hl H20 527 4.800 22.472 38.173 1.00 0.00 ATOM 2771 H2 H20 527 5.246 22.944 39.473 1.00 0.00 ATOM 2772 OH2 H20 528 0.375 -17.917 41.574 1.00 56.36 ATOM 2773 Hl H20 528 -0.351 -18.113 42.169 1.00 0.00 ATOM 2774 H2 H20 528 -0.043 -17.548 40.796 1.00 0.00 ATOM 2775OH2 H20 529 7.016 14.850 51.046 1.00 20.70 ATOM 2776 Hl H20 529 6.142 14.448 50.870 1.00 0.00 ATON 2777 H2 H20 529 6.980 15.645 50.511 1.00 0.00 ATOM 2778 OH2 H20530 -7.683 -1.801 42.232 1.00 34.83 ATOM 2779 Hl H20 530 -8.052 -1.273 42.957 1.00 0.00 ATOM 2780H2 H20 530 -7.249 -2.522 42.702 1.00 0.00 ATOM 2781 OH2 H20531 -21.235 6.653 69.461 1.00 40.97 ATOM 2782 Hl H20 531 -22.089 6.966 69.119 1.00 0.00 ATOM 2783 H2 H20 531 -21.371 6.744 70.411 1.00 0.00 ATOM 2784 OH2 H20532 0.051 -0.240 27.111 1.00 38.10 ATOM 2785Hl H20 532 -0.526 -0.554 26.406 1.00 0.00 ATOM 2786 H2 H20 532 0.153 0.695 26.895 1.00 0.00 ATOM 2787 OH2 H20533 4.720 13.526 50.274 1.00 24.25 ATOM 2788 Hl H20 533 3.779 13.360 50.353 1.00 0.00 ATOM 2789 H2 H20 533 5.030 12.691 49.901 1.00 0.00 ATOM 2790oH2 H20 535 -24.439 -4.493 65.220 1.00 19.89 ATOM 2791 Hl H20 535 -23.921 -4.800 64.468 1.00 0.00 ATOM 2792 H2 H20 535 -23.970 -4.918 65.943 1.00 0.00 ATOM 2793 OX2 H20536 -24.821 -8.124 64.414 1.00 26.52 ATOM 2794 Hl H20 536 -25.733 -8 277 64.141 1.00 0.00 3~ ATOM 2795H2 H20 536 -24.637 -7.232 64.092 1.00 0.00 ATOM 2796 OH2 H20537 -1.448 9.507 51.754 1.00 14.14 ATOM 2797 Hl H20 537 -2.234 9.866 52.178 1.00 0.00 ATOM 2798 H2 H20 537 -1.227 8.752 52.319 1.00 0.00 ATOM 2799 OH2 H20 538 -19.810 -23.909 45.616 1.00 42.72 SUBSTTTUTE ~i~EE~ tRULE 2~i~

CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 2800 Hl H20 538 -20.226 -24.776 45.518 1.00 0.00 ATOM 2801 H2 H20 538 -19.298 -24.029 46.420 1.00 0.00 ATOM 2802 OH2 H20 539 -6.034 -10.821 42.457 1.00 29.94 ATOM 2803 Hl H20 539 -6.800 -10.777 43.033 1.00 0.00 ATOM 2804 H2 H20 539 -5.304 -10.964 43.068 1.00 0.00 ATOM 2805 OH2 H20540 -20.033 10.958 50.001 1.00 31.83 ATOM 2806 Hl H20540 -19.256 10.718 50.512 1.00 0.00 ATOM 2807 H2 H20540 -20.491 10.121 49.920 1.00 0.00 ATOM 2808 OH2 H20541 -5.125 -7.851 62.359 1.00 38.63 ATOM 2809Hl H20 541 -4.372 -8.168 61.862 1.00 0.00 ATOM 2810 H2 H20541 -5.411 -7.104 61.798 1.00 0.00 ATOM 2811 OH2 H20542 -1.080 20.333 46.689 1.00 26.15 ATOM 2812 Hl H20542 -1.337 19.477 47.057 1.00 0.00 ATOM 2813 H2 H20542 -1.916 20.809 46.638 1.00 0.00 ATOM 2814OH2 H20 543 5.975 26.290 37.583 1.00 43.59 ATOM 2815 Hl H20543 6.265 26.840 36.852 1.00 0.00 ATOM 2816 H2 H20543 6.741 26.247 38.153 1.00 0.00 ATOM 2817 OH2 H20 544 -13.632 -13.848 50.081 1.00 27.21 ATOM Z818 Hl H20 544 -13.441 -13.263 50.817 1.00 0.00 ATOM 2819 H2 H20 544 -13.685 -13.228 49.342 1.00 0.00 ATOM 2820 OH2 H20545 6.897 4.096 46.579 1.00 32.58 ATOM 2821 Hl H20545 7.538 4.515 47.182 1.00 0.00 ATOM 2822 H2 H20545 7.296 3.250 46.353 1.00 0.00 ATOM 2823 OH2 H20546 -19.007 6.577 73.627 1.00 51.06 ATOM 2824Hl H20 546 -18.833 7.495 73.390 1.00 0.00 ATOM 2825 H2 H20546 -18.795 6.148 72.791 1.00 0.00 ATOM 2826 OH2 H20547 -0.107 9.991 22.576 1.00 43.45 ATOM 2827 Hl H20547 -0.622 10.655 23.054 1 00 0.00 ATOM 2828 H2 H20547 0.140 10.441 21.766 1.00 0.00 ATOM 2829OH2 H20 549 -20.845 -8.815 51.470 1.00 32.88 ATOM 2830 Hl H20549 -20.910 -9.731 51.186 1.00 0.00 ATOM 2831 H2 H20549 -20.734 -8.346 50.637 i.oo o.oo ATOM 2832 OH2 H20550 -18.995 -8.847 74.340 1.00 33.79 ATOM 2833 Hl H20550 -19.031 -9.373 73.541 1.00 0.00 ATOM 2834H2 H20 550 -18.620 -8.012 74.046 1.00 0.00 ATOM 2835 OH2 H20551 -29.193 1.529 65.322 1.00 28.70 ATOM 2836 Hl H20551 -29.521 1.026 66.091 1.00 0.00 ATOM 2837 H2 H20551 -28.243 1.541 65.504 1.00 0.00 ATOM 2838 OH2 H20 552 -9.376 -14.036 60.634 1.00 39.70 SU8STITUTE S}~E~ (RlJLE 26) WO 97/08300 PCT~US96/13918 ATOM 2839 Hl H20 552 -9.678 -14.141 59.724 l.C0 0.00 ATOM 2840 H2 H20 552 -8.558 -14.547 60.629 1.00 0.00 ATOM 2841 OH2 H20553 15.303 7.535 43.610 1.00 43.10 ATOM 2842 Hl H20 553 15.256 8.508 43.528 1.00 0.00 5 ATOM 2843 H2 H20 553 14.945 7.223 42.779 1.00 0.00 ATOM 2844 OH2 H20554 -6.351 -6.041 58.195 1.00 39.35 ATOM 2845 Hl H20 554 -5.433 -5.940 58.470 1.00 0.00 ATOM 2846 H2 H20 554 -6.453 -6.976 58.404 1.00 0.00 ATOM 2847 OH2 H20555 -26.688 -2.898 68.239 1.00 26.60 ATOM 2848Hl H20 555 -27.261 -2.128 68.123 1.00 0.00 ATOM 2849 H2 H20 555 -26.730 -3.318 67.372 1.00 0.00 ATOM 2850 OH2 H20556 -27.507 -2.530 64.808 1.00 35.40 ATOM 2851 Hl H20 556 -26.716 -3.098 64.836 1 00 0.00 ATOM 2852 H2 H20 556 -27.089 -1.666 64.684 1.00 0.00 ATOM 2853OH2 H20 557 -3.466 0.091 55.103 1.00 31.58 ATOM 2854 Hl H20 557 -4.116 0.662 54.672 1.00 0.00 ATOM 2855 H2 H20 557 -3.730 0.129 56.022 1 00 0.00 ATOM 2856 OH2 H20558 -17.363 11_081 48.313 1.00 34.37 ATOM 2857 Hl H20 558 -18.067 11.741 48.280 1.00 0.00 ATOM 2858H2 H20 558 -17.568 10.638 49.148 1.00 0.00 ATOM 2859 OH2 H20559 -5.182 1.100 51.170 1.00 35.10 ATOM 2860 Hl H20 559 -6.102 0.891 50.910 1.00 0.00 ATOM 2861 H2 H20 559 -4.870 0.273 51.539 1.00 0.00 ATOM 2862 OH2 H20560 -1.672 -2.171 49.168 1.00 30.93 ATOM 2863Hl H20 560 -1.378 -1.786 48.327 1.00 0.00 ATOM 2864 H2 H20 560 -1.186 -1.638 49.811 1.00 0.00 ATOM 2865 OH2 H20 561 -12.968 -16.434 50.268 1.00 38.85 ATOM 2866 Hl H20 561 -13.869 -16.305 49.955 1.00 0.00 ATOM 2867 H2 H20 561 -12.756 -15.504 50.450 1.00 0.00 ATOM 2868OH2 H20 563 8.438 5.804 48.097 1.00 48.55 ATOM 2869 Hl H20 563 7.987 5.826 48.951 1.00 0.00 ATOM 2870 H2 H20 563 9.187 6.397 48.249 i.oo o.oo ATOM 2871 OH2 H20569 -18.518 8.907 70.572 1.00 33.67 ATOM 2872 Hl H20 569 -19.475 8.882 70.611 1.00 0.00 ATOM 2873H2 H20 569 -18.362 9.599 69.917 1.00 0.00 ATOM 2874 OH2 H20570 -3.123 15.254 51.267 1.00 44.68 ATOM 2875 Hl H20 570 -2.857 15.725 50.474 1.00 0.00 ATOM 2876 H2 H20 570 -2.642 14.427 51.213 1.00 0.00 ATOM 2877 OH2 H20572 -4.725 17.961 46.351 1.00 28.78 SUBSmUTE S}~E~ ~RI~LE 2~i~

CA 02226963 l998-02-l2 W O 97/08300 PCTrUS96/13918 ATOM 2878 Hl H20 572 -5.641 18.255 46.416 1.00 0.00 ATOM 2879 H2 H20 572 -4.454 18.331 g5.500 1.00 0.00 ATOM 2880 OH2 H20 573 -17.831 -26.994 47 079 1.00 47.81 ATOM 2881 Hl H20 573 -18.168 -27.861 47.345 1.00 0.00 ATOM 2882H2 H20 573 -16.954 -27.236 46.737 1.00 0.00 ATOM 2883 OH2 H20 574 -11.347 -10.955 43.461 1.00 27.59 ATOM 2884 Hl H20 574 -12.285 -ll.Q31 43.636 1.00 0.00 ATOM 2885 H2 H20 574 -11.302 -10.452 42.652 1.00 0.00 ATOM 2886 OH2 H20575 -7.797 6.237 24.140 1.00 43.37 ATOM 2887Hl H20 575 -8.151 5.827 23.336 1.00 0.00 ATOM 2888 H2 H20 575 -7.042 6.728 23.794 1.00 0.00 ATOM 2889 OH2 H20576 -2.183 3.330 69.045 1.00 33.93 ATOM 2890 Hl H20 576 -3.094 3.131 68.802 1.00 0.00 ATOM 2891 H2 H20 576 -1.964 4.076 68.483 1.00 0.00 ATOM 2892OH2 H20 577 -0.855 -5.759 42.695 1.00 25.76 ATOM 2893 Hl H20 577 -1.157 -5.188 41.984 1.00 0.00 ATOM 2894 H2 H20 577 -0.947 -6.645 42.342 1.00 0.00 ATOM 2895 OH2 H20579 3.333 6.242 53.401 1.00 50.25 ATOM 2896 Hl H20 579 3.451 5.332 53.701 1.00 0.00 ATOM 2897H2 H20 579 4.217 6.487 53.105 1.00 0.00 ATOM 2898 OH2 H20580 -2.444 2.334 61.039 1.00 31.46 ATOM 2899 Hl H20 580 -3.317 2.148 61.413 1.00 0.00 ATOM 2900 H2 H20 580 -2.660 3.049 60.423 1.00 0.00 ATOM 2901 OH2 H20581 -15.655 7.091 35.775 1.00 37.09 ATOM 2902Hl H20 581 -14.694 ' 066 35.713 1.00 0.00 ATOM 2903 H2 H20 581 -15.902 6.185 35.548 1 00 0.00 ATOM 2904 OH2 H20582 2.063 24.320 47.146 1.00 51.91 ATOM 2905 Hl H20 582 1.349 24.295 46.468 1.00 0.00 ATOM 2906 H2 H20 582 2.119 25.295 47.172 1.00 0.00 ATOM 2907OH2 H20 583 -6.779 -2.271 28.633 1.00 40.33 ATOM 2908 Hl H20 583 -6.999 -1.707 27.886 1.00 0.00 ATOM 2909 H2 H20 583 -7.664 -2.443 28.970 1.00 0.00 ATOM 2910 OH2 H20584 11.799 8.386 47.735 1.00 53.26 ATOM 2911 Hl H20 584 12.475 8.197 47.055 1.00 0.00 ATOM 2912H2 H20 584 11.657 9.325 47.602 1.00 0.00 ATOM 2913 OH2 H20585 -13.524 6.050 40 840 1.00 43.92 ATOM 2914 Hl H20 585 -12.588 5.799 40.707 1.00 0.00 ATOM 2915 H2 H20 585 -13.692 5.671 41.705 1.00 0.00 ATOM 2916 OH2 H20 586 -20.205 -18.799 46.340 1.00 35.53 SUBS 11 l UTE S~E~ tRULE 2fi) CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 2917 Hl H20 586 -20.221 -18.803 47.304 1.00 0.00 ATOM 2918 H2 H20 586 -19.889 -17.914 46.132 1.00 0.00 ATOM 2919 OH2 H20587 9.685 9.586 28.857 1.00 23.20 ATOM 2920 Hl H20 587 8.918 9.519 28.276 1.00 0.00 5 ATOM 2921 H2 H20 587 10.422 9.526 28.241 1.00 0.00 ATOM 2922 OH2 H20588 -18.278 15.597 52 143 1.00 37.65 ATOM 2923 Hl H20 588 -17.821 15.619 52.985 1.00 0.00 ATOM 2924 H2 H20 588 -18.442 14.652 52.046 1.00 0.00 ATOM 2925 OH2 H20589 12.004 9.442 43.787 1.00 36.10 ATOM 2926Hl H20 589 11.783 9.993 43.008 1.00 0.00 ATOM 2927 H2 H20 589 12.929 9.683 43.951 1.00 0.00 ATOM 2928 OH2 H20592 -25.871 -5.699 57.447 1.00 24.88 ATOM 2929 Hl H20 592 -26.445 -5.733 58.226 1.00 0.00 ATOM 2930 H2 H20 592 -25.g40 -4.847 57.572 1.00 0.00 ATOM 2931oH2 H20 593 -13.120 10.109 38.496 1.00 33.36 ATOM 2932 Hl H20 593 -12.211 9.803 38.544 1.00 0.00 ATOM 2933 H2 H20 593 -13.553 9.578 39.173 1.00 0.00 ATOM 2934 OH2 H20594 -2.642 17.050 48.010 1.00 31.60 ATOM 2935 Hl H20 594 -2.754 17.725 48.682 1.00 0.00 ATOM 2936H2 H20 594 -3.443 17 194 47.462 1.00 0.00 ATOM 2937 OH2 H20595 13.645 7.886 45.763 1.00 41.58 ATOM 2938 Hl H20 595 14.505 7.762 46.191 1.00 0.00 ATOM 2939 H2 H20 595 13.921 7.739 44.837 1.00 0.00 ATOM 2940 OH2 H20596 11.562 6.029 45.973 1.00 50.87 ATOM 2941Hl H20 596 11.768 5.826 46.893 1.00 0.00 ATOM 2942 H2 H20 596 12.242 6.714 45.805 1.00 0.00 ATOM 2943 OH2 H20597 8.860 -0.601 32.747 1.00 41.20 ATOM 2944 Hl H20 597 8.422 -0.896 31.940 1.00 0.00 ATOM 2945 H2 H20 597 8.194 -0.773 33.420 1.00 0.00 ATOM 2946OH2 H20 598 14.739 10.248 44.027 1.00 61.01 ATOM 2947 Hl H20 598 14.760 11.112 43.590 1.00 0.00 ATOM 2948 H2 H20 598 15.049 10.456 44.920 1.00 0.00 ATOM 2949 OH2 H20599 -14.758 -0.522 39.901 1.00 47.63 ATOM 2950 Hl H20 599 -15.399 -0 544 39 178 1.00 0.00 ATOM 2951H2 H20 599 -14.534 -1.454 39.996 1.00 0.00 ATOM 2952 OH2 H20601 11.055 1.025 33.198 1.00 33.67 ATOM 2953 Hl H20 601 10.283 0.434 33.099 1.00 0.00 ATOM 2954 H2 H20 601 11.463 0.920 32.328 1.00 0.00 ATOM 2955 OH2 H20602 -7.939 5.076 74.158 1.00 35.51 SUBSTITUTE S}~EE~ tRULE ~6) WO 97/0830~ PCTAUs96/13918 ATOM 2956 Hl H20 602 -7.267 5.133 74.849 1.00 0.00 ATOM 2957 H2 H20 602 -7.784 4.156 73.888 1.00 0.00 ATOM 2958 OH2 H20 603 -16.636 -12.874 62.037 1.00 36.29 ATOM 2959 Hl H20 603 -16.225 -13.402 61.337 1.00 0.00 5 ATOM 2960 H2 H20 603 -15.849 -12.404 62.373 1.00 0.00 ATOM 2961 OH2 H20 604 -18.358 -20.653 39.617 1.00 36.43 ATOM 2962 Hl H20 604 -17.998 -20.559 40.507 1.00 0.00 ATOM 2963 H2 H20 604 -17.638 -20.311 39.059 1.00 0.00 ATOM 2964 OH2 H20605 -5.855 -5.527 60.942 1.00 35.83 ATOM 2965Hl H20 605 -6.476 -5.558 60.199 1.00 0.00 ATOM 2966 H2 H20 605 -5.861 -4.592 61.176 1.00 0.00 ATOM 2967 OH2 H20606 -7.119 -2.334 35.830 1.00 31.03 ATOM 2968 Hl H20 606 -7.787 -1.638 35.776 1.00 0.00 ATOM 2969 H2 H20 606 -7.562 -3.033 35.342 1 00 0.00 ATOM 2970OH2 H20 608 -4.292 10.348 58.969 1.00 59.16 ATOM 2971 Hl H20 608 -3.677 9.723 59.379 1.00 0.00 ATOM 2972 H2 H20 608 -3.683 10.944 58.518 1.00 0.00 ATOM 2973 OH2 H20609 -4.131 23.593 29.611 1.00 48.52 ATOM 2974 Hl H20 609 -4.310 24.395 30.105 1.00 0.00 ATOM 2975H2 H20 609 -4.950 23.104 29.684 1.00 0.00 ATOM 2976 OH2 H20 610 -13.858 -29.598 37.538 1.00 34.23 ATOM 2977 Hl H20 610 -13.564 -29.123 38.335 1.00 0.00 ATOM 2978 H2 H20 610 -14.093 -30.430 37.979 1.00 0.00 ATOM 2979 oH2 H20611 -20.921 -9.179 55.419 1.00 26.60 ATOM 2980Hl H20 611 -21.180 -9 388 56 337 1 00 0.00 ATOM 2981 H2 H20 611 -21.260 -9.951 54.942 l.a0 0.00 ATOM 2982 OH2 H20612 -26.331 -2.023 72.803 1.00 53.47 ATOM 2983 Hl H20 612 -26.140 -1.532 73.608 1.00 0.00 ATOM 2984 H2 H20 612 -27.255 -1.793 72.631 1.00 0.00 ATOM 2985OH2 H20 613 -13.525 13.983 37.069 1.00 50.82 ATOM 2986 Hl H20 613 -14.442 14.000 36.781 1.00 0.00 ATOM 2987 H2 H20 613 -13.355 13.043 37.165 1.00 0.00 ATOM 2988 OH2 H20614 -21.926 16.371 65.955 1.00 46.58 ATOM 2989 Hl H20 614 -22.637 17.013 65.941 1.00 0.00 ATOM 2990H2 H20 614 -22.048 15.876 65.146 1.00 0.00 ATOM 2991 OH2 H20615 1.690 -5.302 31.945 1.00 33.74 ATOM 2992 Hl H20 615 1.397 -6.113 31.506 1.00 0.00 ~ ATOM 2993 H2 H20 615 2.121 -5.661 32.733 1.00 0.00 ATOM 2994 OH2 H20 616 -20.949 -21.416 38.360 1.00 46.62 5~BSTiTUTE S}~F~ tRULE 26) CA 02226963 l998-02-l2 WO 97/08300 PCTrUS96/l39l8 ATOM 2995 Hl H20 616 -20.201 -21.991 38.548 1.00 0.00 ATOM 2996 H2 H20 616 -20.536 -20 560 38.533 1.00 0.00 ATOM 2997 OH2 H20617 -12.061 10.750 73.270 1.00 33.05 ATOM 2998 Hl H20 617 -12.819 11.023 72.742 1.00 0.00 5 ATOM 2999 H2 H20 617 -11.922 9.855 72.958 1.00 0.00 ATOM 3000 oH2 H20618 -15.349 12.400 63.729 1.00 37.51 ATOM 3001 Hl H20 618 -15.377 11.908 62.908 1.00 0.00 ATOM 3002 H2 H20 618 -16.272 12.641 63.835 1.00 0.00 ATOM 3003 OH2 H20619 0.949 7.386 53.643 1.00 49.12 ATOM 3004Hl H20 619 1.002 7.867 54.473 1.00 0.00 ATOM 3005 H2 H20 619 1.831 6.951 53.624 1.00 0.00 ATOM 3006 OH2 H20620 -4.534 -8.391 59.287 1.00 32.23 ATOM 3007 Hl H20 620 -4.887 -9.282 59.417 1.00 0.00 ATOM 3008 H2 H20 620 -3.858 -8.571 58.625 1.00 0.00 ATOM 3009oH2 H20 621 -25.465 -6.264 54.211 1.00 48.91 ATOM 3010 Hl H20 621 -24.522 -6.048 54.259 1.00 0.00 ATOM 3011 H2 H20 621 -25.496 -6.709 53.362 1.00 0.00 ATOM 3012 OH2 H20622 -28.810 -0.917 66.953 1.00 54.26 ATOM 3013 Hl H20 622 -28.968 -1.765 66.514 1.00 0.00 ATOM 3014H2 H20 622 -28.017 -0.623 66.496 1.00 0.00 ATOM 3015 oH2 H20623 -1.838 20.090 25.125 1.00 53.05 ATOM 3016 Hl H20 623 -1.624 20.918 24.699 1.00 0.00 ATOM 3017 H2 H20 623 -2.056 19.496 24.392 1.00 0.00 ATOM 3018 oH2 H20624 4.169 12.348 27.338 1.00 59.51 ATOM 3019Hl H20 624 3.885 11.758 26.634 1.00 0.00 ATOM 3020 H2 H20 624 3.382 12 887 27 475 1.00 0.00 ATOM 3021 OH2 H20 625 -20.172 -12.484 57.970 1.00 48.36 ATOM 3022 Hl H20 625 -20.919 -12.902 58.402 1.00 0.00 ATOM 3023 H2 H20 625 -19.544 -12.424 58.696 1.00 0.00 ATOM 3024OH2 H20 626 -2.341 -0 010 29 093 1.00 41.65 ATOM 3025 Hl H20 626 -2.634 -0.652 29.755 1.00 0.00 ATOM 3026 H2 H20 626 -1.592 -0.477 28.705 1.00 0.00 ATOM 3027 OH2 H20627 -5.808 -1.656 39.529 1.00 30.08 ATOM 3028 Hl H20 627 -6.395 -1.472 38.788 1.00 0.00 ATOM 3029H2 H20 627 -5.340 -0.821 39.617 1.00 0.00 END ' ~Note: See copyright notice on page 1.

SUBSTITUTE S~{ F~ ~RULE 2~i) CA 02226963 l998-02-l2 W O 97/08300 PCTrUS96/13918 A~;- II: Coordi~ate~ ~or t~o 3D ~tructure ~f ZAP-NC:z2*

REMARK FTT~ M~="tml-zeta2-watl-slow.pdb"
R~MARK TOPHl9.pep -MACRO ~or protein sequen~e ~reated by user: marcos ATOM 1 CB ASP 3-1.930-4.782 36.991 1.00 37.05 ATOM 2 CG ASP 3-2.570-3.408 37.176 1.00 38.16 ATOM 3 ODl ASP 3-2.370 -2.527 36.311 1.00 37.36 ATOM 4 OD2 ASP 3 -3.265 -3.205 38.197 1.00 37.01 ATOM 5 C ASP 3-2.096-4.960 34.485 1.00 32.75 ATOM 6 O ASP 3-0.916-4.974 34.145 1.00 31.91 ATOM 7 HTl ASP 3-1.022 -6.965 35.742 1.00 0.00 ATOM 8 HT2 ASP 3-2.470 -7.515 35.059 1 00 0.00 ATOM 9 N ASP 3 -2.058 -6 982 35.850 1.00 39.84 ATOM10 HT3 ASP 3-2.314 -7.428 36.750 1.00 0.00 ATOM11 CA ASP3-2.531 -5.568 35.816 1.00 35.10 ATOM12 N PRO 4-3.057-4,449 33.704 1.00 29.48 ATOM13 CD PRO4-4.493 -4.558 34.013 1.00 31.76 ATOM 14 CAPRO 4 -2.860 -3.823 32.394 1.00 27.70 ATOM15 CB PRO4-4.273 -3.399 32.011 1.00 30.04 ATOM16 CG PRO4-5.115 -4.444 32.653 1.00 32.47 ATOM17 C PRO 4-1.929-2.616 32.393 1.00 26.07 ATOM18 O PRO 4-1.563-2.119 31.324 1 00 27.89 ATOM 19 NALA 5 -1.585 -2.121 33.578 1.00 20.52 ATOM20 H ALA 5-1.962-2.491 34.379 1.00 0.00 ATOM21 CA AL~5-0.713 -0.963 33.682 1.00 15.66 ATOM22 CB ALA5-1.363 0.104 34.546 1.00 12.37 ATOM23 C ALA 50.662-1.303 34.222 1.00 15.18 ATOM 24 OALA 5 1.560 -0.474 34.167 1.00 15.42 ATOM25 N ALA 60.849-2.545 34.663 1.00 17.31 ATOM26 H ALA 60.133-3.204 34.566 1.00 0.00 ATOM27 CA ALA 62.118-2.982 35.250 1.00 15.36 ATOM28 CB ALA62.037 -4.448 35.644 1.00 16.18 ATOM 29 CALA 6 3.373 -2.730 34.420 1.00 14.64 ATOM30 O ALA 64.455-2.560 34.970 1.00 15.69 ATOM31 N HIS 73.238-2.712 33.100 1.00 13.68 ATOM32 H HIS 72.333-2.845 32.758 1.00 0.00 ATOM33 CA HIS74.393 -2.487 32.234 1.00 11.91 ~ - 151 -SUBST~TUTE ~}~E~ tRULE 2~i~

CA 02226963 l998-02-l2 ATOM 34 CB HIS 7 4.199 -3.186 30.884 1.00 11.56 ATOM 35 CG HIS 7 2.990 -2.727 30.134 1.00 6.98 ATOM 36 CD2 HIS 7 2.861 -1.908 29.064 1.00 8.55 ATOM 37 NDl HIS 7 1.712 -3.118 30.470 1.00 6.26 ATOM 38 HDl HIS 7 1.443 -3.762 31.161 1.00 0.00 ATOM 39 CEl HIS 7 0.848 -2.558 29.642 1.00 9.39 ATOM 40 NE2 HIS 7 1.524 -1.820 28.778 1.00 9.77 ATOM 41 HE2 HIS 7 1.115 -1.30S 28.037 1.00 0.00 ATOM 42 C HIS 7 4.726 -1.012 32.019 1.00 11.78 ATOM 43 OHIS 7 5.780 -0.688 31.479 1.00 15.61 ATOM 44 N LEU 8 3.821 -0.121 32.421 1.00 11.63 ATOM 45 H LEU 8 3.016 -0.410 32.904 1.00 0.00 ATOM 46 CA LEU 8 4.03S 1.317 32.271 1.00 11.65 ATOM 47 CB LEU 8 2.733 2.076 32.536 1.00 12.00 ATOM 48 CGLEU 8 1.807 2.318 31.340 1.00 14.44 ATOM 49 CDl LEU 8 2.031 1.303 30.248 1.00 14.24 ATOM 50 CD2 LEU 8 0.373 2.309 31.804 1.00 13.16 ATOM Sl C LEU 8S.129 1.799 33.213 1.00 10.74 ATOM S2 O LEU 85.059 1.576 34.419 1.00 13.97 ATOM 53 NPRO 9 6.142 2.500 32.676 1.00 11.59 ATOM 54 CD PRO 96.257 2.872 31.2S6 1.00 10.31 ATOM S5 CA PRO 97.279 3.032 33.439 1.00 9.S3 ATOM S6 CB PRO 98.087 3.778 32.373 1.00 10.S5 ATOM 57 CG PRO 97.724 3.094 31.115 1.00 10.88 ATOM S8 CPRO 9 6.867 3.997 34.S48 1.00 8.S8 ATOM S9 O PRO 97.567 4.134 35.550 1.00 10.26 ATOM 60 N PHE 105.752 4.688 34.340 1 00 7.17 ATOM 61 H PHE 105.256 4.547 33.516 1.00 0.00 ATOM 62 CA PHE 105.247 5.667 35.29S 1.00 8.06 ATOM 63 CBPHE 10 4.772 6.929 34.553 1.00 4.56 ATOM 64 CG PHE 103.822 6.646 33.425 1.00 6.98 ATOM 65 CDl PHE10 2.445 6.666 33.629 1.00 7.37 ATOM 66 CD2 PHE10 4.308 6.349 32.152 1.00 6.47 ATOM 67 CEl PHE10 1.563 6.390 32.578 1.00 8.56 ATOM 68 CE2 PHE 10 3.439 6.074 31.103 1.00 8.81 ATOM 69 CZ PHE 102.060 6.095 31.315 1.00 8.30 ATOM 70 C PHE 104.141 5.125 36.203 1.00 9.03 ATOM 71 O PHE 103.387 5.898 36.795 1.00 9.71 ATOM 72 N PHE 114.020 3.802 36.280 1.00 7.91 SUBSTITUTE ~H E~ ~ULE 2fi) CA 02226963 l998-02-l2 WO 97/08300 PCTrus96/l39l8 ATOM 73 H PHE114.649 3.204 35.823 1.00 0.00 ATOM 74 CA PHE113.026 3.166 37.137 1.00 7.22 ~' ATOM 75 CBPHE 11 2.404 1.964 36.427 1.00 7.31 A ATOM 76 CG PHE111.383 1.237 37.251 1.00 5.77 ATOM 77 CDl PHE11 0.206 1.864 37.635 1.00 2.00 ATOM 78 CD2 PHE11 1.603 -0.078 37.642 1.00 2.95 ATOM 79 CEl PHE11 -0.729 1.192 38.389 1.00 3.12 ATOM 80 CE2 PHE11 0.668 -0.761 38.401 1 00 2.87 ATOM 81 CZPHE 11 -0.497 -0.130 38.775 1.00 2.00 ATOM 82 CPHE 11 3.725 2.725 38 434 1.00 7.69 ATOM 83 OPHE 11 4.710 1.983 38.400 1.00 5.93 ATOM 84 NTYR 12 3.231 3.202 39.573 1.00 6.36 ATOM 85 HTYR 12 2.469 3.818 39.520 1.00 0.00 ATOM 86 CATYR 12 3.836 2.870 40.860 1.00 5.86 ATOM 87 CBTYR 12 3.996 4.130 41.706 1.00 7 27 ATOM 88 CGTYR 12 5.066 5.063 41.193 1.00 8.07 ATOM 89 CDl TYR12 4.862 5.836 40.051 1.00 7.30 ATOM 90 CEl TYR12 5.858 6.672 39.569 1.00 7.12 ATOM 91 CD2 TYR12 6.294 5.156 41.840 1.00 7.58 ATOM 92 CE2 TYR12 7.289 5.987 41.367 1.00 7.70 ATOM 93 CZTYR 12 7.063 6.740 40.234 1 00 8.65 ATOM 94 OHTYR 12 8 068 7.546 39.779 1.00 12.68 ATOM 95 HHTYR 12 8.910 7.326 40.171 1.00 0.00 ATOM 96 CTYR 12 3 114 1 805 41 662 1 00 5.87 ATOM 97 OTYR 12 3.554 1.428 42.749 1 00 5.79 ATOM 98 NGLY 13 2.000 1.325 41.139 1.00 5.99 ATOM 99 HGLY 13 1.656 1.690 40.302 1.00 0.00 ATOM 100 CAGLY 13 1.262 0.299 41.842 1.00 11.58 ATOM 101 CGLY 13 0.420 0.849 42.974 1.00 13.90 ATOM 102 OGLY 13 -0.098 1.960 42.888 1.00 13.74 ATOM 103 NSER 14 0.315 0.087 44.056 1.00 14.19 ATOM 104 HSER 14 0.788 -0.773 44.102 1.00 0.00 ATOM 105 CASER 14 -0.496 0.492 45.190 1.00 15.17 ATOM 106 CBSER 14 -1.162 -0.737 45.810 1.00 14.68 ATOM 107 OGSER 14 -2.009 -0.370 46.884 1.00 23.05 ATOM 108 HGSER 14 -1.439 -0.023 47.586 1.00 0.00 ATOM 109 CSER 14 0.210 1.316 46.265 1.00 16.00 ATOM 110 OSER 14 0.467 0.820 47.363 1.00 16.80 ATOM 111 NILE 15 0.522 2.570 45.950 1.00 15 37 .

SUBSTlTUTE SI~ RULE 26) W O 97/08300 PCTnUS96/13918 ATOM 112 H ILE150.283 2.901 45.Q58 1.00 0.00 ATOM 113 CA ILE151.159 3.467 46.914 1.00 12.48 ATOM 114 CB ILE152.370 4.223 46.304 1.00 10.89 ATOM 115 CG2 ILE 15 3.496 3.237 45.986 1.00 8.22 ATOM 116CGl ILE 15 1.945 5.032 45.074 1.00 7.10 ATOM 117 CD ILE153.062 5.887 44.496 1.00 2.93 ATOM 118 C ILE150.120 4 473 47.426 1.00 12.27 ATOM 119 O ILE15-0.990 4.555 46.889 1.00 11.25 ATOM 120 N SER160.469 5.233 48.459 1.00 8.90 ATOM 121 H SER 16 1.358 5.201 48.836 1.00 0.00 ATOM 122 CA SER16-0.459 6.215 49.010 1.00 10.27 ATOM 123 CB SER16-0.231 6.398 50.512 1.00 7.24 ATOM 124 OG SER16- 1.051 6.950 50.758 1.00 11.57 ATOM 125 HG SER161.119 7.092 51.719 1.00 0.00 ATOM 126 C SER 16 -0.267 7.549 48.316 1.00 8.08 ATOM 127 O SER160.727 7.753 47.608 1.00 5.74 ATOM 128 N ARG17-1.209 8.461 48.549 1.00 8.03 ATOM 129 H ARG17-1.975 8.225 49.117 1.00 0.00 ATOM 130 CA ARG17-1.137 9.792 47.969 1.00 7.35 ATOM 131 CBARG 17 -2.328 10.640 48.407 1.00 6.44 ATOM 132 CG ARG17-2.230 12.078 47.919 1.00 5.73 ATOM 133 CD ARG17-3.359 12.936 48.428 1.00 7.10 ATOM 134 NE ARG17-4.651 12.497 47.919 1.00 10.08 ATOM 135 HE ARG17-4.764 11.542 47.799 1.00 0.00 ATOM 136 CZARG 17 -5.667 13.308 47.651 1.00 12.64 ATOM 137 NHl ARG 17 -5.547 14.615 47.839 1.00 14.72 ATOM 138 HHll ARG17-4.683 14.986 48.174 1.00 0.00 ATOM 139 HH12 ARG17-6.311 15.229 47.642 1.00 0.00 ATOM 140 NH2 ARG 17-6.807 12.807 47.199 1.00 14.47 ATOM 141 HH21 ARG 17 -6.903 11.820 47.061 1.00 0.00 ATOM 142 HH22 ARG17-7.576 13.416 47.005 1.00 0.00 ATOM 143 C ARG 17 0.142 10.462 48.432 1.00 7.25 ATOM 144 O ARG 17 0.814 11.133 47.657 1.00 11.16 ATOM 145 N ALA 18 0.470 10.286 49.704 1.00 8.87 ATOM 146H ALA18 -0.131 9.780 50.291 1.00 0.00 ATOM 147 CA ALA 18 1.674 10.877 50.267 1.00 7.33 ATOM 148 CB ALA181.787 10.544 51.747 1.00 12.14 ATOM 149 C ALA182.904 10.405 49.526 1.00 7.31 ATOM 150 O ALA183.764 11.209 49.168 1.00 8.68 SUBSTITUTE ~ ~ tRULE 26~

CA 02226963 l998-02-l2 W O 97/08300 PCTrus96/13918 ATOM 151 N GLU192.987 9.100 49.292 1.00 8.47 ATOM 152 H GLU192.260 8.510 49.603 1.00 0.00 F ATOM 153 CA GLU194.127 8.530 48.580 1.00 7.37 ~ ATOM 154 CB GLU194.061 7.005 48.589 1.00 9.12 ATOM 155 CG GLU194.085 6.415 49.986 1.00 18.39 ATOM 156 CD GLUl93.901 4.909 50.005 1.00 18.70 ATOM 157 OEl GLU19 4.912 4.190 50.112 1.00 27.52 ATOM 158 OE2 GLU19 2.748 4.439 49.931 1.00 16.92 ATOM 159 C GLU194.166 9.050 47.150 1.00 8.14 ATOM 160 O GLU195.239 9.289 46.596 1.00 8.18 ATOM 161 N ALA202.987 9.229 46.560 1.00 8.26 ATON 162 H ALA202.170 9.017 47.052 1.00 0.00 ATOM 163 CA ALA202.882 9.738 45.197 1.00 9.21 ATOM 164 CB ALA201.432 9.702 44.731 1.00 7.13 ATOM 165 C ALA203.421 11.165 45.122 1.00 7.93 ATOM 166 O ALA204.178 11.510 44.216 1.00 7.73 ATOM 167 N GLU213.042 11.981 46.097 1.00 8.72 ATOM 168 H GLU212.458 11.637 46.807 1.00 0.00 ATOM 169 CA GLU213.474 13.371 46.142 1.00 8.14 ATOM 170 CB GLU212.621 14.156 47.132 1.00 3.54 ATOM 171 CG GLU211.166 14.213 46.698 1.00 4.77 ATOM 172 CD GLU210.276 15.052 47.594 1.00 3.41 ATOM 173 OEl GLU21 -0.882 15.278 47.213 1.00 3.53 ATOM 174 OE2 GLU21 0.716 15.489 48.674 1.00 8.91 ATOM 175 C GLU214 960 13.520 46.434 1 00 7.55 ATOM 176 O GLU215.595 14.470 45.982 1.00 10.13 ATOM 177 N GLU225.521 12.563 47.159 1.00 6.89 ATOM 178 H GLU224.964 11.853 47.531 1.00 0.00 ATOM 179 CA GLU226.941 12.584 47.458 1.00 7.66 ATOM 180 CB GLU227.291 11.489 48.465 1 00 9.80 ATOM 181 CG GLU228.772 11.140 48 465 1.00 20.65 ATOM 182 CD GLU229.231 10.377 49.691 1.00 26.23 ATOM 183 OEl GLU22 8.381 9.865 50.457 1.00 27.98 ATOM 184 OE2 GLU22 10.461 10.304 49.887 1.00 27.22 ATOM 185 C GLU227.754 12.407 46.173 1.00 8.48 ATOM 186 O GLU228.739 13.111 45.949 1.00 11.39 ATOM 187 N HIS237.330 11.473 45.326 1.00 10.23 ATOM 188 H HIS236.513 10.983 45.570 1.00 0.00 ATOM 189 CA HIS238.009 11.199 44.060 1.00 7.78 .

SUBSTITUTE ~E~ tRULE 26) CA 02226963 l998-02-l2 WO 97/083~0 PCTr~S96/13918 ATOM 190 CB HIS 23 7.420 9.954 43.388 1.00 6.65 ATOM 191 CG HIS 23 7.813 8.667 44.047 1.00 7.16 ATOM 192 CD2 HIS 23 9.015 8.056 44.166 1.00 5.40 ATOM 193 NDl HIS 23 6.902 7.835 44.661 1.00 9.76 ATOM 194HDl HIS 23 5.953 8.008 44.836 1.00 0.00 ATOM 195 CEl HIS 23 7.522 6.767 45.125 1.00 5.88 ATOM 196 NE2 HIS 23 8.808 6.879 44.838 1.00 7.2Q
ATOM 197 HE2 HIS 23 9.497 6.257 45.178 1.00 0.00 ATOM 198 C HIS23 7.923 12.380 43.102 1.00 7.58 ATOM 199 O HIS 23 8.893 12.698 42.412 1.00 9.48 ATOM 200 N LEU24 6.758 13.016 43.049 1.00 8.34 ATOM 201 H LEU24 6.007 12.724 43.606 1.00 0.00 ATOM 202 CA LEU24 6.551 14.164 42.174 1.00 6.84 ATOM 203 CB LEU24 5.062 14.527 42.112 1.00 5.05 ATOM 204 CG LEU 24 4.140 13.522 41.392 1.00 9.41 ATOM 205 CDl LEU 24 2.672 13.866 41.630 1.00 2.00 ATOM 206 CD2 LEU 24 4.441 13.479 39.889 1.00 2.21 ATOM 207 C LEU24 7.401 15.340 42.654 1.00 8.80 ATOM 208 O LEU24 7.973 16.072 41.843 1.00 10.47 ATOM 209 N LYS 25 7.521 15.497 43.969 1.00 9.78 ATOM 210 H LYS25 7.026 14.908 44,577 1.00 0.00 ATOM 211 CA LYS25 8.343 16.562 44 540 1.00 10.08 ATOM 212 CB LYS25 8.178 16.621 46.058 1.00 8.96 ATOM 213 CG LYS25 6.849 17.130 46.550 1.00 3.65 ATOM 214 CDLYS 25 6.863 17.140 48.059 1.00 10.29 ATOM 215 CE LYS25 5.533 17.549 48.656 1.00 9.07 ATOM 216 NZ LYS25 5.612 17.513 50.147 1.00 12.20 ATOM 217 HZl LYS 25 6.355 18.162 50.481 1.00 0.00 ATOM 218 HZ2 LYS 25 5.830 16.546 50,457 1.00 0.00 ATOM 219HZ3 LYS 25 4.697 17.805 50.540 1.00 0.00 ATOM 220 C LYS25 9.815 16.312 44.214 1.00 11.23 ATOM 221 O LYS25 10.518 17.204 43.741 1.00 11.13 ATOM 222 N LEU26 10.274 15.086 44.450 1.00 12.69 ATOM 223 H LEU26 9.655 14.414 44.817 1.00 0.00 s ATOM 224 CALEU 26 11.664 14.721 44.188 1.00 11.54 ATOM 225 CB LEU26 11.967 13.322 44.730 1.00 9.05 ATOM 226 CG LEU26 12.030 13.127 46.241 1.00 7.75 ATOM 227 CDl LEU 26 12.144 11.659 46.545 1.00 10.85 ATOM 228 CD2 LEU 26 13.196 13.880 46.822 1.00 8.02 SUBSTlTUTE S}tE~ tRuLE 2~i~

CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATOM 229 C LEU 2612.016 14.770 42.709 1.00 13.09 ATOM 230 O LEU 2613.194 14.788 42.353 1.00 13.85 ATOM 231 N ALA 2710.998 14.768 41.852 1.00 14.57 ATOM 232 H ALA 2710.076 14.716 42.182 1.00 0.00 ATOM 233 CA ALA27 11.207 14.809 40 409 1.00 14.74 ATOM 234 CB ALA27 10.114 14.036 39.690 1.00 11.97 ATOM 235 C ALA 2711.310 16.217 39.847 1.00 14.47 ATOM 236 O ALA 2711.450 16.388 38.637 1.00 18.58 ATOM 237 N GLY 2811.214 17.228 40.701 1.00 14.44 10 ATOM 238 H GLY 2811.100 17.075 41.663 1.00 0.00 ATOM 239 CA GLY28 11.322 18.588 40.208 1.00 16.06 ATOM 240 C GLY 2810.059 19.417 40.277 1.00 18.17 ATOM Z41 O GLY 2810.121 20.638 40.125 1.00 20.12 ATOM 242 N SEM 298.911 18.764 40.445 ~.00 18.95 15 ATOM 243 H SEM 298.916 17.783 40.530 1.00 0.00 ATOM 244 CA SEM29 7.633 19.461 40.560 1.00 19.29 ATOM 245 CB SEM29 7.691 20.394 41.774 1.00 26.13 ATOM 246 CG SEM29 6.357 20.714 42.386 1.00 38.67 ATOM 247 A SEM 295.628 19.139 43.253 1.00 56.20 20 ATOM 248 CE SEM29 4.244 20.250 43.984 1.00 49.18 ATOM 249 C SEM 297.244 20.262 39.307 1.00 17.59 ATOM 250 O SEM 296.551 21.277 39.404 1.00 14.79 ATOM 251 N ALA 307.661 19.799 38.132 1.00 17.50 ATOM 252 H ALA 308.158 18.959 38.095 1.00 0.00 25 ATOM 253 CA ALA30 7.361 20.506 36.883 1.00 17 68 ATOM 254 CB ALA30 8.328 20.078 35.787 1.00 17.19 ATOM 255 C ALA 305.920 20.303 36.427 1.00 18.58 ATOM 256 O ALA 305.336 19.246 36.667 1.00 20.12 ATOM 257 N ASP 315.345 21.323 35.786 1.00 19.30 30 ATOM 258 ~ ASP 315.870 22.127 35.608 1.00 0.00 ATOM 259 CA ASP31 3.967 21.251 35.287 1.00 18.84 ATOM 260 CB ASP31 3.556 22.553 34.585 1.00 22.71 ATOM 261 CG ASP31 3.270 23.682 35.550 1.00 26.71 ATOM 262 ODl ASP 31 3.279 24.850 35.109 1.00 32.54 35 ATOM 263 OD2 ASP 31 3.023 23 415 36.744 1.00 30.87 ATOM 264 C ASP 313.822 20.110 34.298 1.00 15.55 ATOM 265 O ASP 314.678 19.920 33.434 1.00 13.41 ATOM 266 N GLY 322.727 19.371 34.413 1.00 13.36 ATOM 267 H GLY 322.082 19.548 35.121 1.00 0.00 .

SUBSTITUTE ~t E~ ~ULE 2fi~

WO 97/08300 PCT~US96113918 ATOM 268 CA GLY322.500 18.261 33.513 1.00 10.92 ATOM 269 C GLY323.215 17.002 33.956 1.00 10.21 ATOM 270 O GLY323.189 16.002 33.241 1.00 12.71 ATOM 271 N LEU333.920 17.063 35.084 1.00 10.73 ATOM 272 H LEU333.996 17.913 35.563 1.00 0.00 ATOM 273 CA LEU334.608 15.889 35.621 1.00 10.86 ATOM 274 CB LEU335.587 16.297 36.730 1.00 10.14 ATOM 275 CG LEU336.506 15.217 37.309 1.00 8.41 ATOM 276 CDl LEU33 7.578 14.842 36.312 1.00 8.33 0 ATOM 277 CD2 LEU33 7.146 15.735 38.564 1.00 4.68 ATOM 278 C LEU333.486 15.015 36.193 1.00 11.04 ATOM 279 O LEU332.665 15.495 36.g87 1.00 10.22 ATOM 280 N PHE343.431 13.751 35.786 1.00 8.86 ATOM 281 H PHE344.113 13.400 35.173 1.00 0.00 ATOM 282 CA PHE342.369 12.868 36.247 1.00 6 90 ATOM 283 CB PHE341.236 12.837 35.210 }.00 5.89 ATOM 284 CG PHE341.587 12.101 33.941 1.00 7.44 ATOM 285 CDl PHE 34 1.247 10.755 33.784 1.00 8.28 ATOM 286 CD2 PHE 34 2.259 12.746 32.905 1.00 3.28 ATOM 287CEl PHE 34 1.575 10.066 32.615 1.00 10.52 ATOM 288 CE2 PHE 34 2.587 12.070 31.739 1.00 5.20 ATOM 289 CZ PHE342.247 10.727 31.589 1.00 7.45 ATOM 290 C PHE342.820 11.446 36.510 1.00 6.42 ATOM 291 O PHE343.861 11 003 36.026 1.00 7.20 ATOM 292 N LEU 35 2.015 10.724 37.273 1.00 5.42 ATOM 293 H LEU'51.189 11.106 37.637 1.00 0 00 ATOM 294 CA LEU352.294 9.328 37.564 1.00 5.16 ATOM 295 CB LEU353.228 9.170 38.780 1.00 3.91 ATOM 296 CG LEU352.861 9.681 40.178 1.00 5.75 ATOM 297CDl LEU 35 1.822 8.770 40.833 1.00 3.81 ATOM 298 CD2 LEU 35 4.125 9.730 41.033 1.00 5.45 ATo~ 299 C LEU350.950 8.638 37.759 1.00 5.01 ATOM 300 O LEU35-0.071 9 297 37.976 1.00 4.17 ATOM 301 N LEU360.947 7.321 37.628 1.00 5.84 3~ ATOM 302 ~ LEU 36 1.787 6.845 37.447 1.00 0.00 ATOM 303 CA LEU36-0.266 6.543 37.772 1.00 6.22 ATOM 304 CB LEU36-0.513 5.745 36.487 1.00 8.32 ATOM 305 CG LEU36-1.945 5.377 36.090 1.00 12.01 ATOM 306 CDl LEU 36 -2.670 6.628 35.627 1.00 9.93 SUBSTiTUTE ~E~ ~UI E :~fi) W O 97/0830~ PCT~US96/13918 ATOM 307 CD2LEU 36 -1.9244.333 34.975 1.00 11.40 ATOM 308 C LEU36-0.093 5.58738.942 1.00 5.04 ATOM 309 O LEU361.002 5.07539.178 1.00 4.23 ATOM 310 N ARG37-1.156 5.39639.712 1.00 5.30 ATOM 311 H ARG37-1.991 5.87539.531 1.00 0.00 ATOM 312 CA ARG 37 -1.1224.469 40.837 1.00 4.66 ATOM 313 CB ARG 37 -0.8455.190 42.156 1.00 3.66 ATOM 314 CG ARG 37 -1.7136.381 42.403 1.00 2.00 ATOM 315 CD ARG 37 -1.2877.057 43.664 1.00 2.41 1 0 ATOM 316 NE ARG 37 -1.942 8.346 43.828 1.00 2.04 ATOM 317 HE ARG 37 -1.6779.086 43.246 1.00 0.00 ATOM 318 CZ ARG 37 -2.8918.584 44.719 1.00 3.03 ATOM 319 NHlARG 37 -3.3087 614 45.526 1.00 2.03 ATOM 320 HHllARG 37 -2.9236.697 45.464 1.00 0.00 1 5 ATOM 321HH12 ARG 37 -4.022 7 812 46.194 1.00 0.00 ATOM 322 NH2ARG 37 -3.4009.798 44.824 1.00 2.00 ATOM 323 HH21ARG 37 -3.05410.515 44.228 1.00 0.00 ATOM 324 HH22ARG 37 -4.1099.997 45.488 1.00 0.00 ATOM 325 C ARG37-2.443 3.73240.884 1.00 3.21 20 ATOM 326 o ARG37-3.387 4.10540.195 1.00 4.62 ATOM 327 N GLN38-2.496 2.65741.652 1.00 5.11 ATOM 328 H GLN38-1.732 2.44442.213 1.00 0.00 ATOM 329 CA GLN 38 -3.7081.858 41.758 1.00 8.69 ATOM 330 CR GLN 38 -3.3560.428 42.169 1.00 9.37 25 ATOM 331 CG GLN 38 -4 540-0.505 42.289 1.00 12.33 ATOM 332 C~ GLN 38 -4.101-1.914 42.594 1.00 16.53 ATOM 333 OElGLN 38 -3.915-2.283 43.750 1.00 20.00 ATOM 334 NE2 GLN 38 -3.892-2.698 41.555 1.00 19.17 ATOM 335 HE21GLN 38 -4.078-2.315 40.666 1.00 0.00 30 ATOM 336 HEZ2GLN 38 -3.579-3.605 41.714 1.00 0.00 ATOM 337 C GLN38-4.649 2.48342.772 1.00 8.28 ATOM 338 O GLN38-4.209 2.97543.802 1.00 11.23 ATOM 339 N CYS39-5.938 2.47742.469 1.00 8.89 ATOM 340 H CYS39-6.237 2.04441.640 1.00 0.00 35 ATOM 341 CA CYS 39 -6.9333.049 43.361 1.00 8.08 ATOM 342 CB CYS39-8.266 3.16842.638 1.00 5.67 ATOM 343 SG CYS 39 -9.5204.051 43.539 1.00 10.90 ATOM 344 C CYS39-7.085 2.15044.577 1.00 9.83 ATOM 345 O CYS39-7.116 0.92144.451 1.00 7.19 SU85T~TUTE ~tE~ ~RU~ E 26~

CA 02226963 l998-02-l2 ATOM 346 N LEU40 -7.158 2.768 45.750 1.00 7.63 ATOM 347 H LEU40 -7.089 3.751 45.775 1.00 0.00 ATOM 348 CA LEU40 -7.310 2.036 46.994 1.00 9.31 ATOM 349 CB LEU40 -6.505 2.722 48.103 1.00 9.89 ATOM 350 CGLEU 40 -4.997 2.799 47.891 1.00 9.01 ATOM 351 CDl LEU 40 -4.374 3.725 48.921 1.00 11.37 ATOM 352 CD2 LEU 40 -4.388 1.407 47.975 1.00 9.89 ATOM 353 C LEU 40 -8.774 1.974 47.405 1.00 9.85 ATOM 354 O LEU 40 -9.115 1.337 48.399 1.00 11.71 ATOM 355N ARG 41 -9.638 2.622 46.633 1.00 9.83 ATOM 356 H ARG 41 -9.326 3.073 45.825 1.00 0.00 ATOM 357 CA ARG 41 -11.060 2.681 46.952 1.00 9.49 ATOM 358 CB ARG 41 -11.519 4.138 47.000 1.00 8.44 ATOM 359 CG ARG 41 -10.675 5.023 47.900 1.00 5.66 ATOM 360CD ARG41 -11.147 6.449 47.830 1.00 8.87 ATOM 361 NE ARG 41 -11.038 6.990 46.481 1.00 11.49 ATOM 362 HE ARG 41 -10.148 7.039 46.102 1.00 0.00 ATOM 363 CZ ARG 41 -12.057 7.468 45.775 1.00 13.34 ATOM 364 NHl ARG 41 -13.280 7.483 46.280 1.00 15.40 ATOM 365 HHll ARG 41 -13.439 7.153 47.206 1.00 0.00 ATOM 366 HH12 ARG41 -14.048 7 854 45.750 1.00 0.00 ATOM 367 NH2 ARG 41 -11.851 7.937 44.555 1.00 14.77 ATOM 368 HH21 ARG41 -10.937 7.928 44.156 1.00 0.00 ATOM 369 HH22 ARG41 -12.626 8.289 44.031 1.00 0.00 ATOM 370 C ARG 41 -11.990 1.898 46.042 1.00 9.85 ATOM 371 o ARG41 -13.110 1.581 46.434 1.00 8.69 ATOM 372 N SER42 -11.550 1.604 44.827 1.00 10.68 ATOM 373 H SER42 -10.650 1.838 44.525 1.00 0.00 ATOM 374 CA SER42 -12.389 0.859 43.902 1.00 12.49 ATOM 375 CBSER 42 -12.866 1.763 42.764 1.00 12.46 ATOM 376 OG SER42 -11.774 2.306 42.050 1.00 17.74 ATOM 377 HG SER42 -12.149 3.093 41.607 1.00 0.00 ATOM 378 C SER42 -11.651 -0.349 43.352 1.00 14.30 ATOM 379 O SER42 -10.457 -0.528 43.600 1.00 14.79 ATOM 380 N LEU 43 -12.381 -1.209 42.654 1.00 14.42 ATOM 381 H LEU43 -13.322 -1.022 42.491 1.00 0.00 ATOM 382 CA LEU43 -11.795 -2.400 42.062 1.00 14.72 ATOM 383 CB LEU43 -12.800 -3.556 42.094 1.00 15.93 ATON 384 CG LEU43 -13.008 -4.241 43.445 1.00 17.87 .
SUBSTIT~TE ~i~~~ ~RULE 2~i~

CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATOM 385 CDl LEU43 -14.314 -5.017 43.441 1.00 18.61 ATOM 386 CD2 LEU43 -11.835 -5.158 43.740 1.00 19.73 ATOM 387 C LEU43-11.390 -2.091 40.623 1.00 14.52 ~ ATOM 388 O LEU43-12,165 -1.496 39.867 1.00 14.42 ~ 5 ATOM 389 NGLY 44 -10.148 -2.418 40.283 1.00 15.19 ATOM 390 H GLY44-9.563 -2.772 40.986 1.00 0.00 ATOM 391 CA GLY44-9.646 -2.186 38.938 1.00 13.99 ATOM 392 C GLY44-9.496 -0.733 38.533 1.00 11.65 ATOM 393 O GLY44-9,353 -0,434 37 353 1.00 15.02 ATOM 394 NGLY 45 -9.489 0.170 39.503 1.00 9.86 ATOM 395 H GLY45-9.551 -0.116 40.434 1.00 0.00 ATOM 396 CA GLY45-9.360 1.580 39.192 1.00 5.54 ATOM 397 C GLY45-7,943 2.071 39.371 1.00 5.84 ATOM 398 O GLY45-7.088 1.360 39.899 1.00 6.52 ATOM 399 NTYR 46 -7.705 3.312 38.978 1.00 5.35 ATOM 400 H TYR46-8.441 3.865 38.629 1.00 0.00 ATOM 401 CA TYR46-6.389 3.916 39.077 1.00 5.58 ATOM 402 CB TYR46-5.709 3.954 37.694 1.00 5.14 ATOM 403 CG TYR46-5.371 2.597 37.127 1.00 6.25 ATOM 404CDl TYR 46 -4.305 1.853 37.634 1.00 7.73 ATOM 405 CEl TYR46 -4.046 0.573 37.177 1.00 7.63 ATOM 406 CD2 TYR46 -6.157 2.024 36.136 1.00 8.86 ATOM 407 CE2 TYR46 -5.905 0.743 35.670 1.00 7.09 ATOM 408 CZ TYR46-4.858 0.024 36.197 1.00 9.65 ATOM 409 OHTYR 46 -4.640 -1.262 35.765 1.00 14.03 ATOM 410 HH TYR46-4.204 -1.681 36.505 1.00 0.00 ATOM 411 C TYR46-6.548 5.339 39.564 1.00 6.00 ATOM 412 O TYR46_7.667 5.816 39.748 1.00 5.33 ATOM 413 N VAL47-5.429 5.988 39.840 1.00 3.93 ATOM 414 HVAL 47 -4,562 5.532 39.759 1.00 0.00 ATOM 415 CA VAL 47 -5.440 7.384 40.223 1.00 6.45 ATOM 416 CB VAL 47 -5.152 7.623 41.720 1.00 5.21 ATOM 417 CGl VAL47 -5.289 9.116 42.024 1.00 2.00 ATOM 418 CG2 VAL47 -6.108 6.824 42.591 1.00 2.00 ATOM 419 CVAL 47 -4.333 8.033 39.398 1.00 6.52 ATOM 420 o VAL47-3.225 7.504 39.323 1.00 5.99 ATOM 421 N LEU48-4.672 9.119 38.710 1.00 8.11 ATOM 422 H LEU48-5.588 9.443 38.750 1.00 0.00 ATOM 423 CA LEU48-3.720 9.870 37.903 1.00 8.79 SUBS~lTUTE S}{E~ ~RULE

CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 424 CB LEU 48 -4.418 10.427 36.658 1.00 12.43 ATOM 425 CG LEU 48 -3.677 10.764 35.353 1.00 14.11 ATOM 426 CDl LEU 48 -4.438 11 888 34.674 1.00 14.34 ATOM 427 CD2 LEU 48 -2 240 11.183 35.576 1.00 10.17 ATOM 428 C LEU 48 -3.277 11.039 38.779 1.00 11.50 ATOM 429 O LEU48 -4.102 11.873 39.162 1.00 9.63 ATOM 430 N SER49 -1.998 11.078 39.139 1.00 11.61 ATOM 431 H SER49 -1.392 10.383 38.818 1.00 0.00 ATOM 432 CA SER49 -1.479 12.166 39.960 1.00 8.18 ATOM 433 CBSER 49 -0.683 11.611 41.144 1.00 7.55 ATOM 434 OG SER49 -1.495 10.791 41.969 1.00 3.18 ATOM 435 HG SER49 -1.674 10.001 41.438 1.00 0.00 ATOM 436 C SER49 -0.595 13.083 39.108 1.00 9.13 ATOM 437 O SER49 0.371 12.625 38.498 1.00 10.70 ATOM 438 N LEU 50 -0.951 14.363 39.031 1.00 10.96 ATOM 439 H LEU50 -1.751 14.686 39.502 1.00 0 00 ATOM 440 CA LEU50 -0.170 15.315 38.252 1.00 12.63 ATOM 441 CB LEU50 -0.735 15.498 36.827 1.00 16.12 ATOM 442 CG LEU50 -2.127 15.995 36.426 1.00 17.82 ATOM 443CDl LEU 50 -3.182 15.206 37.167 1.00 23.32 ATOM 444 CD2 LEU 50 -2.275 17.479 36.672 1.00 17.92 ATOM 445 C LEU 50 0.064 16.657 38.929 1.00 11.83 ATOM 446 O LEU 50 -0.663 17.056 39.845 1.00 8.52 ATOM 447 N VAL 51 1.099 17.343 38.467 1.00 10.51 ATOM 448H VAL 51 1.613 16.980 37.717 1.00 0.00 ATOM 449 CA VAL 51 1.471 18.635 39,007 1.00 10.18 ATOM 450 CB VAL 51 3.000 18.704 39.283 1.00 9.58 ATOM 451 CGl VAL 51 3.369 20.031 39.938 1.00 5.85 ATOM 452 CG2 VAL 51 3.445 17.520 40.138 1.00 8.60 ATOM 453 C VAL 51 1.111 19.758 38.046 1.00 10.79 ATOM 454 O VAL51 1.283 19.637 36.833 1.00 11.95 ATOM 455 N HIS52 0.545 20.823 38.591 i.oo lo.ls ATOM 456 H HIS52 0.343 20.832 39.556 1.00 0.00 ATOM 457 CA HIS52 0.231 22.005 37.814 1.00 13.16 ATOM 458 CBHIS 52 -1.148 21.937 37.167 1.00 16.99 ATOM 459 CG HIS52 -1.460 23.127 36.308 1.00 19.12 ATOM 460 CD2 HIS 52 -2.483 24.011 36.344 1.00 19.25 ATOM 461 NDl HIS 52 -0.645 23.530 35.269 1.00 21.39 ATOM 462 HDl HIS 52 0.164 23.066 34.951 1.00 0.00 SUBSTITUTE SH F~ RULE 2~;) CA 02226963 l998-02-l2 W O 97/08300 PCTrUS96/13918 ATOM 463 CEl HIS 52 -1.154 24.607 34.702 1.00 18.57 ATOM 464 NE2 HIS 52 -2.271 24.919 35.335 1.00 20.49 ATOM 465 HE2 HIS 52 -2.880 25.642 35.070 1.00 0.00 ATOM 466 C HIS 52 0.285 23.137 38.813 1.00 14.35 5 ATOM 467 O HIS 52 -0.304 23.033 39.884 1.00 14.87 ATOM 468 N ASP 53 1.035 24.186 38.487 1.00 18.31 ATOM 469 H ASP 53 1.499 24.23S 37.643 1.00 0.00 ATOM 470 CA ASP 53 1.182 25.341 39.370 1.00 21.21 ATOM 471 CB ASP 53 -0.156 26.062 39.523 1.00 25.36 t0 ATOM 472CG ASP 53 -0.260 27.272 38.643 1.00 33.50 ATOM 473 ODl ASP 53 -0.918 27.174 37.586 1.00 39.21 ATOM 474 OD2 ASP 53 0.314 28.321 39.016 1.00 35.58 ATOM 475 C ASP 53 1.709 24.977 40.753 1.00 21.34 ATOM 476 O ASP 53 1.213 25.490 41.759 1.00 20.63 ATOM 477N VAL 54 2.706 24.094 40.803 1.00 20.75 ATOM 478 H VAL 54 3.064 23.729 39.964 1.00 0.00 ATOM 479 CA VAL 54 3.298 23.650 42.072 1.00 21.10 ATOM 480 CB VAL 54 4.081 24.806 42.777 1.00 22.31 ATOM 481 CGl VAL 54 4.962 24.261 43.892 1.00 21.47 ATOM 482CG2 VAL 54 4.943 25.546 41.773 1.00 25.32 ATOM 483 C VAL54 2.207 23.094 43.004 1.00 20.23 ATOM 484 O VAL54 2.325 23.144 44.234 1.00 21.96 ATOM 485 N ARG55 1.180 22.502 42.399 1.00 20.64 ATOM 486 H ARG55 1.149 22.431 41.425 1.00 0.00 ATOM 487 CAARG 55 0.049 21.936 43.127 1 00 20.79 ATOM 488 CB ARG55 -1.166 22.862 42.982 1.00 24.88 ATOM 489 CG ARG55 -2.454 22.303 43.543 1 00 37.51 ATOM 490 CD ARG55 -2.330 22.040 45.036 1.00 47.31 ATOM 491 NE ARG55 -3.385 21.152 45.519 1.00 52.82 ATOM 492 HEARG 55 -4.305 21.346 45.243 1.00 0.00 ATOM 493 CZ ARG55 -3.179 20.109 46.319 1.00 54.83 ATOM 494 NHl ARG 55 -1.950 19.818 46.738 i.oo 51.75 ATOM 495 HHll ARG55 -1.181 20.384 46.445 1.00 0.00 ATOM 496 HH12 ARG55 -1.803 19.025 47.333 1.00 0.00 ATOM 497 NH2 ARG 55 -4.204 19.345 46.686 1.00 55.41 ATOM 498 HH21 ARG55 -5.129 19.569 46.367 1.00 0.00 ATOM 499 HH22 ARG55 -4.061 18.561 47.291 1.00 0.00 ATOM 500 C ARG 55 -0.278 20.539 42.586 1.00 17.44 ATOM 501 O ARG 55 -0.162 20.289 41.386 1.00 16.40 SUE~STITUTE }~ RULE 26) W O 97/08300 PCT~US96/13918 ATOM 502 N PHE56 -0.697 19.642 43.472 1.00 12.91 ATOM 503 H PHE56 -0.795 19.904 44.409 1.00 0.00 ATOM 504 CA PHE56 -1.038 18.276 43.087 1.00 11.38 ATOM 505 CB PHE56 -0.670 17.295 44.192 1.00 7.94 5 ATOM 506 CG PHE56 0.767 17.346 44.596 1.00 9.45 ATOM 507 CDl PHE 56 1.134 17.879 45.828 1.00 9.25 ATOM 508 CD2 PHE 56 1.756 16.864 43.751 1.00 7.32 ATOM 509 CEl PHE 56 2.468 17.931 46.213 1.00 7.59 ATOM 510 CE2 PHE 56 3.093 16.911 44.126 1 00 10.67 ATOM 511 CZPHE 56 3.449 17.448 45.362 1.00 7.88 ATOM 512 C PHE56 -2.518 18.128 42.806 1.00 10.74 ATOM 513 O PHE56 -3.354 18.696 43.502 1.00 11.90 ATOM 514 N HIS57 -2.835 17.346 41.786 1.00 12.61 ATOM 515 H HIS57 -2.116 16.929 41.249 1.00 0.00 ATOM 516 CAHIS 57 -4.217 17.082 41.405 1.00 12.51 ATOM 517 CB HIS57 -4.550 17.771 40.076 1.00 15 95 ATOM 518 CG HIS57 -4.415 19~.263 40.108 1.00 16.89 ATOM 519 CD2 HIS 57 -3.346 20.065 39.882 1.00 17.62 ATOM 520 NDl HIS 57 -5.466 20.103 40.413 1.00 21.02 ATOM 521HDl HIS 57 -6.378 19.803 40.644 1.00 0.00 ATOM 522 CEl HIS 57 -5.050 21.356 40.374 1.00 18.85 ATOM 523 NE2 HIS 57 -3.770 21.361 40.056 1.00 17.75 ATOM 524 HE2 HIS 57 -3.184 22.148 40.028 1.00 0.00 ATOM 525 C HIS57 -4.288 15.567 41.245 1.00 11.47 ATOM 526 O HIS 57 _3 451 14.981 40.553 1.00 9.71 ATOM 527 N HIS58 -5.226 14.932 41.947 1.00 10.52 ATOM 528 H HIS58 -5.837 15.442 42.530 1.00 0.00 ATOM 529 CA HIS58 -5.387 13.478 41.892 1.00 7.58 ATOM 530 CB HIS58 -5.236 12.884 43.293 1.00 4.66 ATOM 531 CGHIS 58 -3.964 13.291 43.973 1.00 4.02 ATOM 532 CD2 HIS 58 -3.707 14.285 44.855 1.00 2.46 ATOM 533 NDl HIS 58 -2.748 12.703 43.697 1.00 3.15 ATOM 534 HDl HIS 58 -2.585 11.924 43.109 1.00 0.00 ATOM 535 CEl HIS 58 -1.799 13.318 44.372 1.00 2.00 ATOM 536NE2 HIS 58 -2.354 14.281 45.082 1.00 3.60 ATOM 537 HE2 HIS 58 -1.914 14.927 45.656 1.00 0.00 ATOM 538 C HIS58 -6.734 13.130 41.302 1.00 6.91 ATOM 539 O HIS58 -7.773 13.391 41.905 1.00 10.26 ATOM 540 N PHE59 -6.704 12.588 40.093 1.00 8.54 - 16~ -SUBSTITUTE ~EE~ ~R~JI E 2~i~

CA 02226963 l998-02-l2 ATOM 541 H PHE59-5.843 12.465 39.640 1.00 0.00 ATOM 542 CA PHE59-7.907 12.202 39.372 1.00 5.78 ATOM 543 CB PHE59-7.816 12.653 37.915 1.00 7.34 ~ ATOM 544 CG PHE59-7.752 14.138 37.749 1.00 7.56 r 5 ATOM 545 CDl PHE59 -6.533 14.796 37.774 1.00 8.46 ATOM 546 CD2 PHE59 -8.913 14.881 37.588 1.00 6.77 ATOM 547 CEl PHE59 -6.466 16.181 37.646 1.00 10.40 ATOM 548 CE2 PHE59 -8.856 16.263 37.461 1 00 9.75 ATOM 5~9 CZ PHE59-7.630 16.915 37.492 1.00 11.63 ATOM 550 CPHE 59 -8.126 10.703 39.410 1.00 6.79 ATOM 551 O PHE59-7.342 9.932 38.852 1.00 7.41 ATOM 552 N PRO60-9.188 10.263 40.089 1.00 9.70 ATOM 553 CD PRO60-10.180 11.018 40.877 1.00 6.89 ATOM 554 CA PRO60-9.444 8.826 40.147 1.00 10.01 ATOM 555 CBPRO 60 -10.483 8.718 41.258 1.00 10.34 ATOM 556 CG PRO60-11.247 9.988 41.119 1.00 9.58 ATOM 557 C PRO60-9.983 8.349 38.804 1.00 13.30 ATOM 558 O PRO60-10.806 9.023 38.174 1.00 14.14 ATOM 559 N ILE61-9.457 7.226 38.339 1.00 13.16 ATOM 560 HILE 61 -8.791 6.793 38.870 1.00 0.00 ATOM 561 CA ILE61-9.857 6.625 37.079 1.00 13.78 ATOM 562 CB ILE61-8.615 6.239 36.246 1.00 11.71 ATOM 563 CG2 ILE61 -9.025 5.656 34.906 1.00 13.24 ATOM 564 CGl ILE61 -7.715 7.460 36.041 1.00 9.66 ATOM 565 CDILE 61 -6 386 7.129 35.387 1.00 6.22 ATOM 566 C ILE61-10.651 5.366 37.432 1.00 15.81 ATOM 567 O ILE61-10.165 4.499 38.167 1.00 14.88 ATOM 568 N GLU62-11.883 5.286 36.947 1.00 19.32 ATOM 569 H GLU62-12.238 6.005 36.378 1.00 0.00 ATOM 570 CAGLU 62 -12.723 4.132 37.233 1.00 23.46 ATOM 571 CB GLU62-14.100 4.575 37.737 1.00 28.96 ATOM 572 CG GLU62-14.963 3.422 38.253 1.00 36.57 ATOM 573 CD GLU62-16.337 3.864 38.716 1.00 40.63 ATOM 574 OEl GLU62 -17.320 3.612 37.980 1.00 41.74 ATOM 575OE2 GLU 62 -16.434 4.450 39.819 1.00 41.68 ATOM 576 C GLU62-12.884 3.230 36.021 1.00 21.41 ATOM 577 O GLU62-12.984 3.707 34.892 1.00 21.22 ATOM 578 N ARG63-12.867 1.925 36.262 1.00 21.79 ATOM 579 H ARG63-12.783 1.600 37.186 1.00 0.00 .
- t65 -SUBSTITUTE ~}tE~ tRuLE 26) CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATOM 580 CA ARG 63 -13.036 0.943 35.205 1.00 2S.45 ATOM 581 CB ARG 63 -12.425 -0.391 35.615 1.00 27.80 ATOM 582 CG ARG 63 -12.414 -1.419 34.496 1.00 33.00 ATOM 583 CD ARG 63 -11.931 -2.760 34.997 1.00 33 41 ATOM 584 NE ARG 63 -12.828 -3.269 36.027 1.00 35.94 ATOM 585 HE ARG 63 -13.722 -2.876 36.094 1.00 0.00 ATOM 586 CZ ARG 63 -12.516 -4.231 36.887 1.00 35.92 ATOM 587 NHl ARG63 -11=313 -4 8Q6 35~51 l~QQ 37.94 ATOM 588 HHll ARG 63-10.639 -4.529 36.173 1.00 0.00 ATOM 589 HH12 ARG 63 -11.100 -5.528 37.509 1.00 0.00 ATOM 590 NH2 ARG 63-13.406 -4.610 37.793 1.00 36.87 ATOM 591 HH21 ARG 63-14.306 -4.173 37.818 1.00 0.00 ATOM 592 HH22 ARG 63-13.189 -5.331 38.450 1.00 0.00 ATOM 593 C ARG 63 -14.529 0.767 34.999 1.00 26.74 ATOM 594 O ARG 63 -15.218 0.244 35 872 1.00 29.01 ATOM 595 M GLN 64 -15.028 1.218 33.856 1.00 29.10 ATOM 596 H GLN 64 -14.402 1.626 33.234 1.00 0.00 ATOM 597 CA GLN 64 -16.449 1.125 33.538 1.00 32.01 ATOM 598 CB GLN 64 -16.757 1.886 32.247 1.00 31.94 ATOM 599 CG GLN 64 -16.217 3.306 32.192 1.00 35.07 ATOM 600 CD GLN 64 -16.893 4.236 33.175 1.00 36.14 ATOM 601 OEl GLN64 -16.698 4.135 34.384 1.00 36.71 ATOM 602 NE2 GLN64 -17.681 5.164 32.655 1.00 40.49 ATOM 603 HE21 GLN 64-17.785 5.194 31.683 1 00 0.00 ATOM 604 HE22 GLN 64 -18.122 5.773 33.280 1.00 0.00 ATOM 605 C GLN 64-16.911 -0.318 33.385 1.00 35.23 ATOM 606 O GLN 64-16.117 -1.214 33.084 1.00 36.40 ATOM 607 N LEU 65-18.215 -0.523 33.551 1.00 39.04 ATOM 608 H LEU 65-18.766 0.242 33.804 1.00 0.00 ATOM 609 CA LEU65 -18.834 -1.842 33.428 1.00 41.57 ATOM 610 CB LEU 65-20.361 -1.731 33.578 1.00 45.35 ATOM 611 CG LEU 65-21.194 -1.014 32.498 i.oo 48.79 ATOM 612 CDl LEU65 -22.682 -1.210 32.774 1.00 48.80 ATOM 613 CD2 LEU65 -20.861 0.477 32.425 1.00 48.69 ATOM 614 C LEU 65 -18.490 -2.498 32.089 1.00 40.88 ATOM 615 O LEU 65 -18.406 -3 720 31.988 1.00 41.06 ATOM 616 N ASN 66 -18.281 -1.670 31.070 1.00 40.78 ATOM 617 H ASN 66 -18.363 -0.709 31.237 1.00 0.00 ATOM 618 CA ASN 66 -17.946 -2.155 29.735 1.00 39.66 SUBSTtTUTE ~E~ tRuLE 2~i) CA 02226963 l998-02-l2 WO 97/08300 PCTrus96/l39l8 ATOM 619 CB ASN 66 -18.496 -1.214 28.649 1.00 43.14 ATOM 620 CG ASN 66 -18.333 0.255 28.995 1.00 46.18 ATOM 621 ODl ASN 66 -18.884 0.742 29.987 1.00 48.62 ATOM 622 ND2 ASN 66 -17.605 0.977 28.161 1.00 45.77 ATOM 623 HD21 ASN 66 -17.199 0.536 27.388 1.00 0.00 ATOM 624 HD22 ASN66-17.532 1.927 28.370 1.00 0.00 ATOM 625 C ASN66-16.464 -2.440 29.505 1.00 36.70 ATOM 626 O ASN66-16.045 -2.686 28.375 1.00 35.57 ATOM 627 N GLY67-15.676 -2.408 30.577 1.00 35.06 ATOM 628 H GLY 67 -16.031 -2.213 31.465 1.00 0.00 ATOM 629 CA GLY67-14.253 -2.686 30.467 1.00 32.41 ATOM 630 C GLY67-13.349 -1.520 30.106 1.00 30.31 ATOM 631 O GLY67-12.138 -1.697 29.991 1.00 30.24 ATOM 632 N THR68-13.923 -0.338 29.904 1.00 28.66 ATOM 633 H THR 68 -14.888 -0.234 29.971 1.00 0.00 ATOM 634 CA THR 68 -13.128 0.838 29.574 1.00 25.46 ATOM 635 CB THR 68 -13.872 1.785 28.620 1.00 26.78 ATOM 636 OGl THR 68 -15.186 2.052 29.127 1.00 27.70 ATOM 637 HGl THR 68 -15.620 2.606 28.472 1.00 0.00 ATOM 638CG2 THR 68 -13.957 1.180 27.230 1.00 27.47 ATOM 639 C THR68-12.746 1.596 30.838 1.00 23.00 ATOM 640 O THR68-13.144 1.220 31.938 1.00 22.61 ATOM 641 N TYR69-11.995 2.678 30.673 1.00 20.59 ATOM 642 H TYR69-11.718 2.938 29.778 1.00 0.00 ATOM 643 CATYR 69 -11.551 3.483 31.796 1.00 15.58 ATOM 644 CB TYR69-10.047 3.328 31.978 1 00 12.63 ATOM 645 CG TYR69-9.664 1.936 32.386 1.00 12.79 ATOM 646 CDl TYR 69 -9.485 0.934 31.433 1.00 10.68 ATOM 647 CEl TYR 69 -9.189 -0.370 31.815 1.00 13.20 ATOM 648CD2 TYR 69 -9 533 1.601 33.731 1.00 9.78 ATOM 649 CE2 TYR 69 -9.236 0.308 34.119 1.00 11.49 ATOM 650 CZ TYR69-9.067 -0.674 33.161 1.00 11.48 ATOM 651 OH TYR69-8.785 -1.961 33.546 1.00 13.55 ATOM 652 HH TYR69-8.850 -2.067 34.504 1.00 0.00 ATOM 653 C TYR 69 -11.897 4.936 31.583 1.00 15.95 ATOM 654 O TYR69-11.727 5.468 30.487 1.00 13.25 ATOM 655 N ALA70-12.361 5.591 32.638 1.00 17.69 ATOM 656 H ALA70-12.479 5.142 33.508 1.00 0.00 ATOM 657 CA ALA 70 -12.725 6.991 32.533 1.00 19.16 SU~S~ITUTE ~E~ ~RULE 2~i) CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATOM 658 CB ALA70-14.150 7.121 31.981 1.00 18.87 ATOM 659 C ALA70-12.608 7.742 33.848 1.00 18.59 ATOM 660 O ALA70-12.844 7.184 34.925 1.00 19.11 ATOM 661 N ILE71-12.155 8.985 33.749 1.00 19.47 ATOM 662 H ILE 71 -11.906 9.337 32.870 1.00 0.00 ATOM 663 CA ILE71-12.048 9.864 34.897 1.00 19.95 ATOM 664 CB ILE71-11.037 10.989 34.645 1.00 21.71 ATOM 665 CG2 ILE 71 -11.010 11.948 35.814 1.00 20.85 ATOM 666 CGl ILE 71 -9.644 10.405 34.428 1.00 21.25 ATOM 667 CDILE 71 -8.597 11.453 34.109 1 00 23.55 ATOM 668 C ILE71-13.448 10.455 34.936 1.00 21.14 ATOM 669 O ILE71-14.049 10.673 33.888 1.00 19.95 ATOM 670 N ALA72-13.991 10.669 36.126 1.00 25.60 ATOM 671 H ALA72-13.484 10.472 36.937 1.00 0.00 ATOM 672CA ALA72 -15.335 11.220 36.240 1.00 30.18 ATOM 673 CB ALA72-15.679 11.495 37.698 1.00 31.23 ATOM 674 C ALA72-15.458 12.494 35.412 1.00 33.10 ATOM 675 O ALA72-14.651 13.418 35.551 1.00 34.99 ATOM 676 N GLY73-16.425 12.502 34 500 1 00 33.63 ATOM 677 H GLY 73 -16.972 11.706 34.360 1.00 0.00 ATOM 678 CA GLY 73 -16.643 13.663 33.658 1.00 34.45 ATOM 679 C GLY73-15.998 13.530 32.293 1.00 34.98 ATOM 680 O GLY73-16.470 14.113 31.317 1.00 36.5g ATOM 681 N GLY74-14.931 12.743 32.221 1.00 34.48 ATOM 682 H GLY 74 -14.615 12.263 33.010 1.00 0.00 ATOM 683 CA GLY74-14.230 12.558 30.966 1.00 32.55 ATOM 684 C GLY74-14.704 11.388 30.130 1.00 32.17 ATOM 685 O GLY74-15.632 10.666 30.493 1.00 32.72 ATOM 686 N LYS75-14.040 11.200 28.997 1.00 31.90 ATOM 687 H LYS 75 -13.309 11.813 28.811 1.00 0.00 ATOM 688 CA LYS75-14.361 10.125 28.075 1.00 30.83 ATOM 689 CB LYS75-14.002 10.536 26.645 ~.00 34.04 ATOM 690 CG LYS75-12.604 11.124 26.486 1.00 37.94 ATOM 691 CD LYS75-12.207 11.203 25.022 1.00 40.86 c ATOM 692 CELYS 75 -12.088 9.811 24.408 1.00 44.39 ATOM 693 NZ LYS75-11.678 9.850 22.977 1.00 46.69 ATOM 694 HZl LYS 75 -10.759 10.330 22.888 1.00 0.00 ATOM 695 HZ2 LYS 75 -12.394 10.355 22.419 1.00 0.00 ATOM 696 HZ3 LYS 75 -11.601 8.873 22.628 1.00 0.00 SU8STITUTE ~tE~ tRuLE 26) CA 02226963 l998-02-l2 ATOM 697 C LYS75-13.652 8.825 28.443 1.00 29.70 ATOM 698 O LYS75-12.567 8.840 29.035 1.00 29.72 ATOM 699 N ALA76-14.264 7.705 28.072 1 00 26 68 ATOM 700 H ALA76-15.096 7.775 27.566 1.00 0.00 ATOM 701 CA ALA 76 -13.711 6.388 28.352 1.00 26.38 ATOM 702 CBALA 76 -14.813 5 334 28.327 1.00 26.29 ~ ATOM 703 CALA 76 -12.621 6.028 27.355 1.00 23.85 ATOM 704 OALA 76 -12.590 6.542 26.241 1.00 23.96 ATOM 705 NHIS 77 -11.718 5.149 27.769 1.00 23.92 1 0 ATOM 706 HHIS 77 -11.794 4.779 28.678 1.00 0.00 ATOM 707 CAHIS 77 -10.624 4.715 26.915 1.00 23.21 ATOM 708 CBHIS 77 -9-349 5.468 27.270 1.00 22.18 ATOM 709 CGHIS 77 -9.466 6.947 27.097 1.00 22.49 ATOM 710 CD2 HIS77 -9.273 7.732 26.012 1.00 23.47 1 5 ATOM 711NDl HIS 77 -9.870 7.784 28.111 1.00 25.61 ATOM 712 HDl HIS77 -10.123 7.524 29.028 1.00 0.00 ATOM 713 CEl HIS77 -9.920 9.025 27.662 1.00 25.59 ATOM 714 NE2 HIS77 _9.563 9.020 26.390 1.00 24.65 ATOM 715 HE2 HIS77 -9.544 9.793 25.792 1.00 0.00 2 0 ATOM 716 CHIS 77 -10.413 3.227 27.073 1.00 23.54 ATOM 717 OHIS 77 -10.833 2.640 28.067 1.00 22.48 ATOM 718 NCYS 78 -9.762 2.622 26.086 1.00 24.06 ATOM 719 HCYS 78 -9.468 3.146 25.315 1.00 0.00 ATOM 720 CACYS 78 -9.500 1.186 26.089 1.00 25.49 25 ATOM 721 CBCYS 78 -8.831 0.762 24.782 1.00 28.48 ATOM 722 SGCYS 78 -9.718 1.274 23.311 1.00 45.92 ATOM 723 CCYS 78 -8.625 0.743 27.245 1.00 20.86 ATOM 724 OCYS 78 -8.675 -0.413 27.649 1.00 21.75 ATOM 725 NGLY 79 -7.791 1.646 27.740 1.00 17.20 30 ATOM 726 HGLY 79 -7.750 2.555 27.393 1.00 0.00 ATOM 727 CAGLY 79 -6.919 1.297 28.839 1.00 13.97 ATOM 728 CGLY 79 -6.204 2.501 29.408 1.00 13.22 ATOM 729 OGLY 79 -6.291 3.600 28.848 1.00 12.24 ATOM 730 NPRO 80 -5.473 2.314 30.518 1.00 14.67 35 ATOM 731 CDPRO 80 -5.345 1.022 31.222 1.00 16.84 ATOM 732 CAPRO 80 -4.714 3.358 31.207 1.00 15.78 ATOM 733 CBPRO 80 -4.108 2.610 32.402 1.00 17.64 ATOM 734 CGPRO 80 -4.039 1.179 31.930 1.00 17.90 ATOM 735 CPRO 80 -3.645 3.991 30.321 1.00 14.91 -SUBSmUTE ~E}~ tRULE 2fi) W O 97/~8300 PCTAUS96/13918 ATOM 736 O PRO 80 -3.434 5.206 30.357 1.00 15.49 ATOM 737 N ALA 81 -3.003 3.168 29.500 1.00 13.13 ATOM 738 H ALA 81 -3.231 2.212 29.488 1.00 0.00 ATOM 739 CA ALA 81 -1.969 3.645 28.594 1.00 13.20 5 ATOM 740 CB ALA 81 -l .3252.474 27.882 1.00 11.11 ATOM 741 C ALA 81 -2.585 4.602 27.584 1.00 12.98 ATOM 742 O ALA 81 -2.080 5.706 27.376 1.00 9.81 ATOM 743 N GLU 82 -3.712 4.185 27.006 1.00 15.40 ATOM 744 H GLU 82 -4.074 3.319 27.268 1.00 0,00 1 0 ATOM 745 CA GLU 82 -4.432 4.975 26.007 1.00 16.50 ATOM 746 CB GLU 82 -5.578 4.165 25.391 1.00 18.83 ATOM 747 CG GLU 82 -5.143 3.076 24.417 1.00 22.18 ATOM 748 CD GLU 82 -4.391 1.934 25.087 1.00 29.04 ATOM 749 OEl GLU 82 -4.960 1.286 25.992 1.00 29.04 t 5 ATOM 750 oE2 GLU 82 -3.228 1.678 24.702 1.00 36.49 ATOM 751 C GLU 82 -4.974 6.266 26.594 1.00 16.45 ATOM 752 O GLU 82 -5.064 7.287 25.905 1.00 15.38 ATOM 753 N LEU 83 -5.338 6.215 27.868 1.00 15.01 ATOM 754 H LEU 83 -5.252 5.365 28.350 1.00 0.00 2 0 ATOM 755 CA LEU 83 -5.863 7.378 28.567 1.00 13.23 ATOM 756 CB LEU 83 -6.453 6.957 29.920 1.00 11.92 ATOM 757 CG LEU 83 --7.1918.010 30.748 1.00 9.05 ATOM 758 CDl LEU 83 -8.321 7.365 31.526 1.00 6.47 ATOM 759 CD2 LEU 83 -6.217 8.729 31.669 1.00 8.09 2~ ATOM 760 C LEU 83 -4.770 8.431 28.743 1.00 12.70 ATOM 761 O LEU 83 -4.964 9.603 28.415 1 00 13.58 ATOM 762 N CYS 84 -3.608 8.013 29.228 1.00 12.46 ATOM 763 H CYS 84 -3.484 7.068 29.473 1.00 0.00 ATOM 764 CA CYS 84 -2.508 8.948 29.419 1.00 11.61 ATOM 765 CB CYS 84 -1.387 8.289 30.207 1.00 10.43 ATOM 766 SG CYS 84 --1.9157.860 31.867 1.00 10.33 ATOM 767 C CYS 84 --1.9979.485 28.092 1.00 13.49 ATOM 768 O CYS 84 -1.591 10.640 28.003 1.00 12.47 ATOM 769 N GLU 85 -2.024 8.640 27.064 1.00 16.19 3!~ ATOM 770 H GLU 85 -2.346 7.726 27.199 1.00 0.00 ATOM 771 CA GLU 85 -1.590 9.035 25.729 1.00 18.26 ATOM 772 CB GLU 85 -1.542 7.812 24.802 1.00 19.98 ATOM 773 CG GLU 85 -0.393 6.843 25.144 1.00 26.96 ATOM 774 CD GLU 85 -0.462 5.465 24.456 1.00 28.02 - ~70 -SU8ST~TUTE ~ UI E 26) CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 775 OEl GBU 85 0.570 4.759 24.466 1.00 25.08 ATOM 776 OE2 GLU 85 -1.530 5.069 23.937 l.Q0 27.13 ATOM 777 C GLU85-2.537 10.113 25.192 1.00 19.29 ATOM 778 O GLU85-2.099 11.077 24.564 1.00 22.26 ATOM 779 N PHE 86 -3.824 9.985 25.508 1.00 18.82 ATOM 780 H PHE86-4.103 9.216 26.042 1.30 0.00 ATOM 781 CA PHE86-4.839 10.948 25.080 1.00 15.74 ATOM 782 CB PHE86-6.240 10.391 25.368 1.00 14.90 ATOM 783 CG PHE86-7.350 11.360 25.084 1.00 17.05 ATOM 784CDl PHE 86 -7.867 11.487 23.801 1.00 20.88 ATOM 785 CD2 PHE 86 -7.867 12.167 26.096 1.00 17.90 ATOM 786 CEl PHE 86 -8.883 12.407 23.529 1.00 21.36 ATOM 787 CE2 PHE 86 -8.878 13.089 25.834 1.00 16.83 ATOM 788 CZ PHE86-9.387 13.209 24.551 1.00 20.44 ATOM 789 C PHE 86 -4.674 12.313 25.762 1.00 15.39 ATOM 790 O PHE86-4.705 13.355 25.104 1.00 9.31 ATOM 791 N TYR87-4.511 12.302 27.082 1.00 14.05 ATOM 792 H TYR87-4.518 11.448 27.562 1.00 0.00 ATOM 793 CA TYR 87 -4.357 13.542 27.838 1.00 16.04 ATOM 794CB TYR87 -4.645 13.303 29.316 1 00 15.23 ATOM 795 CG TYR 87 -6.106 13.035 29.553 1.00 17.80 ATOM 796 CDl TYR 87 -6.551 11.781 29.964 1.00 20.66 ATOM 797 CEl TYR 87 -7.911 11.519 30.142 1.00 21.74 ATOM 798 CD2 TYR 87 -7.056 14.028 29.327 1.00 19.58 ATOM 799CE2 TYR 87 -8.411 13.780 29.500 1 00 19.90 ATOM 800 CZ TYR87-8.834 12.526 29.907 1.00 22.31 ATOM 801 OH TYR87-10.179 12.284 30.070 1.00 24.09 ATOM 802 HH TYR87-10.601 13.151 29.992 1.00 0.00 ATOM 803 C TYR87-3.042 14.282 27.629 1.00 15.72 ATOM 804 O TYR 87 -2.918 15.457 27.988 1.00 13.60 ATOM 805 N SER88-2.059 13.598 27.054 1.00 17.80 ATOM 806 H SER88-2.164 12.641 26.866 1.00 0.00 ATOM 807 CA SER88-0.775 14.222 26.763 1.00 23.25 ATOM 808 CB SER880.258 13.165 26.371 1.00 23.49 ATOM 809 OGSER 88 0.617 12.360 27.480 1 00 33.23 ATOM 810 HG SER880.973 12.975 28.143 1.00 0.00 ATOM 811 C SER88-0.938 15.226 25.619 1.00 26.20 ATOM 812 O SER88-0.278 16.265 25.595 1.00 28.26 ATOM 813 N ARG89-1.822 14.908 24.677 1.00 30.06 -SUBSTlTUTE Si~E~ ~RULE

.
CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 814 H ARG 89 -2.342 14.080 24.761 1.00 0.00 ATOM 815 CA ARG 89 -2.070 15.771 23.524 1.00 33.80 ATOM 816 CB ARG 89 -2.350 14.931 22.269 1.00 37.17 ATOM 817 CG ARG 89 -1.112 14.334 21.598 1.00 43.59 ATOM 818CD ARG 89 -0.425 13.287 22.464 1.00 47.19 ATOM 819 NE ARG 89 0.796 12.767 21.848 1.00 51.34 ATOM 820 HE ARG 89 0.710 12.040 21.193 1.00 0.00 ATOM 821 CZ ARG 89 2.023 13.219 22.103 1.00 53.00 ATOM 822 NHl ARG 89 2.212 14.212 22.967 1.00 53.42 ATOM 823 HHll ARG 89 1.435 14.633 23.434 1.00 0.00 ATOM 824 HH12 ARG89 3.142 14.533 23.154 1.00 0.00 ATOM 825 NH2 ARG 89 3.070 12.664 21.503 1.00 54.73 ATOM 826 HH21 ARG89 2.936 11.899 20.870 1.00 0.00 ATOM 827 ~H22 ARG89 3.993 13.004 21.690 1.00 0.00 ATOM 828C ARG 89 -3.224 16.747 23.742 1.00 33.93 ATOM 829 ~ ARG89 -3.220 17.849 23.195 1.00 35.37 ATOM 830 N ASP 90 -4.206 16.342 24 539 1.00 34.09 ATOM 831 H ASP 90 -4.177 15.460 24.968 1.00 0.00 ATOM 832 CA ASP 90 -5.370 17.181 24.797 1.00 32.55 ATOM 833CB ASP 90 -6.533 16.707 23.907 1.00 34.44 ATOM 834 CG ASP 90 -7.780 17.576 2g.028 1.00 37.74 ATOM 835 ODl ASP 90 -8.865 17.075 23.662 1.00 42.07 ATOM 836 OD2 ASP 90 -7.688 18.749 24.464 1.00 36.32 ATOM 837 C ASP90 -5.775 17.137 26.271 1.00 31.21 ATOM 838 O ASP 90 -6.160 16.086 26.784 1.00 29.06 ATOM 839 N PRO91 -5.678 18.280 26.974 1.00 31.00 ATOM 840 CD PRO91 -5.144 19.571 26.500 1.00 31.27 ATOM 841 CA PRO91 -6.046 18.363 28.391 1.00 30.53 ATOM 842 CB PRO91 -5.938 19.860 28.677 1.00 30,79 ATOM 843 CGPRO 91 -4.817 20.280 27.793 1.00 30.18 ATOM 844 C PRO91 -7.479 17.869 28.576 1.00 30.82 ATOM 845 O PRO91 -7.783 17.169 29.536 ~.00 32.23 ATOM 846 N ASP92 -8.358 18.287 27.664 1.00 31.25 ATOM 847 H ASP92 -8.041 18.890 26.966 1.00 0.00 ATOM 848 CAASP 92 -9.768 17.895 27.660 1.00 29.68 ATOM 849 CB ASP92 -9.906 16.470 27.097 1.00 32.25 ATOM 850 CG ASP 92 -11.281 16.192 26.498 1.00 33.34 ATOM 851 ODl ASP 92 -11.880 15.142 26.826 1.00 33.77 ATOM 852 OD2 ASP 92 -11.748 17.009 25.679 1.00 39.38 - ~72 -SUBSTITUTE S~E~ (RULE 2~;~
_ _ W O 97/08300 PCT~US96/13918 ATOM 853 C ASP 92 -10.42318.005 29.043 1.00 30.56 ATOM 854 O ASP 92 -11.20817.142 29.442 1.00 30.28 ., ATOM 855 N GLY 93 -10.09919.079 29.762 1.00 29.01 ATOM 856 H GLY 93 --9.46419.737 29.417 1.00 0.00 ATOM 857 CA GLY 93 -10.66519.285 31.084 1.00 27.68 ATOM 858 C GLY 93 -9.65419.345 32.218 1.00 27.53 ATOM 859 O GLY 93 -9.93319.912 33.278 1.00 28.17 ATOM 860 N LEU 94 -8.48818,737 32.020 1.00 25.94 ATOM 861 H LEU 94 -8.32918.255 31.183 1.00 0.00 1 0 ATOM 862 CA LEU 94 -7.45118.741 33.046 1.00 26.33 ATOM 863 CB LEU 94 -6.35317.725 32.710 1.00 22.36 ATOM 864 CG LEU 94 -6.69616.241 32.594 1.00 22.65 ATOM 865 CDlLEU 94 -5.40315.473 32.399 1.00 20.32 ATOM 866 CD2LEU 94 -7.42915.742 33.829 1.00 21.91 1 5 ATOM 867 C LEU 94 -6.83020.133 33.167 1.00 27.78 ATOM 868 O l,EU 94 -6.92720.942 32.239 1.00 27.47 ATOM 869 N PRO 95 -6.17520.423 34.310 1.00 26.98 ATOM 870 CD PRO 95 -6.07719.560 35.502 1.00 26.89 ATOM 871 CA PRO 95 -5.52621.715 34.558 1.00 26.62 ATOM 872 CB PRO 95 -4.89821.518 35.939 1.00 24.83 ATOM 873 CG PRO 95 --5.82120.556 36.598 1.00 24.86 ATOM 874 C PRO 95 -4.45622.009 33.504 1.00 27.96 ATOM 875 O PRO 95 -4.07323.163 33.301 1.00 29.86 ATOM 876 N CYS 96 -3.92420.944 32.909 1.00 27.78 2 5 ATOM 877 H CYS 96 -4.19720.035 33.153 1.00 0.00 ATOM 878 CA CYS 96 -2.91121.022 31 859 1.00 26.63 ATOM 879 CB CYS 96 --l.S8021.563 32.394 1.00 29.10 ATOM 880 SG CYS 96 -0.78520.559 33.655 1.00 33.00 ATOM 881 C CYS 96 -2.71519.626 31.285 1.00 25.83 3 0 ATOM 882 O CYS 96 -3.11418.633 31.897 1.00 25.07 ATOM 883 N ASN 97 -2.14519.547 30.092 1 00 24.09 ATOM 884 H ASN 97 -1.83320.360 29.642 1.00 0.00 ATOM 885 CA ASN 97 -1.91918.259 29.464 1.00 24.47 ATOM 886 CB ASN 97 --1.61318.432 27.978 1.00 27.75 ATOM 887 CG ASN 97 -0.38419.271 27.734 1.00 30.72 ATOM 888 ODlASN 97 -0.26720.381 28.255 1.00 33.88 ATOM 889 ND2ASN 97 0.54018.754 26.936 1.00 32.61 ATOM 890 HD21ASN 97 0.37017.869 26.542 1.00 0.00 ATOM 891 HD22ASN 97 1.35019.270 26.774 1.00 0.00 SUE~STITUTE S~ E~ tRULE 2~i~

CA 02226963 l998-02-l2 W 0 97/083~0 PCT~US96/13918 ATOM 892 CASN 97 -0.779 17.526 30.154 1.00 22.90 ATOM 893 OASN 97 0.056 18.140 30.820 1.00 21.51 ATOM 894 NLEU 98 -0.756 16.207 29.990 1.00 20.54 F
ATOM 895 HLEU 98 -1.447 15.800 29.429 1.00 0.00 ATOM 896CA LEU 98 0.273 15.369 30.591 1.00 19.00 ATOM 897 CBLEU 98 -0.201 13.913 30.641 1.00 14.90 ATOM 898 CGLEU 98 -1.503 13.668 31.417 1.00 11.64 ATOM 899CDl LEU 98 -1.847 12.182 31.440 1.00 6.04 ATOM 900CD2 LEU 98 -1.368 14.215 32.828 1.00 9.37 t0 ATOM 901C LEU 98 1.568 15.498 29.790 1.00 20.67 ATOM 902 OLEU 98 1.685 14.970 28.683 1.00 22.82 ATOM 903 NARG 99 2.545 16.180 30.372 1.00 20.51 ATOM 904 HARG 99 2.399 16.534 31.271 1.00 0.00 ATOM 905 CAARG 99 3.815 16.425 29.712 1.00 21.55 ATOM 906CB ARG 99 4.261 17.864 29.974 1.00 19.71 ATOM 907CG ARG 99 3.230 18.899 29.558 1.00 22.45 ATOM 908CD ARG 99 3.620 20.296 29.990 1.00 25.64 ATOM 909NE ARG 99 2.530 21.243 29.758 1.00 31.98 ATOM 910HE ARG 99 1.868 21.026 29.067 1.00 0.00 ATOM 911CZ ARG 99 2.366 22.383 30.426 1.00 35.95 ATOM 912NHl ARG 99 3.2Z4 22.733 31.380 1.00 38.13 ATOM =913 HHll ARG99 4.000 22.139 31.586 1.00 0.00 ATOM 914 HH12 ARG 99 3.111 23.583 31.889 1.00 0.00 ATOM 915 NH2 ARG 99 1.342 23.177 30.139 1.00 35.02 ATOM916 HH21 ARG 99 0.700 22.940 29.416 1.00 0.00 ATOM 917 HH2Z ARG 99 1.238 24.034 30.643 1.00 0.00 ATOM 918 CARG 99 = 4.961 15.471 30.022 1.00 23.55 ATOM 919 OARG 99 5.461 14.789 29.125 1.00 28.87 ATOM 920 NLYS 100 5.377 15.408 31.281 1.00 21.07 ATOM 921H LYS 100 4.912 15.896 31.993 1.00 0.00 ATOM 922 CALYS 100 6.507 14.564 31.644 1.00 18.54 ATOM 923 CBLYS 100 7,575 15.441 32.304 1.00 20.05 ATOM 924 CGLYS 100 8.939 14.799 32.507 1.00 27.37 ATOM 925CD LYS 100 9.891 15.784 33.196 1.00 29.35 ATOM 926CE LYS 100 11.321 15.259 33.266 1.00 32.53 s ATOM 927NZ LYS 100 11.443 13.994 34.043 1.00 36.81 ATOM 928HZl LYS 100 10.853 13.266 33.597 1.00 0.00 ATOM 929HZ2 LYS 100 11.123 14.155 35.017 1.00 0.00 ATOM 930HZ3 LYS 100 12.438 13.683 34.047 1.00 0.00 - t74 -S~J~STlTUTE SH ~ RULE 2~;) W O 97/08300 PCT~US96/13918 ATOM 931 C LYS1006.118 13.410 32.563 1.00 17.15 ATOM 932 O LYS1005.586 13.627 33.647 1.00 16.18 ATOM 933 N PRO1016.302 12.162 32.104 1.00 16.34 ATOM 934 CD PRO1016.627 11.735 30.734 1.00 15.63 5 ATOM 935 CA PRO1015.961 11.006 32.937 1.00 16.36 ATOM 936 CB PRO1016.092 9.830 31.965 1.00 16.00 ATOM 937 CG PRO1015.849 10.453 30.620 1.00 17.99 ATOM 938 C PRO1016.987 10.883 34.064 1.00 15.83 ATOM 939 O PRO1018.194 10.987 33.832 1.00 14.18 ATOM 940 N CYS 102 6.510 10.718 35.287 1.00 14.78 ATOM 941 H CYS1025.550 10.658 35.443 1.00 0.00 ATOM 942 CA CYS1027.410 10.576 36.415 1.00 12.30 ATOM 943 CB CYS1026.762 11.078 37.700 1.00 8.52 ATOM 944 SG CYSi027.925 11.184 39.064 1.00 12.86 ATOM 94S C CYS 102 7.714 9.097 36.511 1.00 13.33 ATOM 946 O CYS1027.078 8.364 37.266 1.00 13.67 ATOM 947 N ASNi038.662 8.661 35.693 1.00 13.67 ATOM 948 H ASN1039.085 9-330 35.108 1.00 0.00 ATOM 949 CA ASN 103 9.073 7.264 35.632 1.00 14.10 ATOM 950CB ASN103 10.013 7.041 34.444 1.00 15.80 ATOM 951 CG ASN 103 9.374 7.399 33.124 1.00 18.98 ATOM 952 ODl ASN103 8.206 7.101 32.888 1.00 19.82 ATOM 953 ND2 ASN103 10.132 8.056 32.259 1.00 24.80 ATOM 954 HD21 ASN10311.054 8.272 32.491 1.00 0.00 ATOM 955 HD22 ASN i03 9.730 8.327 31.394 1.00 0.00 ATOM 956 C ASN 103 9.741 6.767 36.899 1.00 13.80 ATOM 957 O ASN 103 10.513 7.483 37.537 1.00 14.29 ATOM 958 N ARG 104 9.448 5.522 37.247 1.00 13.40 ATOM 959 H ARG 104 8.826 5.010 36.697 1.00 0.00 ATOM 960CA ARG104 10.018 4.896 38.426 1.00 14.48 ATOM 961 CB ARG 104 9.501 3.464 38.556 1.00 14.01 ATOM 962 CG ARG 104 8.089 3.354 39.074 1.00 11.01 ATOM 963 CD ARG 104 7.691 1.901 39.222 1.00 13.56 ATOM 964 NE ARG 104 7.262 1.324 37.g51 1.00 18.89 ATOM 965HE ARG104 6.380 1.537 37.599 1.00 0.00 ATOM 966 CZ ARG 104 8.001 0.529 37.190 1.00 16.72 ATOM 967 NHl ARG104 9.227 0.203 37.557 1.00 24.48 ATOM 968 HHll ARG1049.608 0.548 38.418 1.00 0.00 ATOM 969 HH12 ARG1049.771 -0.406 36.979 1.00 0.00 SUE~STITUT~ RULE 2~;) ATOM 970 NH2 ARG1047.501 0.044 36.065 1.00 24.27 ATOM 971 HH21 ARG1046.570 0.27g 35.777 1.00 0.00 ATOM 972 HE22 ARG1048.060 -0.560 35.497 1.00 0.00 ATOM 973 C ARG10411.545 4.871 38.363 1.00 17.95 5 ATOM 974 O ARG10412.128 4.542 37.326 1.00 16.59 ATOM 975 N PRO10512.211 5.235 39.473 1.00 21.58 ATOM 976 CD PRO10511.622 5.709 40.738 1.00 24.11 ATOM 977 CA PRO10513.674 5.248 39.548 1.00 24.61 ATOM 978 CB PRO10513.933 5,750 40.970 l.Q0 2S.94 ATOM 97g CG PRO 105 12.713 6.566 41.285 1.00 26.77 ATOM 980 C PRO10514.174 3.816 39.403 1.00 26.84 ATOM 981 O PRO10513.g93 2.884 39.829 1.00 29.03 ATOM 982 N SER10615.348 3.629 38.805 1.00 29.28 ATOM 983 H SER10615.8S1 4.400 38.484 1.00 0.00 ATOM 984 CA SER 106 15.893 2.283 38.652 1.00 31.72 ATOM 985 CB SER10617.306 2.329 38.074 1.00 34.84 ATOM 986 OG SER10617.273 2.524 36.673 1.00 42.09 ATOM 987 HG SER10616.759 3.302 36.439 1.00 0.00 ATOM 988 C SER10615.904 l.S72 40.002 1.00 31.31 ATOM 989 O SER 106 16.301 2.154 41.017 1.00 32.32 ATOM 990 N GLY10715.433 0.330 40.01S 1.00 27.87 ATOM 991 H GLY10715.089 -0.065 39.190 1.00 0.00 ATOM 992 CA GLY10715.391 -0.420 41.252 1.00 27.05 ATOM 993 C GLY10714.041 -0.345 41.941 1.00 26.16 ATOM 994 O GLY 107 13.837 -0.989 42.971 1.00 26.2S
ATOM 995 N LEU10813.130 0.462 41.406 1.00 25.02 ATOM 996 H LEU10813.318 1.005 40.610 1.00 0.00 ATOM 997 CA LEU10811.800 0.577 41.986 1.00 22.01 ATOM 998 CB LEU10811.375 2.044 42.127 1.00 20.37 ATOM 999 CG LEU 108 10.061 2.277 42.885 1.00 19.84 ATOM 1000 CDl LEU108 10.151 1.672 44.270 1.00 20.62 ATOM 1001 CD2 LEU108 9,749 3.7S8 42.985 1.00 19.42 ATOM 1002 C LEU 108 10.831 -0.173 41.087 1.00 22.30 ATOM 1003 O LEU 108 10.848 -0.020 39.865 1.00 22.42 ATOM 1004N GLU109 10.022 -1.027 41.699 1.00 23.39 ATOM 1005 H GLU 109 10.052 -1.102 42.673 1.00 0.00 ATOM 1006 CA GLU 109 9.041 -1.824 40.975 1.00 21.29 ATOM 1007 CB GLU 109 9.231 -3.310 41.306 1.00 28.00 ATOM 1008 CG GLU 109 10.62S -3.868 40.997 1.00 34.55 SUBST~TUTE S~ RULE 2~i) CA 02226963 l998-02-l2 W 0 97/08300 PCT~US96/13918 ATOM 1009 CD GLU 109 11.018 -3.719 39.536 1.00 39.08 ATOM 1010 OEl GLU 109 11.970 -2.955 39.253 1.00 41.37 ATOM 1011 OE2 GLU 109 10.378 -4.363 38.672 1.00 40.88 ATOM 1012 C GLU109 7.655 -1.385 41.414 1.00 17.67 5 ATOM 1013 O GLU109 7.516 -0.686 42.420 1.00 17.75 ATOM 1014 N PRO110 6.619 -1.718 40.628 1.00 13.39 ATOM 1015 CD PRO110 6.595 -2.348 39.301 1.00 8.68 ATOM 1016 CA PRO110 5.274 -1.316 41.038 1.00 11.28 ATOM 1017 CB PRO110 4.405 -1.856 39.912 1.00 9.37 ATOM 1018 CG PRO 110 5.315 -1.825 38.737 1.00 9.71 ATOM 1019 C PRO110 4.988 -2.029 42.357 1.00 13.59 ATOM 1020 O PRO110 5.280 -3.213 42.503 1.00 15.70 ATOM 1021 ~ GLN111 4.451 -1.293 43.320 1.00 14.83 ATOM 1022 H GLN111 4.224 -0.362 43.128 1.00 0.00 ATOM 1023 CA GLN 111 4.146 -1.817 44.644 1.00 14.80 ATOM 1024 CB GLN111 3.914 -0.630 45.588 1.00 19.62 ATOM 1025 CG GLN111 3.460 -0.972 46.992 1.00 29.16 ATOM 1026 CD GLN111 4.507 -1.733 47.779 1.00 35.22 ATOM 1027 OEl GLN 111 5.675 -1.338 47.828 1.00 39.00 ATOM 1028NE2 GLN 111 4.096 -2.841 48.393 1.00 38.02 ATOM 1029 HE21 GLN111 3.152 -3.094 48.292 1.00 0.00 ATOM 1030 HE22 GLN111 4.763 -3.331 48.921 1.00 0.00 ATOM 1031 C GLN111 2.921 -2.732 44.631 1.00 13.55 ATOM 1032 O GLN111 1.858 -2.337 44.164 1.00 13.13 ATOM 1033 N PRO 112 3.064 -3.980 45.117 1.00 15.54 ATOM 1034 CD PRO112 4.324 -4.595 45.571 1.00 14.21 ATOM 1035 CA PRO112 1.962 -4.954 45.169 1 00 14.46 ATOM 1036 CB PRO112 2.616 -6.176 45.814 1.00 17.80 ATOM 1037 CG PRO112 4.043 -6.060 45.391 1.00 18.S2 ATOM 1038 C PRO 112 0.818 -4.424 46.036 1.00 12.81 ATOM 1039 O PRO112 1.044 -3.924 47.140 1.00 13.23 ATOM 1040 N GLY113 -0.406 -4.590 45.550 1.00 13.74 ATOM 1041 H GLY113 -0.506 -5.038 44.681 1.00 0.00 ATOM 1042 CA GLY113 -1.585 -4.095 46.242 1.00 16.62 ATOM 1043 C GLY 113 -1.920 -4.452 47.682 1.00 20.03 ATOM 1044 O GLY113 -2.178 -3.564 48.492 1.00 25.17 ATOM 1045 N VAL114 -1.964 -5.742 47.985 1.00 15.08 ATOM 1046 H VAL114 -1.759 -6.328 47.241 1.00 0.00 ATOM 1047 CA VAL 114 -2.325 -6.279 49.308 1.00 15.99 SVBSTITUTE SHEE~ tRULE 2h) W O 97/08300 PCT~US96/13918 ATOM 1048 CB VAL 114 -2 159 -5.308 50.525 1.00 15.66 ATOM 1049 CGl VAL 114 -2.735 -5.944 51.787 1.00 15.95 ATOM 1050 CG2 VAL 114 -0.691 -5.029 50.785 1.00 18.12 ATOM 1051 C VAL114 -3,759 -6.788 49.208 1.00 14.14 ATOM 1052 o VAL 114 -4,000 -7.960 49.493 1.00 15.64 ATOM 1053 N PHE115 -4.694 -5.956 48.749 1.00 12.08 ATOM 1054 H PHE115 -4.473 -5.029 48.516 1.00 0.00 ATOM 1055 CA PHE115 -6.065 -6.429 48.583 1.00 8.80 ATOM 1056 CB PHE115 -7.021 -5.316 48.167 1.00 6.19 1~ ATOM 1057 CG PHE 115 -8.474 -5.719 48.214 1.00 3.76 ATOM 1058 CDl PHE 115 -8.900 -6.745 49.054 1.00 2.76 ATOM 1059 CD2 PHE 115 -9.423 -5.046 47.451 1.00 6.51 ATOM 1060 CEl PHE 115 -10.253 -7.090 49.141 1.00 5.06 ATOM 1061 CE2 PHE 115 -10.781 -5.382 47.528 1.00 6.67 ATOM 1062 CZ PHE 115 -11.197 -6.405 48.376 1.00 6.27 ATOM 1063 C PHE115 -5,997 -7.464 47.471 1.00 9.14 ATOM 1064 O PHE115 -6.553 -8.548 47.592 1.00 12.04 ATOM 1065 N ASP116 -5.287 -7.128 46.398 1.00 9.44 ATOM 1066 H ASP116 -4.943 -6.208 46.326 1.00 0.00 ATOM 1067CA ASP 116 -5.120 -8.048 45.272 1.00 12.42 ATOM 1068 CB ASP 116 -4.240 -7.420 44.181 1.00 15.62 ATOM 1069 CG ASP 116 -4.968 -6.372 43,349 1.00 19.07 ATOM 1070 ODl ASP 116 -6.205 -6.246 43 445 1.00 23.g7 ATOM 1071 OD2 ASP 116 -4.287 -5.679 42.569 1.00 25.14 ATOM 1072C ASP 116 -4.466 -9.347 45 740 1.00 11.75 ATOM 1073 O ASP 116 -4 862 -10 445 45.344 1.00 11.50 ATOM 1074 N CLE 117 -3 461 -9.199 46.593 1.00 12.80 ATOM 1075 H CLE 117 -3 267 -8.285 46.841 1.00 0.00 ATOM 1076 CA CLE 117 -2.717 -10.321 47.135 1.00 14.11 ATOM 1077 CB CLE 117 -1.552 -9.797 47.962 1.00 16.88 ATOM 1078 SG CLE117 -0.415 -11.054 48.533 1.00 22.90 ATOM 1079 B CLE117 1.110 -9.552 50.024 1.20 31.80 ATOM 1080 C CLE117 -3.607 -11.241 47.971 1.00 16.15 ATOM 1081 O CLE117 -3.484 -12.466 47.899 1.00 17.64 ATOM 1082 N LEU 118 -4.509 -10.653 48.753 1.00 15.34 ATOM 1083 H LEU118 -4.574 -9.678 48.794 1.00 0.00 ATOM 1084 CA LEU118 -5.419 -11.430 49.579 1.00 13.10 ATOM 1085 CB LEU118 -5.994 -10.574 50.711 1.00 12.53 ATOM 1086 CG LEU118 -5.204 -10.607 52.027 1.00 17.96 .
- t78 -SUBST~TUTE ~i~E~ (~lJLE 2h) CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 1087 CDl LEU 118 -3.763 -10.149 51.845 1.00 20.79 ATOM 1088 CD2 LEU 118 -5.915 -9.758 53.078 1.00 21.05 ATOM 1089 C LEU 118 -6.530 -12.068 48 744 1.00 13.66 ATOM 1090 O LEU 118 -6.899 -13.220 48.977 1.00 13.82 ATOM 1091 N ARG 119 -7.043 -11.343 47.752 1.00 13 95 ATOM 1092 H ARG 119 -6 729 -10.431 47.595 1.00 0.00 ATOM 1093 CA ARG 119 -8.097 -11.890 46.891 1 00 16 99 ATOM 1094 CB ARG 119 -8.685 -10.835 45 952 1 00 18.77 ATOM 1095 CG ARG119 -9.292 -9 633 46.630 1.00 21.75 ~0 ATOM 1096 CD ARG 119 -10.186 -8 859 45 671 1 00 24 22 ATOM 1097 NE ARG119 -9.634 -8.710 44.325 1.00 25.20 ATOM 1098 HE ARG119 -9.753 -9.441 43.686 1 00 0 00 ATOM 1099 CZ ARG119 -8.970 -7.644 43.889 1.00 26.62 ATOM 1100 NHl ARG 119 -8.751 -6.613 44.692 1.00 26.88 ATOM 1101 HHll ARG 119 -9.079 -6.630 45.637 1.00 0.00 ATOM 1102 HH12 ARG119 -8.258 -5 813 44.357 1 00 0.00 ATOM 1103 NH2 ARG119 -8 552 -7 S96 42 632 1 00 28.12 ATOM 1104 HH21 ARG119 -8.731 -8.366 42.018 1.00 0.00 ATOM 1105 HH22 ARG119 -8.055 -6.793 42.296 1.00 0.00 2Q ATOM 1106 C ARG 119 -7.573 -13.042 46.050 1.00 16.34 ATOM 1107 O ARG 119 -8.338 -13 911 45.649 1 00 20 19 ATOM 1108 N ASP 120 -6 279 -13 038 45 747 1.00 16.82 ATOM 1109 H ASP 120 -5.712 -12.290 46.047 1.00 0.00 ATOM 1110 CA ASP 120 -5.699 -14.123 44.963 1.00 16.01 ATOM 1111 CB ASP 120 -4.195 -13.924 44.775 1.00 20 39 ATOM 1112 CG ASP 120 -3 543 -15 068 43.997 1.00 26.16 ATOM 1113 ODl ASP 120 -3.897 -15.260 42.813 1.00 29.33 ATOM 1114 OD2 ASP 120 -2.682 -15.778 44.570 1.00 25.10 ATOM 1115 C ASP 120 -5.972 -15.449 45.668 1.00 12.54 3~ ATOM 1116 O ASP 120 -6.566 -16.346 45.084 1.00 13.46 ATOM 1117 N ALA 121 -5 572 -15.539 46.935 1.00 10 31 ATOM 1118 H ALA 121 -5.115 -14.768 47.334 1.00 0.00 ATOM 1119 CA ALA 121 -5.764 -16.738 47.758 1.00 11.07 ATOM 1120 CB ALA 121 -5.155 -16.521 49.141 1.00 9 11 ATOM 1121 C ALA 121 -7.237 -17.132 47.903 1.00 9.94 ATOM 1122 O ALA 121 -7.585 -18.311 47.927 1.00 13.51 ATOM 1123 N SEM 122 -8.103 -16.140 48.016 1.00 9.68 ATOM 1124 H SEM 122 -7.771 -15.218 48.000 1.00 0.00 SUBSTITUTF S}~E~ ~RULE 2~;) CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATOM 1126 CB SEM122 -10.233 -15.133 48.605 1.00 19.02 ATOM 1127 CG SEM122 -9.687 -14.587 49.905 1.00 29.28 ATOM 1128 A SEM122 -10.585 -13.021 50.550 1.00 42.69 ATOM 1129 CE SEM122 -9.376 -12.528 51.958 1.00 36.95 ATOM 1130 C SEM 122 -10.151 -16.974 46.903 1.00 9.90 ATOM 1131 O SEM122 -11 056 -17.804 46.988 1.00 10.61 ATOM 1132 N VAL123 -9.693 -16.526 45.737 1.00 10.83 ATOM 1133 H VA~123 -8.993 -15.829 45.711 1.00 0.00 ATOM 1134 CA VAL 123 -10.223 -17.029 44.471 1.00 10.83 ATOM 1135CB VAL 123 -9.796 -16.144 43.277 1.00 11.82 ATOM 1136 CGl VAL 123 -10.149 -16.814 41.957 1.00 13.10 ATOM 1137 CG2 VAL 123 -10.489 -14.799 43.358 1.00 12.23 ATOM 1138 C VAL 123 -9.740 -18.469 44.269 1.00 11.72 ATOM 1139 O VAL 123 -10.492 -19.332 43.820 1.00 11.90 ATOM 1140N ARG 124 -8.496 -18.737 44.645 1.00 11.15 ATOM 1141 H ARG 124 -7.934 -18.012 44.992 1 00 0.00 ATOM 1142 CA ARG 124 -7.952 -20.078 44.521 1.00 10.74 ATOM 1143 CB ARG 124 -6.496 -20.113 44.958 1.00 13.48 ATOM 1144 CG ARG 124 -5.588 -19.228 44.150 1.00 22.67 ATOM 1145CD ARG 124 -4.164 -19.371 44.639 1.00 30.29 ATOM 1146 NE ARG 12g -3.677 -20.737 44.462 1.00 34.80 ATOM 1147 HE ARG 124 -3.798 -21.375 45.202 1.00 0.00 ATOM 1148 CZ ARG 124 -3.075 -21.173 43.359 1.00 36.89 ATOM 1149 NHl ARG 124 -2.885 -20.352 42.330 1.00 35.72 ATOM 1150 HHll ARG 124 -3.203 -19.404 42.371 1.00 0.00 ATOM 1151 HH12 ARG124 -2.428 -20.690 41.503 1.00 0.00 ATOM 1152 NH2 ARG124 -2.646 -22.427 43.292 1.00 38.58 ATOM 1153 HH21 ARG124 -2.777 -23.034 44.072 1.00 0.00 ATOM 1154 HH22 ARG124 -2.190 -22.758 42.469 1.00 0.00 ATOM 1155C ARG 124 -8.750 -20.989 45.426 1.00 9.71 ATOM 1156 O ARG 124 -9.144 -22.079 45.029 1 00 10.87 ATOM 1157 N ASP 125 -9.004 -20.526 46.644 1.00 11.13 ATOM 1158 H ASP 125 -8.663 -19.644 46.891 1.00 0.00 ATOM 1159 CA ASP 125 -9.753 -21.311 47.617 1.00 10.38 ATOM 1160CB ASP 125 -9.765 -20.600 48.974 1.00 13.20 ATOM 1161 CG ASP 125 -10.489 -21.397 50.051 1.00 18.39 ATOM 1162 ODl ASP 125 -11.393 -20.831 50.706 1.00 21.49 ATOM 1163 OD2 ASP 125 -10.158 -22.590 50.238 1.00 18.02 ATOM 1164 C ASP 125 -11.174 -21.617 47.140 1.00 8.61 SUBSTITUTE S~3FEl- tRuLE 2~;~

CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATOM 1165 O ASP125 -11.652 -22.741 47.266 1.00 11 19 ATOM 1166 N TYR126 -11.840 -20.621 46.579 1.00 10.44 ATOM 1167 H TYR126 -11.410 -19.747 46.499 1.00 0.00 ATOM 1168 CA TYR126 -13.198 -20.802 46.074 1.00 11.59 ATOM 1169 CB TYR 126 -13.780 -19.452 45.641 1.00 11.23 ATOM 1170 CG TYR126 -15.206 -19.523 45.138 1.00 12.70 ATOM 1171 CDl TYR 126 -16.275 -19.332 46.009 1.00 14.14 ATOM 1172 CEl TYR 126 -17.589 -19.395 45.562 1.00 17.06 ATOM 1173 CD2 TYR 126 -15.488 -19.784 43.794 1.00 13.43 0 ATOM 1174CE2 TYR 126 -16.812 -19.856 43.334 1.00 15.60 ATOM 1175 CZ TYR126 -17.858 -19.655 44.228 1.00 16.20 ATOM 1176 OH TYR126 -19.173 -19.702 43.806 1.00 16.29 ATOM 1177 HH TYR126 -19.739 -19.596 44.573 1.00 0.00 ATOM 1178 C TYR126 -13.248 -21.776 44.888 1 00 13.13 ATOM 1179 ~ TYR 126 -14.131 -22.629 44.815 1.00 11.60 ATOM 1180 N VAL127 -12.318 -21.618 43.948 1.00 13.17 ATOM 1181 H VAL127 -11.653 -20.905 44.039 1.00 0.00 ATOM 1182 CA VAL127 -12.272 -22.469 42.764 1.00 13.56 ATOM 1183 CB VAL127 -11.275 -21.918 41.712 1.00 13.44 ATOM 1184CGl VAL 127 -11.230 -22.826 40.480 1.00 14.23 ATOM 1185 CG2 VAL 127 -11.684 -20.512 41.302 1.00 10.59 ATOM 1186 C VAL127 -11.941 -23.916 43.115 1.00 14.89 ATOM 1187 O VAL127 -12.527 -24.843 42.560 1.00 16.19 ATOM 1188 N ARG128 -11.022 -24.112 44.052 1.00 15.44 ATOM 1189 H ARG 128 -10.583 -23.335 44.470 1.00 0.00 ATOM 1190 CA ARG128 -10.640 -25.450 44.473 1.00 15.05 ATOM ll91 CB ARG128 -9.422 -25.365 45.388 1.00 19.03 ATOM 1192 CG ARG128 -8.887 -26.701 45.848 1.00 24.57 ATOM 1193 CD ARG128 -7.521 -26.528 46.483 1.00 29.44 ATOM 1194 NE ARG 128 -7.551 -25.528 47.544 1.00 32.78 ATOM 1195 HE ARG128 -8.319 -25.519 48.151 1.00 0.00 ATOM 1196 CZ ARG128 -6.614 -24.606 47.732 1.00 32.41 ATOM 1197 NHl ARG 128 -5.557 -24.541 46.929 1.00 28.66 ATOM 1198 HHll ARG128 -5.461 -25.186 46.170 1.00 0.00 ATOM 1199 HH12 ARG 128 -4.855 -23.840 47.078 1.00 0.00 ATOM 1200 NH2 ARG128 -6.742 -23.746 48.729 1.00 34.68 ATOM 1201 HH21 ARG128 -7.528 -23.786 49.343 1.00 0.00 ATOM 1202 HH22 ARG128 -6.015 -23.087 48.879 1.00 0.00 ATOM 1203 C ARG 128 -11.806 -26.118 45.196 1.00 16.91 " .

SUBST~ TE S~E~ ~RUI E 26 CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATOM 1204 OARG 128 -12.185 -27.241 44.884 1.00 16.06 ATOM 1205 NGLN 129 -12.386 -25.399 46.149 1.00 17.04 ATOM 1206 HGLN 129 -12.025 -24.5Q8 46.347 1.00 0.00 ATOM 1207CA GLN 129 -13.516 -25.886 46.924 1.00 17.75 ATOM 1208 CB GLN 129 -13.922 -24.813 47.941 1.00 24.23 ATOM 1209CG GLN 129 -15.184 -25.116 48.735 1.00 35.10 ATOM 1210CD GLN 129 -15.850 -23.854 49.274 1.00 43.22 ATOM 1211OEl GLN 129 -16.998 -23.547 48.934 1.00 45.61 ATOM 1212NE2 GLN 129 -15.134 -23.120 50.124 1.00 44.34 ATOM1213 HE21 GLN 129 -14.232 -23.402 50.371 1.00 0.00 ATOM 1214 HE22 GLN 129 -15.573 -22.317 50.462 1.00 0,00 ATOM 1215C GLN 129 -14.707 -26.215 46.024 1.00 14.94 ATOM 1216O GLN 129 -15.374 -27.227 46.202 1.00 17.51 ATOM 1217N THR 130 -14.967 -25.359 45.051 1.00 12.68 ATOM 1218 H THR 30 -14.422 -24.549 44.954 1.00 0.00 ATOM 1219CA THR 130 -16.094 -25.547 44.151 1.00 14.74 ATOM 1220CB THR 130 -16.473 -24.207 43.491 1.00 16.50 ATOM 1221OGl THR 130 -16.680 -23.223 44.513 1.00 15.75 ATOM 1222HGl THR 130 -17.352 -23.533 45.132 1.00 0.00 ATOM 1223 CG2 THR 130 -17.748 -24.347 42.666 1.00 16.34 ATOM 1224 CTHR 130 -15.909 -26.599 43.063 1.00 14.23 ATOM 1225 oTHR 130 -16.746 -27.481 42.894 1.00 15.79 ATOM 1226 NTRP 131 -14.812 -26.507 42.329 1.00 13.82 ATOM 1227 HTRP 131 -14.156 -25.807 42.510 1.00 0.00 ATOM 1228 CA TRP 131 -14.551 -27.429 41.235 1.00 12.96 ATOM 1229 CBTRP 131 -13.790 -26.702 40.128 1.00 13.33 ATOM 1230 CGTRP 131 -14.586 -25.559 39.589 1.00 15.21 ATOM 1231CD2 TRP 131 -15.383 -25.551 38.398 1.00 16.02 ATOM 1232CE2 TRP 131 -16.037 -24.299 38.342 1.00 16.98 ATOM 1233 CE3 TRP 131 -15.610 -26.483 37.375 1.00 19.06 ATOM 1234CDl TRP 131 -14.773 -24.339 40.183 1.00 16.24 ATOM 1235NEl TRP 131 -15.650 -23.583 39.444 1.00 19.42 ATOM 1236HEl TRP 131 -15.968 -22.696 39.715 1.00 0.00 ATOM 1237CZ2 TRP 131 -16.907 -23.952 37.301 1.00 17.20 ATOM 1238 CZ3 TRP 131 -16.477 -26.137 36.340 1.00 19.80 ATOM 1239CH2 TRP 131 -17.114 -24.880 36.312 1.00 18.84 ATOM 1240 CTRP 131 -13.852 -28.712 41.629 1.00 13.29 ATOM 1241 oTRP 131 -13.892 -29.692 40.883 1.00 12.51 ATOM 1242 NLYS 132 -13.245 -28.710 42.813 1.00 15.49 .

SUBSmUTE ~E~ ~U~ E 2~i~

CA 02226963 l998-02-l2 W O ~7/08300 PCT~US96/}3918 ATOM 1243 H LYS132 -13.261 -27.900 43.361 1.00 0.00 ATOM 1244 CA LYS132 -12 531 -29.872 43.344 1.00 18.55 ATOM 1245 CB LYS132 -13.467 -31.090 43.451 1.00 17.43 ATOM 1246 CG LYS132 -14.374 -31.116 44.670 1.00 19.61 ATOM 1247 CD LYS 132 -15.519 -30.137 44.557 1.00 21.76 ATOM 1248 CE LYS132 -16.482 -30.273 45.727 1.00 20.70 ATOM 1249 MZ LYS132 -15.842 -29.954 47.029 1.00 23.81 ATOM 1250 HZl LYS 132 -15.472 -28.987 47.004 1.00 0.00 ATOM 1251 HZ2 LYS 132 -15 060 -30.615 47.195 1.00 0.00 0 ATOM 1252HZ3 LYS 132 -16.535 -30.033 47.800 1.00 0.00 ATOM 1253 C LYS132 -11.310 -30.220 42.496 1.00 20.84 ATOM 1254 ~ LYS132 -10.973 -31.392 42.325 1.00 21.28 ATOM 1255 N LEU133 -10.635 -29.195 41.991 1.00 22.03 ATOM 1256 H LEU133 -10.915 -28.292 42.231 1.00 0.00 ATOM 1257 CA LEU 133 -9,459 -29.383 41.149 1.00 23.93 ATOM 1258 CB LEU133 -9.539 -28 464 39.930 1.00 22.92 ATOM 1259 CG LEU133 -10.724 -28.710 38.993 1.00 21.45 ATOM 1260 CDl LEU 133 -10.779 -27.638 37.930 1.00 16.33 ATOM 1261 CD2 LEU 133 -10.608 -30.091 38.365 1.00 18.90 ATOM 1262C LEU 133 -8.158 -29.131 41.897 1.00 25.56 ATOM 1263 O LEU 133 -8.137 -28.456 42.921 1.00 24.95 ATOM 1264 N GLU 134 -7.068 -29.675 41.372 1.00 30.15 ATOM 1265 H GLU 134 -7.120 -30.201 40.549 1.00 0.00 ATOM 1266 CA GLU 134 -5.758 -29.501 41.983 1.00 35.39 ATOM 1267CB GLU 134 -5.418 -30.687 42.899 1.00 40.72 ATOM 1268 CG GLU 134 -6.137 -30.693 44.262 1.00 47.74 ATOM 1269 CD GLU 134 -5.572 -29.689 45.276 1.00 52.02 ATOM 1270 OEl GLU 134 -6.063 -29.681 46.427 1.00 52.20 ATOM 1271 OE2 GLU 134 -4.643 -28.916 44.940 1.00 54.41 ATOM 1272 C GLU 134 -4.694 -29.361 40.904 1.00 35.44 ATOM 1273 O GLU134 -4.968 -29.569 39.719 1.00 35.63 ATOM 1274 N GLY135 -3.494 -28.965 41.316 1.00 34.91 ATOM 1275 H GLY135 -3.374 -28.756 42.265 1.00 0.00 ATOM 1276 CA GLY135 -2.392 -28.807 40.382 1.00 34.73 ATOM 1277 C GL~ 135 -2.686 -27.917 39.189 1.00 34.52 ATOM 1278 O GLY135 -3.416 -26.927 39.297 1.00 34.03 ATOM 1279 N GLU136 -2.149 -28.302 38.035 1.00 34.50 ATOM 1280 H GLU136 -1.609 -29.117 38.031 1.00 0.00 ATOM 1281 CA GLU136 -2.324 -27.544 36.799 1.00 34.12 SUBSTITUTE S~F~ ~RULE 2fi) CA 02226963 l998-02-l2 ATOM 1282 CB GLU 136 -1 543 -28.203 35.658 1.00 38.90 ATOM 1283 CG GLU 136 -1.203 -27.256 34.511 1.00 43.32 ATOM 1284 CD GLU 136 -0.456 -26.009 34.980 1.00 46.70 ATOM 1285 OEl GLU 136 0.595 -26.145 35.650 1.00 48.76 5 ATOM 1286 OE2 GLU 136 -0.930 -24.889 34.686 1.00 46.11 ATOM 1287 C GLU 136 -3.787 -27.359 36.399 1.00 31.34 ATOM 1288 O GLU 136 -4.148 -26.351 35.787 1.00 28.55 ATOM 1289 N ALA 137 -4.625 -28.329 36.756 1.00 29.45 ATOM 1290 H ALA 137 -4.285 -29.104 37.238 1.00 0.00 ATOM 1291CA ALA 137 -6.048 -28.258 36.440 1.00 26.31 ATOM 1292 CB ALA137 -6.740 -29.548 36.842 1.00 26.49 ATOM 1293 C ALA137 -6.652 -27.072 37.181 1.00 22.29 ATOM 1294 o ALA137 -7.442 -26.317 36.622 1.00 22.04 ATOM 1295 N LEU138 -6.241 -26.894 38.432 1.00 20.21 ATOM 1296 H LEU 138 -5.577 -27.514 38.813 1.00 0.00 ATOM 1297 CA LEU138 -6.725 -25.792 39.249 1.00 20.63 ATOM 1298 CB LEU138 -6.223 -25.941 40.686 1.00 17.38 ATOM 1299 CG LEU138 -6.519 -24.807 41.670 1.00 17.34 ATOM 1300 CDl LEU 138 -8.013 -24.543 41.738 1.00 16.71 ATOM 1301CD2 LEU 138 -5.986 -25.170 43.040 1.00 15.22 ATOM 1302 C LEU138 -6.243 -24.469 38.659 1.00 21.98 ATOM 1303 O LEU138 -7.027 -23.528 38.513 1.00 21.24 ATOM 1304 N GLU139 -4.965 -24.415 38.288 1.00 23.87 ATOM 1305 H GLU139 -4.423 -25.227 38.393 1.00 0.00 ATOM 1306 CA GLU 139 -4.372 -23.209 37.713 1.00 25.73 ATOM 1307 CB GLU139 -2.914 -23.454 37.334 1.00 28.07 ATOM 1308 CG GLU139 -2.052 -23.944 38.479 1.00 33.00 ATOM 1309 CD GLU139 -2.216 -23.110 39.733 1.00 37.06 ATOM 1310 OEl GLU 139 -2.506 -23.697 40.796 1.00 41.81 ATOM 1311OE2 GLU 139 -2.062 -21.872 39.662 1.00 39.33 ATOM 1312 C GLU 139 -5.138 -22.737 36.487 1.00 26.80 ATOM 1313 O GLU 139 -5.462 -21.555 36.362 i.oo 25.34 ATOM 1314 N GLN 140 -5.434 -23.669 35.588 1.00 25.70 ATOM 1315 H GLN 140 -5.140 -24.594 35.755 1.00 0.00 36 ATOM 1316CA GLN 140 -6.172 -23.361 34.369 1.00 31.92 ATOM 1317 CB GLN 140 -6.270 -24.605 33.479 1.00 38.06 ATOM 1318 CG GLN 140 -4.935 -25.155 32.994 1.00 45.35 ATOM 1319 CD GLN 140 -5.088 -26.459 32.218 1.00 52.31 ATOM 1320 OEl GLN 140 -4.434 -27.461 32.523 1.00 54.99 .

SUBST~TUTE S~tEE~ (RULE 2~i) CA 02226963 l998-02-l2 ATOM 1321 NE2 GLN140 -5.g58 -26.453 31.212 1.00 53.53 ATOM 1322 HE21 GLN140 -6.453 -25.632 31.016 1.00 0.00 ATOM 1323 HE22 GLN140 -6.057 -27.290 30.723 1.00 0.00 ATOM 1324 C GLN 140 -7.579 -22.853 34.690 1.00 30.17 5 ATOM 1325 O GLN 140 -8.068 -21.914 34.058 1.00 29.36 ATOM 1326 N ALA 141 -8.218 -23.472 35.680 1.00 28.89 ATOM 1327 H ALA 141 -7.777 -24.201 36.166 1.00 0.00 ATOM 1328 CA ALA 141 -9.572 -23.099 36.084 1.00 27.36 ATOM 1329 CB ALA141 -10.154 -24.143 37.028 1.00 25.84 ATOM 1330 C ALA 141 -9.665 -21.711 36.709 1.00 26.93 ATOM 1331 O ALA141 -10.584 -20.963 36.396 1.00 25.78 ATOM 1332 N ILE142 -8.725 -21.358 37.581 1.00 27.95 ATOM 1333 H ILE142 -8.010 -22.001 37.791 1.00 0.00 ATOM 1334 CA ILE142 -8.771 -20.043 38.209 1.00 30.29 5 ATOM 1335 CB ILE142 -7.703 -19.856 39.321 1.00 32.16 ATOM 1336 CG2 ILE 142 -7.763 -21.010 40.310 1.00 31.60 ATOM 1337 CGl ILE 142 -6.303 -19.742 38.722 1.00 38.22 ATOM 1338 CD ILE142 -5.205 -19.539 39.750 1.00 41.97 ATOM 1339 C ILE142 -8.628 -18.955 37.153 1.00 30.56 ATOM 1340 O ILE 142 -9.256 -17.911 37.253 1.00 32.19 ATOM 1341 N ILE143 -7.847 -19.223 36.111 1.00 31.49 ATOM 1342 H ILE143 -7.382 -20.088 36.069 1.00 0.00 ATOM 1343 CA ILE143 -7.656 -18.246 35.044 1.00 32.26 ATOM 1344 CB ILE143 -6.618 -18.736 34.000 1.00 34.28 ATOM 1345CG2 ILE 143 -6.480 -17.728 32.868 1.00 34.40 ATOM 1346 CGl ILE 143 -5.254 -18.975 34.661 1.00 36.63 ATOM 1347 CD ILE143 -4.561 -17.724 35.179 1.00 39.46 ATOM 1348 C ILE143 -8.984 -17.951 34.342 1.00 30.93 ATOM 1349 O ILE143 -9.295 -16.799 34.052 1.00 30.08 ATOM 1350 N SER 144 -9.776 -13.989 34.100 1.00 30.90 ATOM 1351 H SER144 -9.524 -19.901 34.367 1.00 0.00 ATOM 1352 CA SER144 -11.056 -18.826 33.427 1.00 33.20 ATOM 1353 CB SER144 -11.434 -20.123 32.704 1.00 35.30 ATOM 1354 OG SER144 -11.353 -21.242 33.569 1.00 40.36 ATOM 1355 HG SER 144 -11.540 -22.026 33.050 1.00 0.00 ATOM 1356 C SER144 -12.197 -18.375 34.343 1.00 34.38 ATOM 1357 O SER144 -13.103 -17.653 33.920 1.00 34.88 ATOM 1358 N GLN145 -12.154 -18.803 35.598 1.00 34.59 ATOM 1359 H GLN145 -11.420 -19.393 35.855 1.00 0.00 SUE~SmUTE Si~EE~ ~RULE 2~i) CA 02226963 l998-02-l2 WO 97108300 PCT~US96/13918 ATOM 1360 CA GLN145 -13.189 -18.444 36.557 1.00 33.70 ATOM 1361 CB GLN145 -13.383 -19.572 37.571 1.00 33.70 ATOM 1362 CG GLN145 -13.934 -20.859 36.978 1.00 35.74 ATOM 1363 CD GLNlg5 -15.369 -20.728 36.503 1.00 37.42 ATOM 1364OEl GLN 145 -15.699 -21.098 35.374 1.00 39.84 ATOM 1365 NE2 GLN 145 -16.238 -20.227 37.374 1.00 38.81 ATOM 1366 HE21 GLN145 -15.932 -19.964 38.263 1.00 0.00 ATOM 1367 HE22 GLN145 -17.171 -20.156 37.086 1.00 0.00 ATOM 1368 C GLN145 -12.948 -17.124 37.292 1.00 32.75 ATOM 1369 O GLN 145 -13.905 -16.450 37.668 1.00 33.82 ATOM 1370 N ALA146 -11.687 -16.735 37.463 1.00 32.02 ATOM 1371 H ALA146 -10.979 -17.277 37.078 1.00 0.00 ATOM 1372 CA ALA146 -11.343 -15.500 38.179 1.00 34.00 ATOM 1373 CB ALA146 -9.858 -15.167 38.003 1.00 32.05 ATOM 1374 C ALA 146 -12.199 -14.278 37.841 1.00 35.44 ATOM 1375 O ALA146 -12.710 -13.607 38.742 1.00 36.48 ATOM 1376 M PRO147 -12.371 -13.970 36.543 1.00 36.46 ATOM 1377 CD PRO147 -11.711 -14.566 35.365 1.00 36.36 ATOM 1378 CA PRO147 -13.178 -12.812 36.145 1.00 35.69 ATOM 1379 CB PRO 147 -13.108 -12.872 34.621 1.00 37.74 ATOM 1380 CG PRO147 -11.741 -13.432 34.380 1.00 37.31 ATOM 1381 C PRO147 -14.627 -12.823 36.632 1.00 35.01 ATOM 1382 O PRO147 -15.170 -11.781 37.008 1.00 34.92 ATOM 1383 N GLN148 -15.232 -14.005 36.662 1.00 34.44 ATOM 1384 H GLN 148 -14.719 -14.803 36.413 1.00 0.00 ATOM 1385 CA GLN148 -16.627 -14.155 37.072 1.00 36.11 ATOM 1386 CB GLN148 -17.194 -15.465 36.507 1.00 40.50 ATOM 1387 CG GLN148 -17.002 -15.634 34.996 1.00 43.75 ATOM 1388 CD GLN148 -17.614 -14.499 34.198 1.00 47.86 ATOM 1389OEl GLN 148 -16.915 -13.779 33.482 1 00 49.23 ATOM 1390 NE2 GLN 148 -18.925 -14.330 34.319 1 00 49.03 ATOM 1391 HE21 GLN148 -19.440 -14.926 34.897 1.00 0.00 ATOM 1392 HE22 GLN148 -19.303 -13.595 33.801 1.00 0.00 ATOM 1393 C GLN 148 -16.892 -14.083 38.581 1.00 34.17 ATOM 1394O GLN 148 -17.963 -13.645 39.018 1.00 34.12 ATOM 1395 N VAL 149 -15.924 -14.518 39.378 1.00 30.55 ATOM 1396 H VAL 149 -15.084 -14.843 38.983 1.00 0.00 ATOM 1397 CA VAL 149 -16.084 -14.506 40.824 1.00 27.34 ATOM 1398 CB VAL 149 -15.730 -15.874 41.424 1.00 26.70 SUBSTITUTE S~EE~ ~RULE 2~i~

CA 02226963 l998-02-l2 W O 97/~8300 PCTrUS96/13918 ATOM 1399 CGl VAL 149 -16 628 -16.942 40.829 1.00 27.05 ATOM 1400 CG2 VAL 149 -14.271 -16.202 41.164 1.00 25.34 ~ ATOM 1401 C VAL 149 -15.258 -13.418 41.506 1.00 27.10 ATOM 1402 O VAL 149 -15.220 -13.341 42.732 1.00 26.82 ATOM 1403 N GLU 150 -14.622 -12.565 40.708 1.00 27.77 ATOM 1404 H GLU 150 -14.683 -12.695 39 739 1.00 0.00 ATOM 1405 CA GLU 150 -13.795 -11.477 41.229 1.00 28.17 ATOM 1406 CB GLU 150 -13.249 -10.616 40.078 1.00 32.48 ATOM 1407 CG GLU 150 -11.848 -10.013 40.336 1.00 42.10 ATOM 1408 CD GLU 150 -11.772 -8.484 40.177 1.00 43.81 ATOM 1409 OEl GLU 150 -12.480 -7.918 39.313 1.00 41.18 ATOM 1410 3E2 GLU 150 -10.981 -7.850 40.915 1.00 45.59 ATOM 1411 C GLU 150 -14.585 -10.600 42.201 1.00 24.18 ATOM 1412 O GLU 150 -14.179 -10.415 43.344 1.00 22.05 ATOM 1413 N LYS 151 -15.721 -10.083 41.749 1.00 21.94 ATOM 1414 H LYS 151 -15.998 -10.281 40.831 1.00 0.00 ATOM 1415 CA LYS 151 -16.552 -9.225 42.584 1.00 22.44 ATOM 1416 CB LYS 151 -17.721 -8.646 41.784 1.00 25.52 ATOM 1417 CG LYS 151 -17.297 -7.656 40.698 1.00 33.26 ATOM 1418 CD LYS 151 -16.749 -6.357 41.293 1.00 36.27 ATOM 1419 CE LYS 151 -15.910 -5.572 40.282 1.00 36.61 ATOM 1420 NZ LYS 151 -14.684 -6.337 39.897 1.00 38.17 ATOM 1421 HZl LYS 151 -14.965 -7.218 39.418 1.00 0.00 ATOM 1422 H22 LYS 151 -14.135 -6.581 40.747 1.00 0.00 2~ ATOM 1423 HZ3 LYS 151 -14.080 -5 784 39.256 1 00 0.00 ATOM 1424 C LYS 151 -17.064 -9.945 43.820 1.00 20.52 ATOM 1425 O LYS 151 -16.935 -9.430 44.925 1.00 21.76 ATOM 1426 N LEU 152 -17.620 -11.139 43.633 1.00 18.37 ATOM 1427 H LEU 152 -17.693 -11.501 42.726 1.00 0.00 ATOM 1428 CA LEU 152 -18.147 -11.936 44.741 1.00 17.20 ATOM 1429 CB LEU 152 -18.532 -13.336 44.249 1.00 18.20 ATOM 1430 CG LEU 152 -18.958 -14.382 45.287 1.00 23.16 ATOM 1431 CDl LEU 152 -20.324 -14.025 45.859 1.00 21.89 ATOM 1432 CD2 LEU 152 -18.993 -15.771 44.648 1.00 22.05 3~ ATOM 1433 C LEU 152 -17.113 -12.059 45.856 1.00 15.24 ATOM 1434 O LEU 152 -17.408 -11.798 47.023 1.00 14.43 ATOM 1435 N ILE 153 -15.896 -12.436 45.482 1.00 12.34 ATOM 1436 H ILE 153 -15.725 -12.621 44.531 1.00 0.00 ATOM 1437 CA ILE 153 -14.817 -12.595 46.441 1.00 13.12 SUBSTITUTE S}~ ULE 2~) CA 02226963 l998-02-l2 WO 97/08300 PCT~US9~13918 ATOM 1438 CB ILE 153 -13.580 -13.261 45.792 1.00 12.78 ATOM 1439 CG2 ILE 153 -12.4g8 -13.469 46.813 1.00 10.18 ATOM 1440 CGl ILE 153 -13.962 -14.611 45.182 1.00 13.04 ATOM 1441 CD ILE 153 -14.603 -15.557 46.135 1.00 12.82 ATOM 1442 C ILE 153 -14.418 -11.265 47.081 1.00 12.71 ATOM 1443 O ILE 153 -14.266 -11.189 48.297 1.00 14.81 ATOM 1444 N ALA 154 -14.299 -10.212 46.276 1.00 11.61 ATOM 1445 H ALA 154 -14.478 -10.311 45.317 1.00 0.00 ATOM 1446 CA ALA 154 -13.914 -8.897 46.789 1.00 11.24 1Q ATOM 1447 CB ALA 154 -13.702 -7.932 45.643 1.00 8.04 ATOM 1448 C ALA 154 -14.918 -8.308 47.788 1.00 11.11 ATOM 1449 O ALA 154 -14.547 -7.850 48.872 1.00 8.33 ATOM 1450 N THR 155 -16.192 -8.345 47.432 1.00 11.93 ATOM 1451 H THR 155 -16.462 -8.779 46.599 1.00 0.00 ATOM 1452 CA THR 155 -17.232 -7.793 48.285 1.00 16.85 ATOM 1453 CB THR 155 -18.566 -7.654 47.509 1.00 19.45 ATOM 1454 OGl THR 155 -19.034 -8.949 47.108 1.00 23.26 ATOM 1455 HGl THR 155 -19.810 -8.856 46.545 1.00 0.00 ATOM 1456 CG2 THR 155 -18.366 -6.795 46.261 1.00 19.86 AT~M 1457 ~ ~XR 15~ -17.45~ -8.583 49,~7~ 1.0C 17.7a ATOM 1458 O THR 155 -18.015 -8.059 50.545 1.00 16.86 ATOM 1459 N THR 156 -16.945 -9 812 49.622 1.00 17.24 ATOM 1460 H THR 156 -16.483 -10.203 48.844 1.00 0.00 ATOM 1461 CA THR 156 -17.110 -10.641 50.805 1.00 16.73 ATOM 1462 CB THR 156 -17.781 -11.991 50.436 1.00 18.95 ATOM 1463 OGl THR 156 -18.349 -12.579 51.610 1.00 28.41 ATOM 1464 HGl THR 156 -17.628 -12 777 52 224 1.00 0.00 ATOM 1465 CG2 THR 156 -16 782 -12.958 49.825 1 00 16 01 ATOM 1466 C THR 156 -15 818 -10 864 51 607 1.00 15.60 ATOM 1467 O THR 156 -15.853 -11.468 52.681 1.00 14.74 ATOM 1468 N ALA 157 -14.712 -10.291 51.134 1.00 11.48 ATOM 1469 H ALA 157 -14.745 -9.796 50.286 1.00 0.00 ATOM 1470 CA ALA 157 -13.404 -10.426 51.780 1.00 9.54 ATOM 1471 CB ALA 157 -12.342 -9.713 50.961 1.00 5.51 ATOM 1472 C ALA 157 -13.312 -9.981 53.239 1.00 8.69 ATOM 1473 O ALA 157 -12.471 -10.476 53.987 1.00 10.31 ATOM 1474 N HIS 158 -14.150 -9.037 53.648 1.00 10.04 ATOM 1475 H HIS 158 -14.761 -8.654 52.995 1.00 0.00 ATOM 1476 CA HIS 158 -14.119 -8.550 55.029 1.00 9.74 SUBSTIT~TE ~E~ tRuLE 2~i~

CA 02226963 l998-02-l2 W 0 97/08300 PCTrUS96/13918 ATOM 1477 CB HIS 158 -15.043 -7.335 55.185 1.00 8.60 ATOM 1478 CG HIS 158 -16.494 -7.631 54.940 1.00 10.37 ATOM 1479 CD2 HIS 158 -17.508 -7.875 55.801 1.0Q 6.93 ATOM 148~ NDl HIS 158 -17.045 -7.685 53.677 1.00 9.52 ATOM 1481 HDl HIS 158 -16.621 -7.506 52.814 1.00 0.00 ATOM 1482 CEl HIS 158 -18.336 -7.952 53.771 1.00 8.21 ATOM 1483 NE2 HIS 158 -18.641 -8.073 55.052 1.00 7.61 ATOM 1484 HE2 HIS 158 -19.542 -8.310 55.393 1.00 0.00 ATOM 1485 C HIS 158 -14.463 -9.621 56.070 1.00 11.48 ATOM 1486 O HIS 158 -13.948 -9.602 57.189 1.00 12.15 ATOM 1487 N GLU 159 -15.292 -10.580 55.673 1.00 12.68 ATOM 1488 H GLU 159 -15.604 -10.612 54.744 1.00 0.00 ATOM 1489 CA GLU 159 -15.734 -11.657 56.554 1.00 16.34 ATOM 1490 CB GLU 159 -16.826 -12.477 55.870 1.00 19.60 ATOM 1491 CG GLU 159 -18.109 -11.703 55.586 1.00 22.36 ATOM 1492 CD GLU 159 -19.133 -12.516 54.811 1.00 25.59 ATOM 1493 OEl GLU 159 -18.923 -13.733 54.614 1.00 27.02 ATOM 1494 OE2 GLU 159 -20.157 -11.933 54.396 1.00 30.21 ATOM 1495 C GLU 159 -14.648 -12.601 57.041 1.00 17.61 ATOM 1496 O GLU 159 -14.881 -13.388 57.958 1.00 19.13 ATOM 1497 N ARG 160 -13.480 -12.552 56.413 1.00 18.47 ATOM 1498 H ARG 160 -13.336 -11.921 55.678 1.00 0.00 ATOM 1499 CA ARG 160 -12.380 -13.428 56.799 1 00 20.02 ATOM 1500 CB ARG 160 -11.637 -13.926 55.555 1.00 23.13 2~ ATOM 1501 CG ARG 160 -12.539 -14.448 54.449 1.00 29.15 ATOM 1502 CD ARG 160 -11.737 -15.149 53 364 1.00 34.59 ATOM 1503 NE ARG 160 -11.157 -16.394 53.856 1.00 37.25 ATOM 1504 HE ARG 160 -10.278 -16.359 54.280 1.00 0.00 ATOM 1505 CZ ARG 160 -11.735 -17.585 53.744 1.00 39.25 ATOM 1506 NHl ARG 160 -12.907 -17.705 53.141 1.00 40.34 ATOM 1507 HHll ARG 160 -13.373 -16.903 52.774 1.00 0.00 ATOM 1508 HH12 ARG 160 -13.329 -18.607 53.067 1.00 0.00 ATOM 1509 NH2 ARG 160 -11.177 -18.647 54.308 1.00 43.48 ATOM 1510 HH21 ARG 160 -10.326 -18.543 54.826 1.00 0.00 ATOM 1511 HH22 ARG 160 -11.612 -19.546 54.229 1.00 0.00 ATOM 1512 C ARG 160 -11.407 -12.697 57.711 1.00 18.50 ATOM 1513 O ARG 160 -10.500 -13.298 58.284 1.00 17.09 ATOM 1514 N SEM 161 -11.610 -11.391 57.841 1.00 18.54 ATOM 1515 H SEM 161 -12.394 -10.969 57.430 1.00 0.00 SUBS 1 l I UTE SHE~ (RU~E 26) CA 02226963 l998-02-l2 ATOM 1516 CA SEN161 -10.746 -10.550 58.651 1.00 16.58 ATOM 1517 CB SEM161 -10.814 -9.109 58.146 1.00 18.99 ATOM 1518 CG SEM161 -10 507 -8.961 56.669 1.00 21.84 ATOM 1519 A SEM161 -8.831 -9.824 56.217 1.00 39.69 5 ATON 1520 CE SEN161 -7.469 -8.584 56.687 1.00 28.84 ATOM 1521 C SEM161 -11.119 -10.620 60.125 1.00 15.27 ATOM 1522 O SE~161 -12.299 -10.641 60.470 1.00 13.98 ATOM 1523 N PRO162 -10.111 -10.624 61.018 1.00 15.37 ATOM 1524 CD PRO162 -8.671 -10.585 60.713 1.00 16.16 ATOM 1525 CA PRO 162 -10.329 -10.689 62.467 1.00 15.23 ATOM 1526 CB PRO162 -8.905 -10.745 63.027 1.00 15.71 ATOM 1527 CG PRO162 -8.091 -10.035 61.988 1.00 15.90 ATOM 1528 C PRO162 -11.121 -9.514 63.039 1 00 16.06 ATOM 1529 O PRO162 -11.734 -9.640 64.096 1.00 15.21 ATOM 1530 N TRP 163 -11.106 -8.375 62.348 1.00 14.60 ATOM 1531 H TRP163 -10.610 -8.340 61.509 1.00 0.00 ATOM 1532 CA TRP163 -11 833 -7.199 62.813 1.00 10.63 ATOM 1533 CB TRP163 -11.211 -5.906 62.271 1.00 9.82 ATON 1534 CG TRP163 -10.807 -5.919 60.808 1.00 8.73 ATOM 1535 CD2 TRP 163 -11.667 -5.754 59.667 1.00 4.19 ATOM 1536 CE2 TRP 163 -10.843 -5.739 58.523 1.00 5.73 ATON 1537 CE3 TRP 163 -13.049 -5 616 59 503 1.00 7.68 ATOM 1538 CDl TRP 163 -9.538 -6.002 60.317 1.00 7.09 ATOM 1539 NEl TRP 163 -9.550 -5.890 58.946 1.00 7.80 ATOM 1540 HEl TRP 163 -8.747 -5.895 58.372 1.00 0.00 ATOM 1541 CZ2 TRP 163 -11.356 -5.586 57.236 1.00 3.92 ATOM 1542 CZ3 TRP 163 -13.559 -5.465 58.222 1.00 6.08 ATOM 1543 C~2 TRP 163 '-12.713 -5.453 57.106 1.00 6.60 ATON 1544 CTRP 163 -13.333 -7.236 62.546 1.00 10.74 ATOM 1545 O TRP 163 -14.068 -6.410 63.069 1.00 11.52 ATOM 1546 NTYR 164 -13.798 -8.207 61.764 1.00 12.03 ATOM 1547 HTYR 164 -13.212 -8.893 61.386 1.00 0.00 ATOM 1548 CATYR 164 -15.225 -8.321 61.471 1.00 11.28 ATOM 1549 CBTYR 164 -15.458 -8.736 60.021 1.00 10.37 ATON 1550 CG TYR 164 -16.922 -8.793 59.634 1.00 8.61 ATOM 1551 CDl TYR 164 -17.645 -7.631 59.372 1.00 6.05 ATOM 1552 CEl TYR 164 -18.986 -7.687 59.010 1.00 5.19 ATOM 1553 CD2 TYR 164 -17.583 -10.013 59.523 1.00 8.20 ATOM 1554 CE2 TYR 164 -18.919 -10.074 59.160 1.00 9.10 SU~STiT~TE S~E~ (RULE 2~) WO 97/08300 PCT~US96/13918 ATOM 1555 CZ TYR 164 -19.609 -8.913 58.904 1.00 6.35 ATOM 1556 OH TYR 164 -20.920 -8.989 58.504 1.00 15.30 ATOM 1557 HH TYR 164 -21.280 -8.115 58.337 1.00 0.00 ATOM 1558 C TYR 164 -15.910 -9.319 62.406 1.00 14.40 5 ATOM 1559 O TYR 164 -15.454 -10.456 62.564 1.00 11.39 ATOM 1560 N HIS 165 -17.014 -8.887 63.016 1.00 15.72 ATOM 1561 H HIS 165 -17.347 -7.989 62.813 1.00 0.00 ATOM 1562 CA HIS 165 -17.769 -9.724 63.945 1.00 15.88 ATOM 1563 CB HIS 165 -17.824 -9.061 65.328 1.00 14.50 10 ATOM 1564 CG HIS 165 -16.476 -8.812 65.939 1.00 13.27 ATOM 1565 CD2 HIS 165 -15.393 -8.142 65.472 1.00 13.68 ATOM 1566 NDl HIS 165 -16.117 -9.296 67.181 1.00 13.92 ATOM 1567 HDl HIS 165 -16.644 -9.884 67.761 1.00 0.00 ATOM 1568 CEl HIS 165 -14.872 -8.937 67.448 1.00 9.42 15 ATOM 1569 NE2 HIS 165 -14.413 -8.240 66.431 1.00 9.18 ATOM 1570 HE2 HIS 165 -13.496 -7.895 66.349 1_00 0.00 ATOM 1571 C HIS 165 -19.170 -9.952 63.382 1.00 18.23 ATOM 1572 O HIS 165 -19.962 -9.017 63.273 1.00 19.85 ATOM 1573 N SER 166 -19.451 -11.201 63.014 1.00 20.28 20 ATOM 1574 H SER 166 -18.770 -11.903 63.124 1.00 0.00 ATOM 1575 CA SER 166 -20.723 -11.619 62.420 1.00 21.65 ATOM 1576 CB SER 166 -20.708 -13.130 62.191 1.00 20.69 ATO~ 1577 OG SER 166 -19.443 -13.555 61.714 1.00 32.02 ATOM 1578 HG SER 166 -19.263 -13.122 60.873 1.00 0.00 25 ATOM 1579 C SER 166 -21.985 -11.260 63.197 1.00 22.80 ATOM 1580 O SER 166 -23.005 -10.924 62.597 1.00 23.80 ATOM 1581 N SER 167 -21.944 -11.424 64.515 1.00 24.13 ATOM 1582 H SER 167 -21.139 -11.759 64.954 1.00 0.00 ATOM 1583 CA SER 167 -23.089 -11.117 65.364 1.00 26.47 30 ATOM 1584 CB SER 167 -23.831 -12.391 65.775 1 00 26 47 ATOM 1585 OG SER 167 -24.476 -12.991 64.664 1.00 33.37 ATOM 1586 HG SER 167 -25.120 -13.631 64.981 1.00 0.00 ATOM 1587 C SER 167 -22.598 -10.401 66.599 1.00 26.39 ATOM 1588 O SER 167 -22.019 -11.016 67.492 1.00 31.31 35 ATOM 1589 N LEU 168 -22.788 -9.089 66.616 1.00 25.40 ATOM 1590 H LEU 168 -23.244 -8.656 65.859 1.00 0.00 ATOM 1591 CA LEU 168 -22.378 -8.254 67.731 1.00 21.28 ~ ATOM 1592 CB LEU 168 -20.975 -7.692 67.514 1.00 19.91 ATOM 1593 CG LEU 168 -19.787 -8.250 68.290 1.00 19.49 -SUBSTITUTE ~E~ ~RULE 2~) CA 02226963 l998-02-l2 ATOM 1594 CDl LEU168 -18.688 -7.208 68.269 1.00 17.54 ATOM 1595 CD2 LEU168 -20.165 -8.547 69.717 1.00 20.20 ATOM 1596 C LEU 168 -23.338 -7.096 67.799 1 00 20.38 ATOM 1597 O LEU 168 -23.574 -6.420 66.797 1.00 23.06 5 ATOM 1598 N THR 169 -23.935 -6.897 68.961 1.00 18.27 ATOM 1599 H THR 169 -23.739 -7.470 69.729 1.00 0.00 ATOM 1600 CA THR 169 -24.846 -5.788 69.138 1.00 14.78 ATOM ~601 CB THR 169 -25.898 -6.091 70.224 1.00 17.59 ATOM 1602 OGl THR169 -25.244 -6.312 71.482 1.00 16.95 ATOM 1603 HGl THR 169 -25.904 -6.666 72.097 1.00 0.00 ATOM 1604 CG2 THR169 -26.709 -7.327 69.854 1.00 18.12 ATOM 1605 C THR 169 -23.962 -4.647 69.612 1.00 14.12 ATOM 1606 O THR 169 -22.784 -4.853 69.918 1.00 13.47 ATOM 1607 N ARG 170 -24.532 -3.453 69.683 1.00 13.49 ATOM 1608 H ARG 170 -25.461 -3.362 69.374 1.00 0.00 ATOM 1609 CA ARG 170 -23.819 -2.271 70.142 1.00 12.83 ATOM 1610 CB ARG 170 -24.768 -1.075 70.111 1.00 9.01 ATOM 1611 CG ARG 170 -24.200 0.203 70.663 1.00 7.72 ATOM 1612 CD ARG 170 -25.258 1.271 70.649 1.00 7.48 ATOM 1613 NE ARG 170 -24.693 2.587 70.897 1.00 9.76 ATOM 1614 HE ARG 170 -24.435 2.810 71.815 1.00 0.00 ATOM 1615 CZ ARG 170 -24.515 3.512 69.962 1.00 9.38 ATOM 1616 NHl ARG170 -23.989 4.681 70.290 1.00 8.60 ATOM 1617 HHll ARG 170-23.732 4.855 71.242 1.00 0.00 ATOM 1618 HH12 ARG 170 -23.839 5.384 69.600 1.00 0.00 ATOM 1619 NH2 ARG 170-24.872 3.277 68.705 1.00 6.68 ATOM 1620 HH21 ARG 170-25.304 2.407 68.477 1.00 0.00 ATOM 1621 HH22 ARG 170-24.748 3.982 68.003 1.00 0.00 ATOM 1622 C ARG 170 -23.295 -2.478 71.564 1.00 14.22 ATOM 1623 O ARG 170 -22.162 -2.113 71.876 1.00 15.95 ATOM 1624 N GLU 171 -24.133 -3.044 72.425 1.00 16.49 ATOM 1625 H GLU 171 -25.006 -3.316 72.108 1.00 0.00 ATOM 1626 CA GLU 171 -23.764 -3.294 73.815 1.00 18.76 ATOM 1627 CB GLU 171 -24.946 -3.879 74.596 1.00 23.85 ATOM 1628 CG GLU 171 -26.031 -2.873 74.999 1.00 33.82 ATOM 1629 CD GLU 171 -26.910 -2.398 73.838 1.00 38.04 ATOM 1630 OEl GLU171 -27.491 -1.288 73.952 1.00 36.00 ATOM 1631 OE2 GLU171 -27.034 -3.132 72.826 1.00 37.18 ATOM 1632 C GLU 171 -22.584 -4.249 73.900 1.00 17.67 - ~92 -SUB5TITUTE ~EET ~RULE 26) CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 1633 O GLU171 -21.632 -4.009 74.645 1.00 17.85 ATOM 1634 N GLU172 -22.660 -5.331 73.130 1.00 17.32 ATOM 1635 H GLU172 -23.444 -5.443 72.559 1.00 0.00 ATOM 1636 CA GLU172 -21.606 -6.340 73.090 1.00 15.02 5 ATOM 1637 CB GLU172 -22.061 -7.542 72.267 1.00 15.64 ATOM 1638 CG GLU172 -23.194 -8.329 72.899 1.00 19.91 ATOM 1639 CD GLU172 -23.906 -9.255 71.918 1.00 25.18 ATOM 1640 OEl GLU172 -25.002 -9.751 72.253 1.00 30.20 ATOM 1641 OE2 GLU172 -23.390 -9.481 70.804 1.00 27.42 1 0 ATOM 1642 C GLU 172 -20.315 -5.764 72.519 1.00 14.37 ATOM 1643 O GLU 172 -19.221 -6.107 72.970 1.00 15.38 ATOM 1644 N ALA 173 -20.443 -4.888 71.527 1.00 12.66 ATOM 1645 H ALA 173 -21.328 -4.667 71.181 1.00 0.00 ATOM 1646 CA ALA 173 -19.282 -4.250 70.913 1.00 10.27 15 ATOM 1647 CB ALA173 -19.709 -3.376 69.747 1.00 9.98 ATOM 1648 C ALA173 -18.551 -3.415 71.953 1.00 9.42 ATOM 1649 O ALA173 -17.339 -3.527 72.102 1.00 10.18 ATOM 1650 N GLU174 -19.295 -2.599 72.694 1.00 11.48 ATOM 1651 H GLU174 -20.266 -2.557 72.540 1.00 0.00 20 ATOM 1652 CA GLU174 -18.697 -1.761 73.725 1.00 11.44 ATOM 1653 CB GLU174 -19.727 -0.810 74.322 1.00 10.86 ATOM 1654 CG GLU174 -20.082 0.331 73.398 1.00 13.06 ATOM 1655 CD GLU174 -20.959 1.383 74.050 1.00 15.17 ATOM 1656 OEl GLU174 -20.984 1.474 75.297 1.00 14.77 25 ATOM 1657 oE2 GLU174 -21.622 2.132 73.306 1.00 15.98 ATOM 1658 C GLU 174 -18.061 -2.589 74.824 1.00 11.55 ATOM 1659 O GLU 174 -17.005 -2.237 75.345 1.00 15.49 ATOM 1660 N ARG 175 -18.707 -3.684 75.194 1.00 13.21 ATOM 1661 H ARG 175 -19.572 -3.890 74.766 1.00 0.00 30 ATOM 1662 CA ARG 175 -18.169 -4.550 76.232 1.00 15.31 ATOM 1663 CB ARG175 -19.136 -5.693 76.514 1.00 16.15 ATOM 1664 CG ARG175 -18.747 -6.564 77.685 1.00 24.24 ATOM 1665 CD ARG175 -19.658 -7.776 77.764 1.00 31.62 ATOM 1666 NE ARG175 -21.073 -7.405 77.758 1.00 38.21 35 ATOM 1667 HEARG 175 -21.507 -7.272 76.885 1.00 0.00 ATOM 1668 CZ ARG 175 -21.813 -7.241 78.852 1.00 43.81 ATOM 1669 NHl ARG 175 -21.276 -7.421 80.056 1.00 42.92 ATOM 1670 HHll ARG 175 -20.313 -7.677 80.134 1.00 0.00 ATOM 1671 HH12 ARG 175 -21.827 -7.290 80.881 1.00 0.00 - 1~3 -SlJBSTITUTE ~HE~ (RULE 2fi) CA 02226963 l998-02-l2 ATOM 1672 NH2 ARG 175 -23.087 -6.869 78.741 1.00 45.14 ATOM 1673 HH21 ARG 175 -23.483 -6.719 77.836 1.00 0.00 ATOM 1674 HH22 ARG 175 -23.645 -6.731 79.561 1.00 0.00 ATOM 1675 C ARG 175 -16.808 -5.102 75.808 1.00 15.70 5 ATOM 1676 O ARG 175 -15.875 -5.124 76.606 1.00 14.24 ATOM 1677 N LYS 176 -16.691 -5.522 74.550 1.00 15.99 ATOM 1678 H LYS 176 -17.474 -5.464 73.956 1.00 0.00 ATOM 1679 CA LYS 176 -15.432 -6.061 74.031 1.00 18.88 ATOM 1680 CB LYS 176 -15.643 -6.727 72.672 1.00 20.03 ATOM 1681 CG LYS 176 -16.324 -8.074 72.733 1.00 24.38 ATOM 1682 CD LYS 176 -16.319 -8.737 71.365 1.00 28.28 ATOM 1683 CE LYS 176 -16.972 -10.118 71.402 1.00 32.74 ATOM 1684 NZ LYS 176 -16.224 -11.112 72.229 1.00 33.50 ATOM 1685 HZl LYS 176 -16.180 -10.765 73.210 1.00 0.00 ATOM 1686 HZ2 LYS 176 -15.257 -11.220 71.853 1.00 0.00 ATOM 1687 HZ3 LYS 176 -16.712 -12.029 72.190 1.00 0.00 ATOM 1688 C LYS 176-14.336 -5.002 73.903 1.00 19.37 ATOM 1689 O LYS 176-13.164 -5.275 74.164 1.00 20.28 ATOM 1690 N LEU 177-14.722 -3.799 73.490 1.00 16.82 ATOM 1691 H LEU 177 -15.661 -3.666 73.244 1.00 0.00 ATOM 1692 CA LEU 177-13.776 -2.704 73.325 1.00 15.13 ATOM 1693 CB LEU 177-14.379 -1.617 72.428 1.00 13.20 ATOM 1694 CG LEU 177-14.633 -2.023 70.973 1.00 11.03 ATOM 1695 CDl LEU177 -15.280 -0.876 70.229 1.00 8.85 ATOM 1696 CD2 LEU 177 -13.329 -2.429 70.302 1.00 5.60 ATOM 1697 C LEU 177-13.315 -2.111 74.654 1.00 16.41 ATOM 1698 O LEU 177-12.157 -1.730 74.800 1.00 16.11 ATOM 1699 N TYR 178-14.227 -2.014 75.615 1.00 17.85 ATOM 1700 H TYR 178-15.136 -2.325 75.444 1.00 0.00 ATOM 1701 CATYR 178 -13.900 -1.471 76.929 1.00 19.30 ATOM 1702 CB TYR 178-15.174 -1.068 77.676 1.00 15.30 ATOM 1703 CG TYR 178-15.706 0.301 77.313 1.00 11.87 ATOM 1704 CDl TYR178 -14.866 1.413 77.301 1.00 9.08 ATOM 1705 CEl TYR178 -15.356 2.681 77.014 1.00 8.80 ATOM 1706 CD2 TYR 178 -17.051 0.493 77.023 1.00 8.22 ATOM 1707 CE2 TYR178 -17.549 1.756 76.736 1.00 8.10 ATOM 1708 CZ TYR 178-16.696 2.846 76.734 1.00 10.05 ATOM 1709 OH TYR 178-17.183 4.110 76.465 1 00 12.49 ATOM 1710 HH TYR 178-18.142 4.016 76.455 1.00 0.00 SUE35 111 UTE ~EE~ ~RULE 26~

CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/l3918 ATOM 1711 C TYR178-13.135 -2.494 77.752 1.00 22.26 ATOM 1712 O TYR178-12.287 -2.148 78.572 1.00 22.67 ATOM 1713 N SER179-13.432 -3.764 77.514 1.00 28.96 ATOM 1714 H SER179-14.082 -4.002 76.825 1.00 0.00 5 ATOM 1715 CA SER179-12.791 -4.850 78.237 1.00 32.67 ATOM 1716 CB SER179-13.775 -6.013 78.416 1.00 34.27 ATOM 1717 OG SER179-14.956 -5.590 79.095 1.00 32.95 ATO~ 7718 HG 5ER17~ 62 -5.0g7 78.445 1.00 0.
ATOM 1719 C SER179-11.518 -5.320 77.544 1.00 34.73 ATOM 1720 O SER 179 -11.467 -6.416 76.994 1_00 37.10 ATOM 1721 N GLY180-10.490 -4.483 77.578 1.00 37.24 ATOM 1722 H GLY180-10.577 -3.618 78.040 1.00 0.00 ATOM 1723 CA GLY180-9.230 -4.834 76.951 1.00 39.63 ATOM 1724 C GLY180-8.163 -3.809 77.266 1.00 41.09 ATOM 1725 O GLY 180 -8.217 -3.151 78.305 1.00 41.30 ATOM 1726 N ALA181-7.201 -3.659 76.361 1 00 43.10 ATOM 1727 H ALA181-7.216 -4.226 75.564 1.00 0.00 ATOM 1728 CA ALA 181 -6.116 -2.699 76.541 1.00 43.62 ATOM 1729 CB ALA181-5.003 -2.975 75.547 1.00 44.37 ATOM 1730 C ALA 181 -6.608 -1.261 76.393 1.00 44.60 ATOM 1731 O ALA181-5.962 -0.327 76.865 1.00 47.43 ATOM 1732 N GLN182-7.749 -1.091 75.731 1.00 42.79 ATOM 1733 H GLN182-8.217 -1.875 75.390 1.00 0.00 ATOM 1734 CA GLN 182 -8.339 0.229 75.516 1.00 41.06 ATOM 1735CB GLN 182 -8.819 0.840 76.837 1.00 40.78 ATOM 1736 CG GLN 182 -10.005 0.113 77.453 1.00 42.40 ATOM 1737 CD GLN 182 -10.574 0.836 78.661 1.00 45.06 ATOM 1738 OEl GLN182 -10.583 2.069 78.717 1.00 45.31 ATOM 1739 NE2 GLN182 -11.067 0.075 79.626 1.00 44.73 ATOM 1740 HE21 GLN 182 -11.050 -0.897 79.502 1.00 0.00 ATOM 1741 HE22 GLN182-11.427 0.496 80.437 1.00 0.00 ATOM 1742 C GLN182-7.405 1.189 74.784 1.00 39.41 ATOM 1743 O GLN182-7.449 2.406 74.994 1.00 39.06 ATOM 1744 N THR183-6.580 0.625 73.908 1.00 38.44 ATOM 1745 H THR 183 -6.587 -0.340 73.784 1.00 0.00 ATOM 1746 CA THR183-5.632 1.390 73.109 1.00 35.60 ATOM 1747 CB THR183-4.702 0.455 72.333 1.00 37.11 ATOM 1748 OGl THR183 -4.298 -0.628 73.180 1.00 40.31 ATOM 1749 HGl THR183 -3.583 -1.085 72.722 1.00 0.00 SUE~SmUTE ~i~EE~ tRuLE 2~;) CA 02226963 l998-02-l2 WO 97/08300 PCTrUS96/13918 ATOM 1750 CG2 THR183 -3.477 1.212 71.842 1.00 38.58 ATOM 1751 C THR 183 -6.398 2.212 72.081 1.00 32.82 ATOM 1752 O THR 183 -7.365 1.725 71.485 1.00 30.53 ATOM 1753 N ASP 184 -5,957 3.444 71.856 1.00 29.67 5 ATOM 1754 H ASP 184 -5.161 3.761 72.327 1.00 0.00 ATOM 1755 CA ASP 184 -6.616 4.312 70.889 1.00 27.05 ATOM 1756 CB ASP 184 -5.947 5.693 70.862 1.00 28.47 ATOM 1757 CG ASP 184 -6.205 6.506 72.126 1.00 30.50 ATOM 1758 ODl ASP184 -5.410 7.432 72.391 1.00 32.80 ATOM 1759OD2 ASP 184 -7.198 6.244 72.844 1.00 29.45 ATOM 1760 C ASP184-6.582 3.679 69.495 1.00 24.36 ATOM 1761 O ASP184-5.569 3.109 69.089 1.00 21.86 ATOM 1762 N GLY185-7,707 3.752 68.790 1.00 20.06 ATOM 1763 H GLY185-8.508 4.173 69.171 1.00 0.00 ATOM 1764 CA GLY 185 -7.784 3.190 67.458 1.00 16.45 ATOM 1765 C GLY185-8.218 1.737 67.404 1.00 13.20 ATOM 1766 O GLY185-8.296 1.173 66.318 1.00 14.03 ATOM 1767 N LYS186-8.438 1.111 68.557 1.00 13.12 ATOM 1768 H LYS186-8.274 1.583 69.398 1.00 0.00 ATOM 1769 CA LYS 186 -8.888 -0.282 68.606 1.00 13.63 ATOM 1770 CB LYS186-8.986 -0.748 70.057 1.00 17.81 ATOM 1771 CG LYS186-8.738 -2.226 70.287 1.00 22.20 ATOM 1772 CD LYS186-7.246 -2.526 70.257 1.00 30.53 ATOM 1773 CE LYS186-6.949 -3.956 70.685 1.00 34.36 ATOM 1774 NZ LYS 186 -5.4g3 -4.283 70.606 1.00 33.77 ATOM 1775 HZl LYS186 -4.967 -3.644 71.232 1.00 0.00 ATOM 1776 HZ2 LYS186 -5.150 -4.182 69.632 1.00 0.00 ATOM 1777 HZ3 LYS186 -5.356 -5.264 70.919 1.00 0.00 ATOM 1778 C LYS186-10.282 -0.245 67.980 1.00 10.77 ATOM 1779 O LYS 186 -11.107 0.573 68 376 1.00 10.89 ATOM 1780 N PHE187-10.563 -1.139 67.038 1.00 9.58 ATOM 1781 H PHE187-9.906 -1.827 66.789 1.00 0.00 ATOM 1782 CA PHE187-11.849 -1.114 66.354 1.00 5.69 ATOM 1783 CB PHE187-11.718 -0.276 65.066 1.00 6.05 ATOM 1784 CG PHE 187 -10.985 -0.991 63.949 1.00 6.66 ATOM 1785 CDl PHE187 -11.684 -1.540 62.876 1.00 5.77 ATOM 1786 CD2 PHE187 -9.600 -1.149 63.991 1.00 7.01 ATOM 1787 CEl PHE187 -11.022 -2.240 61.868 1.00 6.32 ATOM 1788 CE2 PHE187 -8.926 -1.853 62.978 1.00 6.92 SU85TITUTE ~}~ (RULE 2~i) CA 02226963 l998-02-l2 ATOM 1789 CZPHE 187 -9.640 -2.397 61.919 1.00 5.13 ATOM 1790 CPHE 187 -12.368 -2.485 65.962 1.00 6.09 t ATOM 1791 OPHE 187 -11.659 -3.482 66.040 1.00 6.46 ATOM 1792 NLEU 188 -13.612 -2.506 65.502 1.00 4.37 ATOM 1793 H LEU 188 -14.139 -1.682 65.510 1.00 0.00 ATOM 1794 CALEU 188 -14.253 -3.711 65.018 1.00 4.97 ATOM 1795 CBLEU 188 -14.849 -4.529 66.164 1.00 8.12 ATOM 1796 CGLEU 188 -15.937 -3.971 67.079 1.00 6.99 ATOM 17g7 CDl LEU188 -17.293 -3.940 66.382 1.00 4.98 t0 ATOM 1798CD2 LEU 188 -16.005 -4.869 68.296 1.00 9.58 ATOM 1799 CLEU 188 -15.328 -3.269 64.044 1.00 4.81 ATOM 1800 OLEU 188 -15.705 -2.099 64.021 1.00 7.29 ATOM 1801 NLEU 189 -15.776 -4.185 63.201 1.00 4.31 ATOM 1802 HLEU 189 -15.415 -5.099 63.217 1.00 0.00 ATOM 1803 CA LEU 189 -16.816 -3.887 62.234 1.00 6.28 ATOM 1804 CBLEU 189 -16.289 -3.999 60.806 1 00 6.37 ATOM 1805 CGLEU 189 -17.305 -3.588 59.747 1.00 9.47 ATOM 1806 CDl LEU189 -17.422 -2.078 59.738 1.00 13.86 ATOM 1807 CD2 LEU189 -16.874 -4.083 58.383 1.00 14.76 ATOM 1808C LEU 189 -17.892 -4.921 62.468 1.00 6.49 ATOM 1809 O LEU 189 -17.590 -6.097 62.647 1.00 7.98 ATOM 1810 N ARG 190 -19.146 -4.492 62.457 1.00 7.83 ATOM 1811 H ARG 190 -19.341 -3.547 62.290 1.00 0.00 ATOM 1812 CA ARG190 -20.249 -5.407 62.706 1.00 8.00 ATOM 1813CB ARG 190 -20.660 -5.307 64.181 1.00 8.07 ATOM 1814 CG ARG190 -21.012 -3.879 64.610 1.00 5.07 ATOM 1815 CD ARG190 -21.372 -3.771 66.080 1.00 9.21 ATOM 1816 NE ARG190 -21.369 -2.379 66.535 1.00 9.70 ATOM 1817 HE ARG190 -20.510 -2.002 66.808 1.00 0.00 ATOM 1818CZ ARG 190 -22.446 -1.603 66.6}8 1.00 7.61 ATOM 1819 NHl ARG190 -23.644 -2.069 66.288 1.00 9.52 ATOM 1820 HHll ARG 190 -23.756 -3.016 65.981 1.00 0.00 ATOM 1821 HH12 ARG 190 -24.437 -1.466 66.366 1.00 0.00 ATOM 1822 NH2 ARG 190 -22.314 -0.342 66.995 1.00 5.65 ATOM 1823 HH21 ARG 190 -21.402 0.008 67.211 1.00 0.00 ATOM 1824 HH22 ARG 190 -23.111 0.252 67.069 1.00 0.00 ATOM 1825 CARG 190 -21.444 -5.057 61.847 1.00 10.51 ATOM 1826 OARG 190 -21.683 -3.880 61.565 1.00 14.83 ATOM 1827 NPRO 191 -22.176 -6.071 61.361 1.00 10.83 CUBST~TUTE ~iHEE~ tRUl.E ~

CA 02226963 l998-02-l2 W O 97/08300 PCTrUS96/13918 ATOM 1828 CD PRO 191-21.942 -7.523 61.465 1.00 10.41 ATOM 1829 CA PRO 191-23.352 -5.787 60.540 1.00 10.84 ATOM 1830 CB PRO 191-23.690 -7.156 59.946 1.00 9.30 t ATOM 1831 CG PRO 191-23.267 -8.095 61.017 1.00 9.83 ATOM 1832 C PRO 191 -24.462 -5.298 61.471 1.00 12.64 ATOM 1833 ~ PRO 191-24.466 -5.630 62.659 1.00 15.28 ATOM 1834 N ARG 192-25.363 -4.469 60.963 1.00 12.45 ATOM 1835 H ARG 192-25.336 -4.180 60.025 1.00 0,00 ATOM 1836 CA ARG 192 -26.454 -3 983 61.787 1.00 12.10 ATOM 1837 CBARG 192 -26.689 -2.491 61.575 1.00 9.12 ATOM 1838 CG ARG 192-25.592 -1.606 62.105 1.00 2.40 ATOM 1839 CD ARG 192-25.878 -0.148 61.810 1.00 7.40 ATOM 1840 NE ARG 192-27.001 0 383 62.583 1.00 8.66 ATOM 1841 HE ARG 192-26.904 0.465 63.553 1.00 0.00 ATOM 1842 CZARG 192 -28.172 0.743 62.064 1.00 8.48 ATOM 1843 NHl ARG192 -28.390 0.628 60.764 1.00 11.77 ATOM 1844 HHll ARG 192-27.658 0.282 60.181 1.00 0.00 ATO~ 1845 HH12 ARG 192-29.261 0.900 60.355 1.00 0.00 ATOM 1846 NH2 ARG 192-29.121 1.243 62.841 1.00 11.80 ATOM 1847 HH21 ARG 192 -28.968 1.357 63.822 1.00 0.00 ATOM 1848 HH22 ARG 192-29.999 1.507 62.438 1.00 0.00 ATOM 1849 C ARG 192-27.708 -4.761 61.449 1.00 16.67 ATOM 1850 O ARG 192-27.713 -5.581 60.530 1.00 16.54 ATOM 1851 N LYS 193-28.765 -4.497 62.207 1.00 24.12 ATOM 1852 H LYS 193 -28.664 -3.846 62.939 l.C0 0.00 ATOM 1853 CA LYS 193-30.052 -5.154 62.021 1.00 27.69 ATOM 1854 CB LYS 193-31.054 -4.605 63.040 1.00 30.58 ATOM 1855 CG LYS 193-32.442 -5.207 62.954 1.00 36.83 ATOM 1856 CD LYS 193-33.390 -4.538 63.950 1.00 42.21 ATOM 1857 CELYS 193 -34.851 -4.902 63.677 1.00 43.76 ATOM 1858 NZ LYS 193-35.100 -6.373 63.679 1.00 45.07 ATOM 1859 HZl LYS193 -34.800 -6.768 64.593 1.00 0.00 ATOM 1860 HZ2 LYS193 -34.562 -6.822 62.914 1.00 0 00 ATOM 1861 HZ3 LYS193 -36.117 -6.545 63.544 1.00 0.00 ATOM 1862 C LYS 193 -30.595 -5.004 60.595 1.00 29.29 ATOM 1863 O LYS 193-31.078 -5.970 60.009 1.00 30.78 ATOM 1864 N GLU 194-30.505 -3.803 60.027 1.00 30.08 ATOM 1865 H GLU 194-30.052 -3.073 60.494 1.00 0.00 ATOM 1866 CA GLU 194-31.010 -3.580 58.672 1.00 29.65 SUBSIIIUTE ~I~E~(RULE26) CA 02226963 l998-02-l2 ATOM 1867 CB GLU 194-31.443 -2.124 58.468 1.00 31.51 ATOM 1868 CG &LU 194-32.478 -}.620 59.468 1.00 34.14 ATOM 1869 CD GLU 194-31.843 -1.000 60.701 1 00 3g.1S
ATOM 1870 OEl GLU194 -32.144 -1.447 61.828 1.00 43.02 ATOM 1871 OE2 GLU194 -31.040 -0.057 60.545 1.00 42.87 ATOM 1872 C GLU 194 -29.996 -3.978 57.608 1.00 29.35 ATOM 1873 O GLU 194 -28.815 -3.656 57.708 1.00 30.02 ATOM 1874 N GLN 195 -30.475 -4.676 56 585 1.00 27.79 ATOM 1875 H GLN 195 -31.430 -4.874 56.579 1.00 0.00 ATOM 1876 CA GLN 195 -29.638 -5.143 55.486 1.00 26.98 ATOM 1877 CB GLN 195 -30.495 -5.896 54.468 1.00 32.16 ATOM 1878 CG GLN 195 -31.179 -7.137 55.007 1.00 38.27 ATOM 1879 CD GLN 195 -30.242 -8.321 55.098 1.00 42.30 ATOM 1880 OEl GLN195 -29.244 -8.286 55.816 1.00 46.88 ATOM 1881 NE2 GLN195 -30.550 -9.375 54.356 1.00 43.75 ATOM 1882 HE21 G~N 195 -31.346 -9.348 53.792 1.00 0.00 ATOM 1883 HE22 GLN 195 -29.951 -10.143 54.423 1.00 0.00 ATOM 1884 C GLN195 -28.949 -3.987 54.779 1.00 23.15 ATOM 1885 O GLN195 -29.574 -2.973 54.488 1.00 24.44 20 ATOM 1886 N GLY196 -27.661 -4.142 54.502 1.00 20.21 ATOM 1887 H GLY196 -27.192 -4.960 54.770 1.00 0.00 ATOM 1888 CA GLY196 -26.934 -3.096 53.811 1.00 17.86 ATOM 1889 C GLY196 -26.347 -2.009 54.687 1.00 17.20 ATOM 1890 O GLY196 -25.769 -1.050 54.169 1.00 15.58 25 ATOM 1891 N THR197 -26.517 -2.130 56.003 1.00 16.43 ATOM 1892 H THR197 -27.003 -Z.893 56.375 1.00 0.00 ATOM 1893 CA THR197 -25.966 -1.160 56.944 1.00 12.41 ATOM 1894 CB THR197 -27.056 -0.415 57.740 1.00 12.16 ATOM 1895 OGl THR197 -27.907 -1.361 58.392 1.00 12.64 30 ATOM 1896 HGl THR197 -28.275 -1.934 57.715 1.00 0.00 ATOM 1897 CG2 THR197 -27.883 0.478 56.826 1.00 7.90 ATOM 1898 C THR197 -25.050 -1.897 57.912 1.00 12.59 ATOM }899 O THR197 -25.333 -3.033 58.312 1.00 13.67 ATOM 1900 N TYR198 -23.933 -1.259 58.244 1.00 8.91 35 ATOM 1901 H TYR198 -23.787 -0 345 57.907 1.00 0.00 ATOM 1902 CA TYR198 -22.936 -1.814 59.148 1.00 8.91 ATOM 1903 CB TYR198 -21.686 -2.239 58.363 1.00 6.61 - ATOM 1904 CG TYR198 -21.941 -3.345 57.363 1.00 9.50 ATOM 1905 CDl TYR198 -22.509 -3.072 56.118 1.00 6.46 ., .

SUBSmUTE ~E~ ~RULE

CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 1906 CEl TYR198 -22.777 -4.092 55.212 1.00 9.83 ATOM 1907 CD2 TYR198 -21.643 -4.671 57.675 1.00 9.33 ATOM 1908 CE2 TYR198 -21.905 -5.693 56.778 1.00 12.76 ATOM 1909 CZ TYR 198 -22.469 -5.403 55~549 1.00 13.23 ATOM 1910 OH TYR 198 -22.692 -6.430 54.649 1.00 15.25 ATOM 1911 HH TYR 198 -23.165 -6.078 53.883 1.00 0.00 ATOM 1912 C TYR 198 -22.560 -0.696 60.091 1.00 8.51 ATOM 1913 O TYR 198 -23.001 0.436 59.912 1.00 11.67 ATOM 1914 N ALA 199 -21.748 -1.001 61.091 1.00 8.59 0 ATOM 1915 H ALA 199 -21.423 -1.916 61.229 1.00 0.00 ATOM 1916 CA ALA 199 -21.306 0.025 62.017 1.00 6.98 ATOM 1917 CB ALA 199 -22.149 0.012 63.283 1.00 7.55 ATOM 1918 C ALA 199-19.851 -0 214 62.348 1.00 8.45 ATOM 1919 O ALA 199-19.422 -1.361 62.501 1.00 9.19 ATOM 1920 N LEU 200 -19.084 0.869 62.380 1.00 7.78 ATOM 1921 H LEU 200-19.476 1.742 62.171 1.00 0.00 ATOM 1922 CA LEU 200-17.674 0.821 62.715 1.00 7.79 ATOM 1923 CB LEU 200-16.893 1.746 61.784 1.00 9.17 ATOM 1924 CG LEU 200-15.369 1.757 61.924 1.00 15.15 ATOM 1925 CDl LEU 200 -14.783 0.386 61.569 1.00 12.28 ATOM 1926 CD2 LEU200 -14.793 2.844 61.012 1.00 13.36 ATOM 1927 C LEU 200-17.571 1.313 64.158 1.00 9.38 ATOM 1928 O LEU 200-17.970 2.433 64.461 1.00 13.05 ATOM 1929 N SER 201-17.087 0.463 65.057 1.00 10.24 ATOM 1930 H SER 201 -16.753 -0.412 64.768 1.00 0.00 ATOM 1931 CA SER 201-16.961 0.824 66.466 1 00 8.31 ATOM 1932 CB SER 201-17.707 -0.196 67.339 1.00 6.89 ATOM 1933 OG SER 201-19.077 -0.311 66.977 1.00 7.26 ATOM 1934 HG SER 201-19.090 -0.707 66.093 1.00 0.00 ATOM 1935 C SER 201 -15.491 0.869 66.862 1.00 9.36 ATOM 1936 O SER 201-14.765 -0.104 66.653 1.00 9.48 ATOM 1937 N LEU 202-15.051 1.984 67.439 1.00 10.31 ATOM 1938 H LEU 202-15.662 2.736 67.609 1.00 0.00 ATOM 1939 CA LEU 202-13.657 2.124 67.853 1.00 11.15 ATOM 1940 CBLEU 202 -12.835 2.838 66.771 1.00 11.80 ATOM 1941 CG LEU 202-12.959 4.352 66.596 1.00 12.43 ATOM 1942 CDl LEU202 -11.634 5.027 66.905 1.00 15.63 ATOM 1943 CD2 LEU202 -13.371 4.665 65.176 1.00 18.37 ATOM 1944 C LEU 202 -13.534 2.893 69.156 1.00 14.24 SUBST~TUTE ~HE~ tR~JLE 2~i) ATOM 1945 O L~U202-14.446 3.617 69.546 1.00 12.46 ATOM 1946 N ILE203-12.399 2.736 69.825 1.00 17.13 ATOM 1947 H ILE203-11.707 2.154 69.453 1.00 0.00 ATOM 1948 CA ILE203-12.162 3.433 71.081 1.00 18.71 ATOM 1949 CB ILE 203 -11.490 2.540 72.137 1.00 19.35 ATOM 1950 CG2 ILE203 -11.866 3.011 73.529 1.00 21.06 ATOM 1951 CGl ILE203 -11.887 1.084 71.957 1.00 23.07 ATOM 1952 CD ILE203-10.981 0.139 72.713 1.00 26.33 ATOM 1953 C ILE203-11.195 4.580 70.853 1.00 19.13 ATOM 1954 O ILE 203 -10.265 4.481 70.046 1.00 20.24 ATOM 1955 N TYR204-11.419 5.667 71.571 1.00 19.51 ATOM 1956 H TYR204-12.205 5.723 72.147 1.00 0.00 ATOM 1957 CA TYR 204 -10.544 6.818 71.520 1.00 20.06 ATOM 1958 CB TYR 204 -10.831 7.714 70.324 1.00 21.97 ATOM 1959CG TYR 204 -9.864 8.866 70 276 1.00 23.47 ATOM 1960 CDl TYR204 -8.493 8.637 70.173 1.00 24.19 ATOM 1961 CEl TYR204 -7.590 9.685 70.211 1.00 26.94 ATOM 1962 CD2 TYR204 -10.307 10.177 70.411 1.00 24.45 ATOM 1963 CE2 TYR204 -9.410 11.232 70.449 1 00 26.76 ATOM 1964 CZ TYR 204 -8.056 10.977 70.354 1.00 28.21 ATOM 1965 OH TYR204-7.160 12.014 70.424 1.00 37.45 ATOM 1966 HH TYR204-7.642 12.839 70.522 1.00 0.00 ATOM 1967 C TYR204-10.724 7.594 72.814 1.00 20.33 ATOM 1968 O TYR204-11.827 8.055 73.125 1.00 18.87 ATOM 1969 N GL" 205 -9.643 7.695 73.584 1.00 21.84 ATOM 1970 H GLY205-8.815 7.295 73.279 1.00 0.00 ATOM 1971 CA GL'~' 205 -9.684 8.394 74.858 1.00 20.17 ATOM 1972 C GL}'205-10.621 7.710 75.837 1.00 19.37 ATOM 1973 O GL}'205-11.482 8.360 76.424 1.00 21.75 ATOM 1974 N LYS 206 -10.494 6.390 75.963 1.00 18.95 ATOM 1975 H LYS206-9.814 5.924 75.440 1.00 0.00 ATOM 1976 CA LYS206-11.330 5.597 76.866 1.00 21.57 ATOM 1977 CB LYS206-11.065 5.982 78.323 1.00 23.25 ATOM 1978 CG LYS206-9.920 5.239 78.982 1.00 27.37 ATOM 1979 CD LYS 206 -9.687 5.772 80.394 1.00 33.80 ATOM 1980 CE LYS206-9.061 4.730 81.315 1.00 35.90 ATOM 1981 NZ LYS206-10.000 3.606 81.620 1.00 37.25 ATOM 1982 HZl LYS206 -10.264 3.129 80.733 1.00 0.00 ATOM 1983 HZ2 LYS206 -10.854 3.986 82.078 1.00 0.00 SUBSTITUTE S~EEl ~RULE

CA 02226963 l998-02-l2 W O 97/08300 PCTrus96/13918 ATOM 1984 HZ3 LYS206 _9,536 2.926 82.259 1.00 0.00 ATOM 1985 C LYS 206-12.829 5.688 76.577 1.00 21.03 ATOM 1986 O LYS 206-13.649 5.298 77.403 1.00 22.71 ATOM 1987 N THR 207-13.185 6.174 75.396 1.00 20.66 ATOM 1988 H THR 207 -12.532 6.456 74.735 1.00 0.00 ATOM 1989 CA THR 207-14.582 6.297 75.020 1.00 20.40 ATOM 1990 CB THR 207-14.992 7.782 74.9Q7 1.00 23.55 ATOM 1991 OGl THR207 -14.482 8.507 76.033 1 00 25.33 ATOM 1992 HGl THR207 -13.533 8.667 75.914 1.00 0.00 0 ATOM 1993 CG2 THR 207 -16.507 7.919 74.890 1.00 24.82 ATOM 1994 C THR 207-14.777 5.589 73.679 1.00 19.07 ATOM 1995 O THR 207-13.893 5.630 72.824 1.00 20.35 ATOM 1996 N VAL 208-15.906 4.900 73.531 1.00 16.81 ATOM 1997 H VAL 208-16.535 4.881 74.280 1.00 0.00 ATOM 1998 CAVAL 208 -16.240 4.156 72.317 1.00 15.40 ATOM 1999 CB VAL 208-16.952 2.803 72.665 1.00 12.63 ATOM 2000 CGl VAL208 -17.532 2.159 71.422 1.00 16.18 ATOM 2001 CGZ VAL208 -15.972 1.841 73.316 1.00 8.54 ATOM 2002 C VAL 208-17.115 4.965 71.355 1.00 15.91 ATOM 2003 O VAL 208 -18.159 5.483 71.748 1.00 16.07 ATOM 2004 N TYR 209-16.668 5.061 70.100 1.00 17.15 ATOM 2005 H TYR 209-15.820 4.658 69.884 1.00 0.00 ATOM 2006 CA TYR 209-17.366 5.775 69.026 1.00 13.45 ATOM 2007 CB TYR 209-16.393 6.701 68.298 1.00 12.87 ATOM 2008 CGTYR 209 -15.821 7.795 69.153 1.00 12.70 ATOM 2009 CDl TYR209 -16.246 9 107 69.005 1.00 14.59 ATOM 2010 CEl TYR209 -15.721 10.124 69.786 1.00 17.80 ATOM 2011 CD2 TYR209 -14.851 7.523 70.108 1.00 12.27 ATOM 2012 CE2 TYR209 -14.322 8.531 70.896 1.00 15.57 ATOM 2013 CZTYR 209 -14.760 9.830 70.732 1.00 16.21 ATOM 2014 OH TYR 209-14.250 10.837 71.519 1.00 16.78 ATOM 2015 HH TYR 209-14.677 11.671 71.296 1.00 0.00 ATOM 2016 C TYR 209-17.956 4.790 68.014 1.00 11.19 ATOM 2017 O TYR 209-17.350 3.770 67.706 1.00 12.29 ATOM 2018 N HIS 210 -19.143 5.096 67.505 1.00 10.27 ATOM 2019 H HIS 210-19.587 5.914 67.804 1.00 0.00 ATOM 2020 CA HIS 210-19.811 4.244 66.525 1.00 9.28 ATOM 2021 CB HIS 210-21.123 3.697 67.085 1.00 11.42 ATOM 2022 CG HIS 210-20.981 2.980 68.390 1.00 13.02 SUBSTITUTE S~E~ tRuLE 26~

CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 2023 CD2 HIS210 -21.058 3.429 69.663 1.00 12.81 ATOM 2024 NDl HIS210 -20.751 1.624 68.474 1.00 12.75 j ATOM 2025 HDl HIS210 -20.594 1 000 67.722 1.00 0.00 ATOM 2026 CEl HIS210 -20.696 1.268 69.744 1.00 13.87 5 ATOM 2027 NE2 HIS210 -20.878 2.345 70.485 1.00 13.61 ATOM 2028 HE2 HIS210 -20.870 2.365 71.458 1.00 0.00 ATOM 2029 C HIS210 -20.143 5.074 65.301 1.00 9.07 ATOM 2030 O HIS210 -20.690 6.165 65.430 1.00 11.99 ATOM 2031 N TYR211 -19.839 4.550 64.119 1.00 9.30 10 ATOM 2032 H TYR211 -19.408 3.671 64.065 1.00 0.00 ATOM 2033 CA TYR211 -20.115 5.239 62.860 1.00 8.50 ATOM 2034 CB TYR211 -18.810 5.602 62.136 1.00 7.82 ATOM 2035 CG TYR211 -17.960 6.618 62.866 1 00 9.31 ATOM 2036 CDl TYR211 -17.064 6.224 63.862 1.00 10.88 15 ATOM 2037 CEl TYR211 -16.270 7.154 64.531 1.00 9.13 ATOM 2038 CD2 TYR211 -18.043 7.973 62.559 1.00 10.28 ATOM 2039 CE2 TYR211 -17.254 8 911 63.223 1.00 9.76 ATOM 2040 CZ TYR211 -16.371 8.492 64.205 1.00 9.78 ATOM 2041 OH TYR211 -15.579 9.405 64.857 1.00 11.29 20 ATOM 2042 HH TYR211 -15.854 10.307 64.614 1.00 0.00 ATOM 2043 C TYR211 -20.958 4.331 61.981 1.00 6.82 ATOM 2044 ~ TYR211 -20.728 3.124 61.917 1.00 8.26 ATOM 2045 N LEU212 -21.949 4.917 61.324 1.00 6.71 ATOM 2046 H LEU212 -22.062 5.893 61.376 1.00 0.00 2~ ATOM 2047 CA LEU212 -22.852 4.185 60.451 1.00 5.46 ATOM 2048 CB LEU212 -24.174 4.959 60.360 1.00 7.18 ATOM 2049 CG LEU212 -25.494 4.395 59.818 1.00 9.03 ATOM 2050 CDl LEU212 -25.835 5.015 58.480 1.00 12.52 ATOM 2051 CD2 LEU212 -25.475 2.889 59.756 1.00 11.67 30 ATOM 2052 C LEU212 -22.226 4.035 59.065 1.00 6.62 ATOM 2053 O LEU212 -21.636 4.975 58.535 1.00 5.44 ATOM 2054 N ILE213 -22.275 2.827 58.521 1.00 7.03 ATOM 2055 H ILE213 -22.665 2.078 59.020 1.00 0.00 ATOM 2056 CA ILE213 -21.757 2.583 57.187 1.00 6.11 3~ ATOM 2057 CB ILE213 -20.691 1.477 57.174 1.00 8.10 ATOM 2058 CG2 ILE213 -20.328 l.lll 55.733 1.00 8.26 ATOM 2059 CGl ILE213 -19.446 1.940 57.935 1.00 7.79 ATOM 2060 CD ILE213 -18.405 0.858 58.106 1.00 4.59 ATOM 2061 C ILE213 -22.972 2.142 56.384 1.00 7.52 .

SUBSTITUTE SI~E~ ~RULE 2 CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATOM 2062 O ILE 213-23.708 1.254 56.806 1.00 7.66 ATOM 2063 N SER 214-23.212 2.781 55.250 1.00 8.29 ATOM 2064 H SER 214-22.616 3.483 54.920 1.00 0.00 ATOM 2065 CA SER 214-24.365 2.429 54.442 1.00 11.71 5 ATOM 2066 CB SER 214-25.403 3.550 54.517 1.00 13.40 ATOM 2067 OG SER 214-26.664 3.122 54.045 1.00 21.53 ATOM 2068 HG SER 214-27.246 2.924 54.794 1.00 0.00 ATOM 2069 C SER 214-23.944 2.183 53.000 1.00 13.39 ATOM 2070 O SER 214-22.868 2.608 52.574 1.00 14.33 ATOM 2071 N GLN 215 -24.773 1.454 52.266 1.00 16.85 ATOM 2072 H GLN 215-25.622 1.144 52.659 1.00 0.00 ATOM 2073 CA GLN 215 -24.501 1.145 50.870 1.00 21.53 ATOM 2074 CB GLN 215 -24.656 -0.356 50.632 1.00 21.76 ATOM 2075 CG GLN 215 -24.198 -0.815 49.265 1.00 25.99 ATOM 2076 CD GLN 215 -24.267 -2.320 49.102 1.00 27.71 ATOM 2077 OEl GLN215 -24.990 -3.002 49.825 1.00 31.50 ATOM 2078 NE2 GLN215 -23.500 -2.848 48.160 1.00 26.57 ATOM 2079 HE21 GLN 215-22.916 -2.272 47.626 1.00 0.00 ATOM 2080 HE22 GLN 215-23.571 -3.817 48.059 1.00 0.00 ATOM 2081 C GLN 215 -25.496 1.919 50.014 1.00 23.57 ATOM 2082 O GLN 215 -26.702 1.807 50.218 1.00 26.27 ATOM 2083 N ASP 216 -24.997 2.742 49.096 1.00 24.50 ATOM 2084 H ASP 216 -24.024 2.829 49.029 1.00 0.00 ATOM 2085 CA ASP 216 -25.878 3.523 48.239 1.00 25.05 ATOM 2086 CB ASP 216 -25.195 4.820 47.769 1.00 24.39 ATOM 2087 CG ASP 216 -23.933 4.580 46.941 1.00 24.49 ATOM 2088 ODl ASP216 -23.826 3.556 46.232 1.00 24.62 ATOM 2089 OD2 ASP216 -23.041 5.451 46.986 1.00 22.90 ATOM 2090 C ASP 216-26.447 2.743 47.055 1.00 26.80 ATOM 2091 O ASP 216 -26.222 1 539 46.923 1.00 27.31 ATOM 2092 N LYS 217-27.143 3.454 46.173 1.00 30.69 ATOM 2093 H LYS 217-27.270 4.407 46.343 1.00 0.00 ATOM 2094 CA LYS 217-27.762 2.863 44.986 1.00 32.79 ATOM 2095 CB LYS 217-28.498 3.946 44.189 1.00 36.64 ATOM 2096 CGLYS 217 -27.606 4.818 43.290 1.00 41.04 ATOM 2097 CD LYS 217-26.611 5.688 44.067 1.00 45.48 ATOM 2098 CE LYS 217-27.307 6.796 44.850 1.00 49.13 ATOM 2099 NZ LYS 217-26.330 7.760 45.446 1.00 51.31 ATOM 2100 HZl LYS217 -25.793 8.221 44.683 1.00 0.00 SUBSTITUTE ~i~E~ ~RULE 2~i) W O 97/08300 PCT~US96/13918 ATOM 2101 HZ2 LYS217 -25.684 7.252 46.083 1.00 0.00 ATOM 2102 HZ3 LYS217 -26.846 8.482 45.988 1.00 0.00 i ATOM 2103 C LYS 217 -26.758 2.156 44.077 1.00 31.55 ATOM 2104 O LYS 217 -27.058 1.116 43.497 1.00 33.38 5 ATOM 2105 N ALA 218 -25.567 2.731 43,959 1.00 30.81 ATOM 2106 H ALA 218 -25.384 3.544 44.464 1.00 0.00 ATOM 2107 CA ALA 218 -24.517 2.175 43.113 1.00 28.71 ATOM 2108 CB ALA218 -23.534 3.265 42.728 1.00 27.61 ATOM 2109 C ALA218 -23.781 1.011 43.773 1.00 29.11 10 ATOM 2110 O ALA218 -22.812 0.490 43.217 1.00 31.99 ATOM 2111 N GLY219 -24.222 0.624 44.968 1.00 26.78 ATOM 2112 H GLY219 -25.007 1.034 45.378 1.00 0.00 ATOM 2113 CA GLY 219 -23.588 -0.472 45.674 1.00 22.67 ATOM 2114 C GLY219 -22.322 -0.078 46.411 1.00 22.34 t5 ATOM 2115 O GLY219 -21.617 -0.937 46.943 1 00 22.37 ATOM 2116 N LYS220 -22.043 1.218 46 472 1.00 18.20 ATOM 2117 H LYS220 -22.639 1.850 46.038 1.00 0.00 ATOM 2118 CA LYS220 -20.857 1.699 47.157 1.00 15.98 ATOM 2119 CB LYS220 -20.334 2.951 46.464 1.00 19.42 20 ATOM 2120 CG LYS220 -19.724 2.658 45.103 1.00 24.14 ATOM 2121 CD LYS220 -19.446 3.937 44.349 1.00 30.32 ATOM 2122 CE LYS220 -18.686 3.669 43.057 1.00 35.44 ATOM 2123 NZ LYS220 -17.267 3.293 43.318 1.00 39.63 ATOM 2124 HZl LYS220 -17.249 2.479 43.959 1.00 0.00 25 ATOM 2125 HZ2 LYS220 -16.790 4.091 43.777 1.00 0 00 ATOM 2126 HZ3 LYS220 -16.781 3.043 42.432 1.00 0.00 ATOM 2127 C LYS 220 -21.119 1.954 48.636 1.00 13.83 ATOM 2128 Q LYS 220 -22.221 2.346 49.019 1.00 12.56 ATOM 2129 N TYR 221 -20.112 1.677 49.459 1.00 10.21 30 ATOM 2130 H TYR 221 -19.285 1.336 49.059 1.00 0.00 ATOM 2131 CA TYR 221 -20.194 1.863 50.903 1.00 9.57 ATOM 2132 CB TYR 221 -19-445 0.7S9 51.641 1.00 8.91 ATOM 2133 CG TYR 221 -19.910 -0.632 51.334 1.00 9.85 ATOM 2134 CDl TYR221 -19.410 -1.318 50.231 1.00 9.27 35 ATOM 2135 CEl TYR221 -19.782 -2.629 49.974 1.00 13.17 ATOM 2136 CD2 TYR221 -20.805 -1.289 52.174 1.00 10.94 ATOM 2137 CE2 TYR221 -21.185 -2.605 51.928 1.00 13.53 ATOM 2138 CZ TYR 221 -20.665 -3.267 50.826 1.00 12.86 ATOM 2139 OH TYR 221 -20.995 -4.579 50.584 1.00 19.40 SUE~STITUTE ~HEE~ tRULE 2~i~

CA 02226963 l998-02-l2 WO 97/08300 PCT~US96~13918 ATOM 2140 H~ TYR221 -20.857 -4.758 49.645 1.00 0.00 ATOM 2141 C TYR221 -19.574 3.174 51.330 1.00 10.79 ATOM 2142 O TYR221 -18.616 3.651 50.714 l.Q0 10.37 ATOM 2143 N CYS222 -20.090 3.724 52.422 1.00 9.88 ATOM 2144 H CYS222 -20.863 3.315 52.870 1.00 0.00 ATOM 2145 CA CYS222 -19.570 4.964 52.967 l.C0 9.81 ATOM 2146 CB CYS222 -19.774 6.126 51.986 l.C0 10.60 ATOM 2147 SG CYS222 -21.492 6.676 51.784 1.00 17.23 ATOM 2148 C CYS222 -20.244 5.331 54.270 1.00 9.69 1 0 ATOM 2149 O CYS 222 -21.345 4.860 54.579 1.00 7.62 ATOM 2150 N ILE223 -19.521 6.097 55.074 1.00 10.22 ATOM 2151 H ILE223 -18.601 6.331 54.815 1.00 0.00 ATOM 2152 CA ILE223 -20.059 6.638 56.306 1.00 9.93 ATOM 2153 CB ILE223 -18.925 6.995 57.300 l.CC 6.84 ATOM 2154 CG2 ILE223 -19.475 7.742 58.498 1.~0 5.29 ATOM 2155 CGl ILE223 -18.225 5.712 57.762 1.00 6 96 ATOM 2156 CD ILE223 -16.938 5.946 58.525 l.C0 9.34 ATOM 2157 C ILE223 -20.697 7.902 55.706 1.00 11.78 ATOM Z158 o ILE223 -20.109 8.528 54.823 1.00 12.45 20 ATOM 2159 N PRO224 -21.936 8.234 56.102 1.00 13.13 ATOM 2160 CD PRO224 -22.736 7.595 57.167 1.00 13.77 ATOM 2161 CA PRO224 -22.621 9.422 55.572 1.00 12.77 ATOM 2162 CB PRO224 -23 707 9.672 56.616 1.00 12.95 ATOM 2163 CG PRO224 -24.088 8.271 57.014 1.00 13.82 25 ATOM 2164 C PRO224 -21.715 10.647 55.374 l.C0 11.50 ATOM 2165 O PRO224 -21.090 11.126 56.315 1.00 9.13 ATOM 2166 N GLU225 -21.645 11.124 54.132 1.00 14.71 ATOM 2167 ~ GLU225 -22.179 10.664 53.448 1.00 0.00 ATOM 2168 CA GLU225 -20.830 12.280 53.738 l.G0 15.88 30 ATOM 2169 CB GLU225 -21.055 13.465 54.680 1.00 20.79 ATOM 2170 CG GLU225 -22.439 14.080 54.631 1.00 26.35 ATOM 2171 CD GLU225 -22.526 15.306 55.516 1.00 32.15 ATOM 2172 OEl GLU225 -22.863 15.151 56.712 1.00 33.44 ATOM 2173 OE2 GLU225 -22.228 16.418 55.020 1.00 34.61 35 ATOM 2174 C GLU225 -19.330 12.006 53.641 1.00 13.50 ATOM 2175 O GLU225 -18.536 12.937 53.502 1.00 14.62 ATOM 2176 N GLY226 -18.939 10.740 53.707 1.00 10.60 ATOM 2177 H GLY226 -19.593 10.021 53 791 1.00 0.00 ATOM 2178 CA GLY226 -17.532 10.407 53.626 1.00 9.49 -SUBSTlTUTE ~HL~ tRULE 26~

CA 02226963 l998-02-l2 w o 97/n8300 PCT~US96/13918 ATOM 2179 C GLY 226-17.172 9.830 52.273 1.00 7.50 ATOM 2180 O GLY 226-18.004 9.771 51.373 1.00 7.18 ATOM 2181 N THR 227-15.926 9.395 52.140 1.00 11.32 ATOM 2182 H THR 227-15.314 9.439 52.909 1.00 0.00 ATOM 2183 CATHR 227 -15.419 8.798 50.907 1.00 11.27 ATOM 2184 CB THR 227-13.911 8.469 51.054 1.00 10.87 ATOM 2185 OGl THR227 -13.191 9.664 51.370 1.00 11.75 ATOM 2186 HGl THR227 -13.305 10.261 50.623 1.00 0.00 ATOM 2187 CG2 THR227 -13.350 7.891 49.783 1.00 9.00 ATOM 2188 C THR 227 -16.191 7.513 50.609 1.00 11.40 ATOM 2189 O THR 227-16.643 6.835 51.530 1.00 13.43 ATOM 2190 N LYS 228-16.343 7.187 49.330 1.00 11.00 ATOM 2191 H LYS 228-15.978 7.748 48.614 1.00 0.00 ATOM 2192 CA LYS 228-17.056 5.986 48.927 1.00 11.19 ATOM 2193 CBLYS 228 -18.118 6.329 47.882 1.00 15.00 ATOM 2194 CG LYS 228-19.153 7.293 48.448 1.00 11.92 ATOM 2195 CD LYS 228-20.385 7.410 47.598 1.00 15.46 ATOM 2196 CE LYS 228-21.505 8.048 48.399 1.00 16.88 ATOM 2197 NZ LYS 228-21.135 9.394 48.914 1.00 26.16 ATOM 2198 HZl LYS 228 -20.889 10.007 48.111 1.00 0.00 ATOM 2199 HZ2 LYS228 -20.321 9.311 49.557 1.00 0.00 ATOM 2200 HZ3 LYS228 -21.945 9.804 49.428 1.00 0.00 ATOM 2201 C LYS 228-16.114 4.890 48.452 1.00 10.75 ATOM 2202 O LYS 228-15.136 5.153 47.745 1.00 8.11 2~ ATOM 2203 N PHE 229 -16.412 3.661 48.866 1.00 8.50 ATOM 2204 H PHE 229-17.223 3.514 49.399 1.00 0.00 ATOM 2205 CA PHE 229-15.590 2.504 48.552 1.00 5.46 ATOM 2206 CB PHE 229-14.963 1.973 49.843 1.00 4.60 ATOM 2207 CG PHE 229-14.272 3.031 50.669 1.00 4.48 ATOM 2208 CDl PHE 229 -14.983 3.792 51.590 1.00 7.15 ATOM 2209 CD2 PHE229 -12.913 3.269 50.525 1.00 5.66 ATOM 2210 CEl PHE229 -14.350 4.767 52.352 1.00 4.56 ATOM 2211 CE2 PHE229 -12.280 4.242 51.284 1.00 5.66 ATOM 2212 CZ PHE 229-13.003 4.991 52.199 1.00 2.65 ATOM 2213 C PHE 229 -16.403 1.398 47.891 1.00 8 16 ATOM 2214 O PHE 229-17.617 1.312 48.086 1.00 5.71 ATOM 2215 N ASP 230-15.728 0.538 47.126 1.00 9.14 ATOM 2216 H ASP 230-14.760 0.670 47.008 1.00 0.00 ATOM 2217 CA ASP 230 -16.394 -0.574 46.445 1.00 9.38 SIJBSTITUTE ~}~EET ~RUI E 26~

CA 02226963 l998-02-l2 W O 97/08300 PCTrUS96/13918 ATOM 2218 CB ASP 230 -15.574 -1.052 45.246 1.00 8.63 ATOM 2219 CG ASP 230 -15.869 -0.274 43.981 1.00 8.43 ATOM 2220 ODl ASP 230 -15.274 -0.608 42.947 1.00 9.85 ATOM 2221 OD2 ASP 230 -16.698 0.654 43.998 1.00 11.91 ATOM 2222 C ASP 230 -16.651 -1.761 47.363 1.00 10.64 ATOM 2223 O ASP230 -17.541 -2.573 47.108 1.00 11.10 ATOM 2224 N THR231 -15.824 -1.904 48.391 1.00 10.48 ATOM 2225 H THR231 -15.090 -1.275 48.547 1.00 0.00 ATOM 2226 CA THR231 -15.971 -3.007 49.321 1.00 6.74 ATOM 2227 CB T~R 231 -14.953 -4.131 49.036 1.00 7.00 ATOM 2228 OGl THR 231 -13.627 -3.614 49.171 1.00 8.09 ATOM 2229 HGl THR 231 -13.496 -3.068 48.382 1.00 0.00 ATOM 2230 CG2 THR 231 -15.127 -4.692 47.635 1.00 9.33 ATOM 2231 C THR231 -15.700 -2.501 50.719 1.00 5.98 ATOM 2232 O THR 231 -15.050 -1.477 50.898 1.00 4.61 ATOM 2233 M LEU232 -16.211 -3.224 51.704 1.00 7.05 ATOM 2234 H LEU232 -16.795 -3.989 51.481 1.00 0.00 ATOM 2235 CA LEU232 -16.001 -2.885 53.099 1.00 8.76 ATOM 2236 CB LEU232 -16.881 -3.761 53.994 1.00 6.96 ATOM 2237 CG LEU 232 -18.367 -3.450 54.121 1.00 6.67 ATOM 2238 CDl LEU 232 -19.044 -4.612 54.828 1.00 7.35 ATOM 2239 CD2 LEU 232 -18.576 -2.150 54.897 1.00 6.04 ATOM 2240 C LEU232 -14.534 -3,090 53.473 1.00 7.18 ATOM 2241 O LEU232 -14.021 -2.433 54.374 1.00 9.95 ATOM 2242 N TRP 233 -13.873 -4.022 52.796 1.00 6.47 ATOM 2243 H TRP233 -14.348 -4.510 52.099 1.00 0.00 ATOM 2244 CA TRP233 -12.464 -4.305 53.057 1.00 6.87 ATOM 2245 CB TRP233 -11.979 -5.466 52.188 1.00 3.74 ATOM 2246 CG TRP233 -10.687 -6.058 52.650 1.00 4.57 ATOM 2247CD2 TRP 233 -9.359 -5.570 52.381 1.00 8.34 ATOM 2248 CE2 TRP 233 -8.458 -6.423 53.060 1.00 6.83 ATOM 2249 CE3 TRP 233 -8.844 -4.493 51.641 1.00 8.52 ATOM 2250 CDl TRP 233 -10.536 -7.154 53.440 1.00 5.21 ATOM 2251 NEl TRP 233 -9.204 -7.380 53.693 1.00 6.92 ATOM 2252HEl TRP 233 -8.861 -8.107 54.265 1.00 0.00 ATOM 2253 CZ2 TRP 233 -7.073 -6.237 53.021 1.00 8.01 ATOM 2254 CZ3 TRP 233 -7.458 -4.308 51.601 1.00 6.16 ATOM 2255 CH2 TRP 233 -6.592 -5.177 52.292 1.00 7.69 ATOM 2256 C TRP 233 -11.617 -3.062 52.772 1.00 7.29 SUBSTITUTE St~E~ (RUI_E 2~i~

CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 2257 O TRP233-10.733 -2.700 53.561 1.00 9.21 ATOM 2258 N GLN234-11.902 -2.403 51.652 1.00 5.93 ATOM 2259 H GLN234-12.613 -2.733 51.066 1.00 0.00 ATOM 2260 CA GLN 234 -11.169 -1.204 51.262 1.00 4.78 ATOM 2261CB GLN 234 -11.443 -0.862 49.798 1.00 6.84 ATOM 2262 CG GLN 234 -10.836 -1.880 48.848 1.00 10.82 ATOM 2263 CD GLN 234 -11.380 -1.789 47.432 1.00 10.56 ATOM 2264 OEl GLN234 -12.586 -1.878 47.209 1.00 8.62 ATOM 2265 NE2 GLN234 -10.487 -1.652 46.469 1.00 11.25 ATOM 2266 HE21 GLN 234 -9.531 -1.629 46.708 1.00 0.00 ATOM 2267 HE22 GLN234-10.789 -1.580 45.537 1.00 0.00 ATOM 2268 C GLN234-11.449 -0.015 52.160 1.00 3.62 ATOM 2269 O GLN234-10.554 0.781 52.430 1.00 5.94 ATOM 2270 N LEU235-12.689 0.106 52.615 1.00 5.89 1~ ATO~ 2271 H LEU 235 -13.364 -0.541 52.324 1.00 0.00 ATOM 2272 CA LEU235-13.081 1.190 53.511 1.00 4.73 ATOM 2273 CB LEU235-14.566 1.059 53.872 1.00 4.90 ATO~ 2274 CG LEU235-15.185 2.047 54.874 1.00 6.15 ATOM 2275 CDl LEU235 -16.630 2.350 54.483 1.00 8.45 ATOM 2276CD2 LEU 235 -15.109 1.496 56.298 1.00 4.62 ATOM 2277 C LEU 235 -12.216 1.146 54.769 1.00 5.64 ATOM 2278 O LEU 235 -11.579 2.133 55.134 1.00 6.99 ATOM 2279 N VAL 236 -12.158 -0.025 55.390 1.00 5.96 ATOM 2280 H VAL 236 -12.661 -0 789 55.026 1.00 0.00 ATOM 2281CA VAL 236 -11.383 -0.223 56.603 1.00 8.27 ATOM 2282 CB VAL 236 -11.604 -1.650 57.157 1.00 9.38 ATO~ 2283 CGl VAL236 -10.658 -1.938 58.330 1.00 7.51 ATOM 2284 CG2 VAL236 -13.042 -1.816 57.587 1.00 5.71 ATOM 2285 C VAL236-9.892 0.031 56.406 1.00 9.49 ATOM 2286 O VAL 236 -9.270 0.731 57.197 1.00 12.68 ATOM 2287 N GLU237-9.317 -0.524 55.347 1.00 10.79 ATOM 2288 H GLU237-9.854 -1.062 54.733 1.00 0.00 ATOM 2289 CA GLU237-7.887 _0.3g9 55.094 1.00 11.35 ATOM 2290 CB GLU237-7.430 -1.272 53.976 1.00 16.61 3~ ATOM 2291CG GLU 237 -7.605 -2.731 54.340 1.00 22.80 ATOM 2292 CD GLU 237 -6.787 -3.144 55.547 1.00 24.22 ATOM 2293 OEl GLU237 -5.597 -2.765 55.618 1.00 22.20 ATOM 2294 OE2 GLU237 -7.340 -3.852 56.416 1.00 23.12 ATOM 2295 C GLU 237 -7.474 1.076 54.796 1.00 9.15 SUBSTITUTE S~{EE~ tRUI E 2~i) CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/l3918 ATOM 2296 O GLU237-6.380 1.498 55.156 1.00 12.17 ATOM 2297 N TYR238-8.355 1.809 54.128 1.00 9.53 ATOM 2298 H TYR238-9.205 1.398 53.859 1.00 0.00 ATOM 2299 CA TYR238-8.125 3.205 53.785 1.00 6.78 ATOM 2300 CB TYR 238 -9.226 3.674 52.835 1.00 5.11 ATOM 2301 CG TYR238_9.016 5.049 52.254 1.00 6.85 ATOM 2302 CDl TYR238 -8.241 5.232 51.112 1.00 6.52 ATOM 2303 CEl TYR238 -8.072 6.503 50.549 1.00 10.87 ATOM 2304 CD2 TYR238 -9.619 6.169 52.830 1.00 9.19 ATOM 2305CE2 TYR 238 -9.458 7.438 52.281 1.00 10.07 ATOM 2306 CZ TYR238-8.686 7.596 51.141 1.00 10.71 ATOM 2307 OH TYR238-8.540 8.843 50.592 1.00 14.33 ATOM 2308 HH TYR238-9.060 9.481 51.085 1.00 0.00 ATOM 2309 C TYR238-8.160 4.042 55.057 1.00 6.62 ATOM 2310 O TYR 238 -7.335 4.929 55.247 1.00 6.71 ATOM 2311 N LEU239-9.113 3.731 55.931 1.00 7.40 ATOM 2312 H LEU239-9.745 3.006 55.745 1.00 0.00 ATOM 2313 CA LEU239-9.276 4.443 57.191 1.00 9.62 ATOM 2314 CB LEU239-10.675 4.198 57.774 1.00 8.00 ATOM 2315 CG LEU 239 -11.814 4.773 56.918 1.00 8.26 ATOM 2316 CDl LEU239 -13.168 4.365 57.461 1.00 2.00 ATOM 2317 CD2 LEU239 -11.696 6.285 56.865 1.00 6.62 ATOM 2318 C LEU239-8.170 4.092 58.187 1.00 11.33 ATOM 2319 o LEU239-8.076 4.689 59.261 1.00 11.19 ATOM 2320 N LYS 240 -7.360 3.091 57.848 1.00 12.90 ATOM 2321 H LYS240-7.552 2.545 57.064 1.00 0.00 ATOM 2322 CA LYS240-6.221 2.725 58.687 1.00 15.35 ATOM 2323 CB LYS240-5.709 1.326 58.368 1.00 12.42 ATOM 2324 CG LYS240-6.446 0.171 59.010 1.00 16.17 ATOM 2325 CD LYS 240 -5.570 -1.069 58.865 1.00 18.37 ATOM 2326 CE LYS240-6.272 -2.347 59.239 1.00 21.75 ATOM 2327 NZ LYS240-5.382 -3.491 58.897 1.00 22.57 ATOM 2328 HZl LYS240 -4.536 -3.458 59.499 1.00 0.00 ATOM 2329 HZ2 LYS240 -5.113 -3.415 57.895 1.00 0.00 ATO~ 2330HZ3 LYS 240 -5.890 -4.386 59.045 1.00 0.00 ATOM 2331 C LYS240-5.103 3.706 58.351 1.00 16.14 ATOM 2332 O LYS240-4.316 4.084 59.212 1.00 18.31 ATOM 2333 N LEU241-5.039 4.096 57.081 1.00 17.44 ATOM 2334 H LEU241-5.702 3.764 56.447 1.00 0.00 - 21~ -SUBSTtTUTE ~t~:~ tRUl_E ;~

CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATOM 2335 CA LEU241-4.023 5.015 56.584 1.00 20.78 ATOM 2336 CB LEU241-3.838 4.814 55.080 1.00 23.79 ATOM 2337 CG LEU241-3.473 3.389 54.637 1.00 29.02 ATOM 2338 CDl LEU241 -3.580 3.258 53.116 1.00 31.10 ATOM 2339CD2 LEU 241 -2.072 3.023 55.123 1.00 29.32 ATOM 2340 C LEU241-4.336 6.479 56.882 1.00 20.10 ATOM 2341 O LEU241-3.430 7.271 57.127 1.00 22.00 ATOM 2342 N LYS242-5.608 6.849 56.829 1.00 19.66 ATOM 2343 H LYS242-6.313 6.208 56.582 1.00 0.00 ATOM 2344 CA LYS 242 -5.g96 8.224 57.114 1.00 19.53 ATOM 2345 CB LYS242-5.892 9.082 55.844 1.00 22.06 ATOM 2346 CG LYS242-6.778 8.639 54.688 1.00 24.44 ATOM 2347 CD LYS242-6.367 9.308 53.386 1.00 24.79 ATOM 2348 CE LYS242-5.120 8.664 52.808 1.00 23.03 ATOM 2349 NZ LYS 242 -4.732 9 280 51 518 1.00 23.85 ATOM 2350 HZl LYS242 -4.553 10.291 51.657 1.00 0.00 ATOM 2351 HZ2 LYS242 -5.490 9 155 50.820 1.00 0.00 ATOM 2352 HZ3 LYS242 -3.864 8.824 51.169 1.00 0.00 ATOM 2353 C LYS242-7.395 8.279 57.716 1.00 16.00 ATOM 2354 O LYS 242 -8.313 7.645 57.218 1.00 15.48 ATOM 2355 N ALA243-7.540 9.047 58.793 1.00 18.41 ATOM 2356 H ALA243-6.733 9.494 59.123 1.00 0.00 ATOM 2357 CA ALA243-8.814 9.192 59.507 1.00 18.23 ATOM 2358 CB ALA243-8.690 10.251 60.597 1.00 15.43 ATOM 2359 C ALA 243 -10.018 9.497 58.620 1.00 18.79 ATOM 2360 O ALA243-11.102 8.965 58.839 1.00 21.98 ATOM 2361 N ASP244-9.834 10.408 57.669 1.00 18.70 ATOM 2362 H ASP244-8.942 10.786 57.579 1.00 0.00 ATOM 2363 CA ASP244-10.888 10.804 56.737 1.00 19.33 ATOM 2364 CB ASP 244 -11.023 9.741 55.633 1.00 19.97 ATOM 2365 CG ASP244-11.885 10.197 54.466 1.00 23.11 ATOM 2366 ODl ASP244 -12.653 9.359 53.958 1.00 27.17 ATOM 2367 OD2 ASP244 -11.802 11.374 54.045 1.00 24.99 ATOM 2368 C ASP244-12.245 11.108 57.402 1.00 19.28 ATOM 2369 O ASP 244 -13 293 10.622 56.969 1.00 19.97 ATOM 2370 N GLY245-12.219 11.934 58.445 1.00 19.45 ATOM 2371 H GLY245-11.383 12.294 58.773 1.00 0.00 ATOM 2372 CA GLY245-13.447 12.295 59.133 1.00 16.82 ATOM 2373 C GLY245-13.591 11.656 60.499 1.00 15.03 SUBST~TUTE S}~E~ ~RULE ~fi) W 0 97/08300 PCTnUS96/13918 ATO~ 2374 OGLY 245 -14.25912.202 61.369 1.00 16.04 ATOM 2375 NLEU 246 -13.00010.482 60.676 1.00 13. Sl ATOM Z376 HLEU 246 -12.51710.063 S9.930 1.00 0.00 ATOM 2377 CALEU 246 -13.0699.791 61.g51 1.00 12.38 ATOM 2378 CBLEU 246 -12.4848.377 61.836 1.00 10.62 ATOM 2379 CGLEU 246 -13.1177.342 60.907 1.00 8.08 ATOM 2380 CDl LEU 246 --12.370 6.037 61.059 1.00 7.46 ATOM 2381 CD2 LEU 246 -14.568 7.138 61.240 1.00 9.01 ATOM 2382 CLEU 246 -12.31110.576 63.019 1.00 12.72 1 0 ATOM 2383 O LEU 246 -11.451 11.411 62.704 1.00 12.81 ATOM 2384 NILE 247 -12.62710.288 64.279 1.00 13.47 ATOM 2385 HILE 247 --13.3299.624 64.457 1.00 0.00 ATOM 2386 CAILE 247 -ll.g9510.947 65.418 1.00 13.85 ATOM 2387 CBILE 247 -12.76210.635 66.734 1.00 15.16 1 5 ATOM 2388CG2 ILE 247 --12.608 9.163 67.118 1.00 12.79 ATOM 2389 CGl ILE 247 -12.268 11.529 67.869 1.00 15.17 ATOM 2390 CDILE 247 -12.63612.970 67.713 1.00 18.15 ATOM 2391 CILE 247 --10.54210.502 65.550 1.00 15.68 ATOM 2392 OILE 247 --9.70911.218 66.100 1.00 15.94 2 0 ATOM 2393 M TYR 248 --10.244 9.320 65.020 1.00 17.12 ATOM 2394 HTYR 248 -10.9338.784 64.573 1.00 0.00 ATOM 2395 CATYR 248 -8.9028.760 65.071 1.00 18.04 ATOM 2396 CBTYR 248 -8.6238.221 66 478 1.00 19.67 ATOM 2397 CGTYR 248 -7.1608.036 66.808 1.00 22.04 2 5 ATOM 2398CDl TYR 248 -6.666 6.795 67.194 1.00 21.97 ATOM 2399 CEl TYR 248 -5.330 6.630 67.539 1.00 24.30 ATOM 2400 CD2 TYR 248 -6.277 9.113 66.770 1.00 25.29 ATOM 2401 CE2 TYR 248 --4,940 8.962 67.113 1.00 26.21 ATOM 2402 CZTYR 248 -4.4717.720 67.498 1.00 26.00 3 0 ATOM 2403OH TYR 248 -3.147 7.572 67.853 1.00 27.81 ATOM 2404 HHTYR 248 -2.6958.422 67.810 1.00 0.00 ATOM 2405 CTYR 248 -8.8267.618 64.053 1.00 18.31 ATOM 2406 OTYR 248 --9.8396.992 63.737 1.00 15.87 ATOM 2407 NCYS 249 -7.6257.363 63.543 1.00 18.92 3 5 ATOM 2408~I CYS 249 -6.862 7.889 63.852 1.00 0.00 ATOM 2409 CACYS 249 --7.4026.305 62.561 1.00 22.24 ATOM 2410 CBCYS 249 -5.9966.413 61.961 1.00 25.63 ATOM 2411 SGCYS 249 --5.7867.673 60.701 1.00 35.34 ATOM 2412 CCYS 249 -7.5544.915 63.162 1.00 21.45 SUE~S I ITUTE ~E~ tRuLE 2~i~

W O 97/08300 PCT~US96/13918 ATOM 2413 O CYS249 -7.292 4.709 64.350 1.00 22.48 ATOM 2414 N L~U250 -7.940 3.963 62.321 1.00 19.48 ATOM 2415 H LEU250 -8.101 4.207 61.383 1.00 0.00 ATOM 2416 CA LEU250 -8.104 2.579 62.735 1.00 18.62 ATOM 2417 CB LEU 250 -8.828 1.801 61.643 1.00 14.55 ATOM 2418 CG L~U250 -10.355 1.767 61.685 1.00 15.19 ATOM 2419 CDl LEU 250 -10.924 2.936 62.474 1.00 15.11 ATOM 2420 CD2 LEU 250 -10.909 1.703 60.275 1.00 10.15 ATOM 2421 C LEU250 -6.717 1.999 62.958 1.00 19.97 ATOM 2422 O LEU 250 -5.874 2.037 62.064 1.00 20.94 ATOM 2423 N LYS251 -6.469 1 496 64.158 1.00 20.78 ATOM 2424 H LYS251 -7.187 1.486 64.818 1.00 0.00 ATOM 2425 CA LYS251 -5.167 0.937 64.479 1.00 22.81 ATOM 2426 CB LYS251 -4.605 1.601 65.737 1.00 22.15 ATOM 2427 CG LYS 251 -4.299 3.082 65.586 i.00 27.38 ATOM 2428 CD LYS251 -3.054 3.298 64.739 1.00 33.83 ATOM 2429 CE LYS251 -2.720 4.776 64.587 1.00 36.07 ATOM 2430 NZ LYS251 -3.778 5.512 63.835 1.00 39.79 ATOM 2431 HZl LYS 251 -4.678 5.441 64.346 1.00 0.00 ATOM 2432HZ2 LYS 251 -3.889 5.099 62.891 1.00 0.00 ATOM 2433 HZ3 LYS 251 -3.501 6.511 63.746 1.00 0.00 ATOM 2434 C LYS251 -5.217 -0.574 64.657 1.00 24.22 ATOM 2435 O LYS251 -5.026 -1.329 63.703 1.00 27.36 ATOM 2436 N GLU252 -5.516 -1.013 65.871 1.00 24.92 ATOM 2437 H GLU 252 -5.766 -0.390 66.588 1.00 0.00 ATOM 2438 CA GLU252 -5.565 -2.430 66.174 1 00 27.42 ATOM 2439 CB GLU252 -5.012 -2.671 67.577 1.00 32.86 ATOM 2440 CG GLU252 -3.569 -2.212 67.765 1.00 43.35 ATOM 2441 CD GLU252 -3.268 -1.746 69.186 1.00 49.35 ATOM 2442OEl GLU 252 -3.435 -2.543 70.137 1.00 51.97 ATOM 2443 OE2 GLU 252 -2.858 -0.575 69.348 1.00 50.94 ATOM 2444 C GLU 252 -6.978 -2.977 66.071 1.00 26.08 ATOM 2445 O GLU 252 -7.929 -2.360 66.550 1.00 25.56 ATOM 2446 N ALA 253 -7.108 -4.132 65.432 1.00 24.39 ATOM 2447H ALA 253 -6.318 -4.560 65.066 1.00 0.00 ATOM 2448 CA ALA 253 -8.395 -4.786 65.278 1.00 25.57 ATOM 2449 CB ALA253 -8.343 -5.756 64.123 1.00 24.04 ATOM 2450 C ALA253 -8.747 -5.537 66.555 1.00 27.38 ATOM 2451 O ALA253 -7.876 -6.121 67.194 1.00 27.58 -: - 213 -SUBSl ITUTE S~E~ (RULE ~

W O 97/08300 PCT~US96113918 ATOM 2452 NCYS 254 -10.014-5.479 66.949 1. C0 31.53 ATOM 2453 HCYS 254 -10.650--4.969 66.417 1.00 0.00 ATOM 2454 CACYS254 -10.492-6.198 68.125 1.00 32.99 ATOM 2455 CBCYS254 --11.780-5.561 68.652 1.00 33.76 ATOM 2456 SGCYS2S4 -12.375-6.219 70.229 1.00 27.18 ATOM 2457 CCYS 254 --10.767-7.569 67.511 1.00 36.46 ATOM 2458 OCYS 254 -11.755-7.746 66.799 1.00 36.39 ATOM 2459 NPRO 255 --9.875-8.542 67.759 1.00 41.03 ATOM 2460 CDPRO255 --8.830-8.385 68.790 1.00 42.01 1 0 ATOM 2461 CAPRO255 --9.899-9.928 67.273 1.00 44.44 ATOM 2462 CBPRO255 -8.601-10.493 67.840 1.00 45.11 ATOM 2463 CGPRO255 --8.523--9.817 69.164 1.00 43.82 ATOM 2464 CPRO 255 -11.081--10.826 67.628 1.00 46.86 ATOM 2465 OPRO 255 -12.133-10.365 68.071 1 00 47.30 1 5 ATOM 2466 NASN 256 -10.888-12.119 67.377 1.00 51.27 ATOM 2467 HASN 256 -10.045-12.478 67.027 1.00 0.00 ATOM 2468 CAASN256 -11.871-13.161 67.655 1.00 53.98 ATOM 2469 CBASN256 -12.685-13.504 66.400 1.00 54.04 ATOM 2470 CGASN256 -13.596--12.375 65.964 1.00 53.84 ATOM 2471 ODl ASN 256 -14.807 -12.413 66.187 1.00 53.28 ATOM 2472 ND2 ASN 256 -13.021 -11.366 65.336 1.00 52.61 ATOM 2473 HD21 ASN 256 -12.055 --11.405 65.202 1.00 0.00 ATOM 2474 HD22 ASN 256 -13.555 -10.623 65.004 1.00 0.00 ATOM 2475 CASN 256 -11.085-14.393 68.105 1.00 55.88 ATOM 2476 OASN 256 -11.316-14.859 69.241 1.00 56.61 ATOM 2477 OTASN256 -10.212-14.846 67.326 1.00 57.33 ATOM 2478 CGLY 301 -28.5996.538 66.632 1.00 34.96 ATOM 2479 OGLY 301 --28.6897.658 66.126 1.00 35.59 ATOM 2480 HTlGLY301 -29.7556.289 64.304 1.00 0.00 ATOM 2481 HT2GLY301 -30,9096.664 65.460 1.00 0.00 ATOM 2482 NGLY 301 -30.3635.888 65.043 1.00 38.32 ATOM 2483 HT3GLY301 -30.9415.100 64.692 1.00 0.00 ATOM 2484 CAGLY 301 -29.4705.406 66.131 1.00 35.83 ATOM 2485 NLEU 302 -27.7606.248 67.620 1.00 32.78 ATOM 2486 HLEU 302 --27.7415.327 67.985 1.00 0.00 ATOM 2487 CALEU 302 -26.8617.240 68.203 1.00 28.83 ATOM 2488 CBLEU 302 -26.8407.061 69.721 1.00 30.89 ATOM 2489 CGLEU 302 -26.7268.304 70.601 1.00 35.75 ATOM 2490 CDlLEU302 -27.0937.919 72.026 1.00 34.77 SUBSTtTUTE ~}~EE~ ~RULE 2~i~

CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATOM 2491 CD2 LEU302 -25.328 8.914 70.520 1.00 36.69 ATOM 2492 C LEU 302-25.465 7.028 67.613 1.00 24.31 ATOM 2493 O LEU 302-24.620 6.352 68.205 1.00 22.95 ATOM 2494 N PTY 303-25.236 7.580 66.427 1.00 20.12 5 ATOM 2495 H PTY 303-25.916 8.143 65.984 1.00 0.00 ATOM 2496 CA PTY 303-23.952 7.422 65.758 1.00 17.44 ATOM 2497 CB PTY 303-24.137 6.739 64.399 1.00 15.28 ATOM 2498 CG PTY 303-24.685 5.341 64.531 1.00 11.57 ATOM 2499 CDl PTY303 -23.836 4.247 64.6S2 1.00 14.15 ATOM 2500 CEl PTY 303 -24.342 2.959 64.848 1.00 14.74 ATOM 2501 CD2 PTY303 -26.053 S.121 64.602 1.00 14.21 ATOM 2S02 CE2 PTY303 -26.570 3.847 64.796 1.00 14.14 ATOM 2S03 CZ PTY 303 -2S.714 2.772 64.918 1.00 15.16 ATOM 2504 OH PTY 303 -26.257 1.519 65.078 1.00 16.76 5 ATOM 2505 ORl PTY303 -27.377 1.226 67.142 1.00 15.99 ATOM 2S06 OR2 PTY303 -24.983 1.051 67.202 1.00 lS.90 ATOM 2S07 OR3 PTY303 -26.327 -0.668 66.144 1.00 16.79 ATOM 2508 PR PTY 303-26.181 0.776 66.437 1.00 13.90 ATOM 2S09 C PTY 303-23.217 8.735 6S.605 1.00 16.36 ATOM 2S10 O PTY 303 -23.831 9.79S 65.484 1.00 19.96 ATOM 2511 N ASN 304-21.895 8.660 65.620 1.00 15.34 ATOM 2512 H ASN 304-21.498 7.781 65.684 1.00 0.00 ATOM 2513 CA ASN 304-21.062 9.841 65.492 1.00 17.74 ATOM 2514 CB ASN 304-19 676 9.S69 66.078 1 00 17.48 2~ ATOM 2515 CGASN 304 -19.731 9.186 67.544 1.00 21 95 ATOM 2516 ODl ASN304 -19.541 10.024 68.421 1.00 25.74 ATOM 2517 ND2 ASN304 -20.008 7.918 67.818 1.00 20.37 ATOM 2518 HD21 ASN 304-20.117 7.310 67.059 1.00 0.00 ATOM 2519 HD22 ASN 304-20.130 7.655 68.755 1.00 0.00 ATOM 2520 C ASN 304 -20.959 10.277 64.033 1.00 18.33 ATOM 2521 O ASN 304-20.992 9.450 63.118 1.00 19.64 ATOM 2522 N GLU 305-20.917 11.583 63.814 1.00 19.12 ATOM 2523 H GLU 305-20.936 12.208 64.568 1.00 0.00 ATOM 2524 CA GLU 305-20.802 12.114 62.463 1 00 22.88 3~ ATOM 2525 CBGLU 305 -21.555 13.441 62.336 1.00 28.84 ATOM 2526 CG GLU 305-23.071 13.318 62.315 1.00 37.99 ATOM 2527 CD GLU 305-23.767 14.669 62.216 1.00 43.48 ATOM 2528 OEl GLU305 -24.877 14.800 62.775 1.00 46.82 ATOM 2529 OE2 GLU30S -23.214 15.597 61.S80 1.00 45.74 , .

SlJBSTiTUTE ~tE~ (R~JLE 2~) CA 02226963 l998-02-l2 W 0 97/08300 PCTnUS96/l3918 ATOM 2530 C GLU 305 -19.329 12.339 62 158 1.00 21.37 ATOM 2531 O GLU 305 -18.504 12.412 63.068 l.Q0 21.67 ATOM 2532 N LEU 306 -19.002 12.437 60.878 1.00 19.52 ATOM 2533 H LEU 306 -19.698 12.382 60.192 1.00 0.00 5 ATOM 2534 CA LEU 306 -17.628 12.667 60.469 1.00 17.30 ATOM 2535 CB LEU 306 -17.451 12.319 58.992 1.00 16.06 ATOM 2536 CG LEU 306 -17.537 10.838 58.627 1.00 12.83 ATOM 2537 CDl LEU 306 -17.235 10.669 57.151 1.00 16.69 ATOM 2538 CD2 LEU 306 -16.555 10.040 59.462 1.00 10.12 0 ATOM 2539 C LEU 306 -17.251 14.119 60.706 1.00 17.36 ATOM 2540 O LEU 306 -18.070 15.014 60.519 1.00 17.26 ATOM 2541 N GLN 307 -16.019 14.341 61.147 1.00 18.44 ATOM 2542 H GLN 307 -15.442 13.576 61.304 1.00 0.00 ATOM 2543 CA GLN 307 -15.509 15.685 61.396 1.00 23.01 ATOM 2544 CB GLN 307 -14.187 15.618 62.167 1.00 25.06 ATOM 2545 CG GLN 307 -14.138 14.590 63.278 1.00 29.12 ATOM 2546 CD GLN 307 -14.549 15.148 64.618 1.00 30.60 ATOM 2547 OEl GLN 307 -15.721 15.453 64.849 1.00 34.83 ATOM 2548 NE2 GLN 307 -13.583 15.285 65.517 1.00 31.12 ATOM 2549 HE21 GLN 307 -12.680 15.007 65.262 1.00 0.00 ATOM 2550 HE22 GLN 307 -13.830 15.662 66.384 1.00 0.00 ATOM 2551 C GLN 307 -15.219 16.248 60.017 1.00 24.16 ATOM 2552 O GLN 307 -14.087 16.149 59.546 1.00 20.19 ATOM 2553 N LYS 308 -16.245 16.781 59.354 1.00 30.35 ATOM 2554 H LYS 308 -17.125 16.772 59.791 1.00 0.00 ATOM 2555 CA LYS 308 -16.110 17.348 58.004 1.00 33.42 ATOM 2556 CB LYS 308 -17.486 17.666 57.388 1.00 34.90 ATOM 2557 CG LYS 308 -18.534 16.560 57.453 1.00 35.45 ATOM 2558 CD LYS 308 -19.567 16.860 58.532 1.00 36.09 ATOM 2559 CE LYS 308 -20.215 18.229 58.316 1.00 37.61 ATOM 2560 NZ LYS 308 -21.196 18.594 59.391 1.00 37.36 ATOM 2561 HZl LYS 308 -20.711 18.602 60.310 ~.00 0.00 ATOM 2562 HZ2 LYS 308 -21.961 17.891 59.403 1.00 0.00 ATOM 2563 HZ3 LYS 308 -21.589 19.535 59.193 1 00 0.00 ATOM 256g C LYS 308 -15.296 18.632 58.059 1.00 34.50 ATOM 2565 O LYS 308 -15.720 19.675 57.561 1.00 36.22 ATOM 2566 N ASP 309 -14.110 18.542 58.637 1.00 34.96 ATOM 2567 H ASP 309 -13.714 17.697 58.867 1.00 0.00 ATOM 2568 CA ASP 309 -13.247 19.684 58.786 1.00 40.11 SIJBSTITUTE ~i~FE~ ~RUI E 2li~

CA 02226963 l998-02-l2 W O 97/08300 PCTrUs96/l39l8 ATOM 2569 CB ASP 309 -13.833 20.653 59.825 1.00 43.76 ATOM 2570 CG ASP 309 -12.937 21.857 60.076 1.00 49.11 ATOM 2571 ODl ASP 309 -12.285 21.902 61.147 1.00 50.11 ATOM 2572 oD2 ASP 309 -12.878 22.752 59.198 1.00 53.22 ATOM 2573 CASP 309 -11.919 19.147 59.266 1.00 41.03 ATOM 2574 OASP 309 -11.021 18.889 58.468 1.00 42.47 ATOM 2575 NLYS 310 -11.848 18.882 60.565 1.00 42.27 ATOM 2576 HLYS 310 -12.637 19.008 61.117 1.00 0.00 ATOM 2577 CALYS 310 -10.634 18.385 61.192 1.00 43.52 ATOM 2578 CBLYS 310 -10.941 17.848 62.595 1.00 42.96 ATOM 2579 CGLYS 310 -11.586 18.868 63.525 1.00 42.02 ATOM 2580 CDLYS 310 -11.779 18.312 64.933 1.00 41.98 ATOM 2581 CELYS 310 -10.445 18.138 65.654 1.00 41.82 ATOM 2582 MZLYS 310 -10.613 17.544 67.012 1.00 40.90 ATOM 2583 HZl LYS 310 -11.030 16.595 66.920 1.00 0.00 ATOM 2584 HZ2 LYS 310 -11.238 18.146 67.589 1.00 0.00 ATOM 2585 HZ3 LYS 310 -9.684 17.470 67.471 1.00 0.00 ATOM 2586 C LYS 310 -9.895 17.331 60.372 1.00 43.43 ATOM 2587 O LYS 310 -8.664 17.323 60.353 1.00 46.61 ATOM 2588 N ARG 311 -10.629 16.461 59.680 1.00 42.01 ATOM 2589 H ARG 311 -11.604 16.507 59.665 1.00 0.00 ATOM 2590 CA ARG 311 -9.982 15.415 58.891 1.00 42.72 ATOM 2591 CB ARG 311 -10.023 14.081 59.644 1.00 44.23 ATOM 2592 CG ARG 311 -10.718 14.119 61.003 1.00 45.03 ATOM 2593 CD ARG 311 -9.748 14.485 62.100 1 00 45.93 ATOM 2594 NE ARG 311 -10.418 14.685 63.378 1.00 48.24 ATOM 2595 HE ARG 311 -11.373 14.913 63.367 1.00 0.00 ATOM 2596 CZ ARG 311 -9.818 14.577 64.561 1.00 51.76 ATOM 2597 NHl ARG 311 -8.530 14.264 64.635 1.00 54.63 ATOM 2598 HHll ARG 311 -7.990 14.102 63.808 1.00 0.00 ATOM 2599 HH12 ARG 311 -8.100 14.179 65.535 1.00 0.00 ATOM 2600 NH2 ARG 311 -10.503 14.798 65.675 1.00 53.00 ATOM 2601 HH21 ARG 311 -11.469 15.04i 65.619 1.00 0.00 ATOM 2602 HH22 ARG 311 -10.059 14.715 66.567 1.00 0.00 ATOM 2603 C ARG 311 -10.555 15.212 57.491 1.00 42.09 ATOM 2604 O ARG 311 -11.725 14.856 57.346 1.00 40.29 ATOM 2605 N ALA 312 -9.714 15.389 56.469 1.00 44.22 ATOM 2606 H ALA 312 -8.797 15.704 56.637 1.00 0.00 ATOM 2607 CA ALA 312 -10.130 15.204 55.077 1.00 45.11 SUBS 111 UTE S~E}~ ~RULE 2~i) CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATOM 2608 CB ALA 312 -11.440 15.947 54.818 1.00 46.77 ATOM 2609 C ALA 312 -9.086 15.616 54.024 1.00 47.98 ATOM 2610 O ALA 312 -8.221 16.462 54.283 1.00 50.03 ATOM 2611 N GLU 313 -9.168 14.980 52.852 1.00 45.77 ATOM 2612 H GLU 313 -9.890 14.332 52.717 1.00 0.00 ATOM 2613CA GLU 313 -8.306 15.252 51.693 1.00 43.28 ATOM 2614CB GLU 313 -7.513 14.005 51.283 1.00 46.48 ATOM 2615 CG GLU 313 -6.297 13.659 52.143 1.00 46.91 ATOM 2616 CD GLU 313 -5.519 12.454 51.605 1.00 46.04 1 0 ATOM 2617OEl GLU 313 -6.023 11.761 50.692 1.00 44.53 ATOM 2618 OE2 GLU313 -4.397 12.198 52.097 1.00 45.88 ATOM 2619 C GLU 313 -9.314 15.575 50.583 1.00 42.06 ATOM 2620 O GLU 313 -10.513 15.680 50.869 1.00 45.47 ATOM 2621 N ALA 314 -8.870 15.668 49.329 1.00 31.51 15 ATOM 2622 H ALA 314 -7.925 15.544 49.104 1.00 0.00 ATOM 2623 CAALA 314 -9.801 15.967 48.239 1.00 27.16 ATOM 2624 CBALA 314 -10.156 17.447 48.238 1.00 25.68 ATOM 2625 C ALA 314 -9.311 15.545 46.858 1.00 24.26 ATOM 2626 O ALA 314 -8.204 15.896 46.447 1.00 26.34 20 ATOM 2627 N PTY 315 -10.127 14.766 46.158 1.00 18.14 ATOM 2628 H PTY 315 -11.001 14.528 46.522 1.00 0.00 ATOM 2629 CAPTY 315 -9.787 14.306 44.814 1.00 17.87 ATOM 2630 CBPTY 315 -10.410 12.934 44.531 1.00 16.23 ATOM 2631 CGPTY 315 -9.653 11.782 45.147 1.00 13.44 25 ATOM 2632 CDl PTY315 -8.546 11.233 44.504 1.00 10.57 ATOM 2633 CEl PTY315 -7.821 10.199 ~5.083 --1.00 12.~6 ATOM 2634 CD2 PTY315 -10.024 11.261 46.388 1.00 14.63 ATOM 2635 CE2 PTY315 -9.308 10.226 46.977 1.00 12.19 ATOM 2636 CZ PTY 315 -8.207 9.702 46.319 1.00 14.21 30 ATOM 2637 OH PTY 315 -7.508 8.671 46.896 1.00 10.17 ATOM 2638 ORl PTY315 -6.491 9.535 48.913 1.00 12.42 ATOM 2639 OR2 PTY315 -5.416 9.978 46.850 1.00 12.44 ATOM 2640 OR3 PTY315 -5.389 7.728 47.750 1.00 8.98 ATOM 2641 PRPTY 315 -6.156 8.991 47.608 1.00 11.81 ~
35 ATOM 2642 C PTY 315 -10.273 15.318 43 781 1.00 18.42 ATOM 2643 o PTY 315 -11.328 15.928 43.950 1.00 18.97 ATOM 2644 N SER 316 -9.500 15.502 42.718 1.00 18.72 ATOM 2645 ~ SER 316 -8.700 14.957 42.602 1.00 0.00 ATOM 2646 CASER 316 -9.871 16.443 41.676 1.00 17.28 SU85Ti~UTE ~{EE~ ~RIJLE ;2f;~

W O 97/08300 PCT~US96/13918 ATOM 2647 CB SER316-8.642 16.849 40.874 1.00 16.40 ATOM 2648 OG SER316-7.653 17.434 41.705 1.00 23.25 ATOM 2649 HG SER316-7.610 16.969 42.563 1.00 0.00 ATOM 2650 C SER316-10.895 15.799 40.762 1.00 17.80 5 ATOM 2651 O SER316-11.065 14.581 40.763 1.00 18.76 ATOM 2652 N GLU317-11.578 16.619 39.978 1.00 21.98 ATOM 2653 H GLU317-11.430 17.585 39.995 1.00 0.00 ATOM 2654 CA GLU317-12.577 16.113 39.048 1.00 26.81 ATOM 2655 CB GLU317-13.956 16.070 39.718 1.00 28.26 ATOM 2656 CG GLU 317 -14.954 15.164 39.010 1.00 34.96 ATOM 2657 CD GLU317-16.232 14.947 39.803 1.00 40.11 ATOM 2658 OEl GLU317 -17.320 14.948 39.180 1.00 42.24 ATOM 2659 OE2 GLU317 -16.153 14.763 41.041 1.00 42.30 ATOM 2660 C GLU317-12.594 17.020 37.826 1.00 27.50 ATOM 2661 O GLU 317 -12.160 18.170 37.908 1 00 28.44 ATOM 2662 N ILE318-12.985 16.479 36.676 1 00 30.01 ATOM 2663 H ILE318-13.247 15.532 36.647 1.00 0.00 ATOM 2664 CA ILE318-13.052 17.287 35.463 1 00 32.57 ATOM 2665 CB ILE318-12.991 16.428 34.176 1.00 31.13 ATOM 2666CG2 ILE 318 -13.313 17.282 32.955 1.00 30.52 ATOM 2667 CGl ILE318 -11.598 15.824 34.009 1.00 29.07 ATOM 2668 CD ILE318-11.436 15.012 32.736 1.00 29.47 ATOM 2669 C ILE318-14.368 18.051 35.510 1.00 36.48 ATOM 2670 O ILE318-15.438 17.474 35.299 1.00 37.22 2~ ATOM 2671 N GLY 319 -14.281 19.335 35.841 1.00 40.36 ATOM 2672 H GLY319-13.427 19.760 36.061 1.00 0.00 ATOM 2673 CA GLY319-15.461 20.174 35.922 1.00 45.03 ATOM 2674 C GLY319-15.094 21.595 36.305 1.00 47.82 ATOM 2675 O GLY319-14.951 22.445 35.395 1 00 50 47 ATOM 2676 OT GLY 319 -14.941 21.860 37.516 1.00 49.68 ATOM 2677 OH2 H20501 -16.699 6.688 54.302 1 00 10.61 ATOM 2678 Hl H20501 -16.511 6.418 53.393 1.00 0.00 ATOM 2679 H2 H20501 -16.240 7.548 54.364 1.00 0.00 ATOM 2680 OH2 H20502 -7.254 -1.610 48.935 1.00 17.08 ATOM 2681Hl H20 502 -6.444 -2.072 49.204 1.00 0.00 ATOM 2682 H2 H20502 -7.404 -0.987 49.670 1.00 0.00 ATOM 2683 OH2 H20503 -8.059 0.563 50.782 1.00 14.29 ATOM 2684 Hl H20503 -8.518 0.793 49.971 1.00 0.00 ATOM 2685 H2 H20503 -8.748 0.792 51.423 1.00 0.00 SUBSTITUTE ~HE~ (RULE 2~) CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATON 2686 oH2 H20504 -6.332 5.449 46.114 1.00 17.64 ATOM 2687 Hl H20504 -5,403 5.611 45.858 1.00 0.00 ATOM 2688 H2 H20504 -6.621 6.329 46.396 1.00 0.00 ATOM 2689 OH2 H20505 -15.290 -6.823 51.705 1.00 5.22 ATOM 2690Hl H20 505 -15.750 -6.668 50.860 1.00 0.00 ATOM 2691 H2 H20 505 -14.376 -6.905 51.376 1.00 0.00 ATOM 2692 OH2 H20506 -7.617 -1.501 46.161 1.00 17.32 ATOM 2693 Hl H20 506 -7.518 -1.538 47.137 1.00 0.00 ATOM 2694 H2 H20 506 -6.696 -1.494 45.885 1.00 0.00 ATOM 2695OH2 H20 507 -3.651 7.250 49.955 1.00 15.71 ATOM 2696 Hl H20 507 -4.520 7.609 50.184 1.00 0.00 ATOM 2697 H2 H20 507 -3.891 6.758 49.154 1.00 0.00 ATOM 269B OH2 H20508 -19.945 3.732 76.340 1.00 29.44 ATOM 2699 Hl H20 508 -20.832 3.744 75.964 1.00 0.00 ATOM 2700H2 H20 508 -19.954 4.642 76.685 1.00 0.00 ATOM 2701 OH2 H20509 10.902 10.846 41.751 1.00 27.04 ATOM 2702 Hl H20 509 10.681 10.574 40.852 1.00 0.00 ATOM 2703 H2 H20 509 10.412 11.675 41.818 1.00 0.00 ATOM 2704 OH2 H20510 -18.163 -5.347 50.709 1.00 9.29 ATOM 2705Hl H20 510 -18.386 -6.283 50.714 1.00 0.00 ATOM 2706 H2 H20 510 -19.045 -4.964 50.769 1.00 0.00 ATOM 2707 OH2 H20511 -3.361 4.879 45.414 1.00 16.59 ATOM 2708 Hl H20 511 -3.647 4.007 45.146 1.00 0.00 ATOM 2709 H2 H20 511 -2.506 4.681 45.802 1.00 0.00 ATOM 2710OH2 H20 512 -15.018 8.551 55.143 1.00 25.00 ATOM 2711 Hl H20 512 -14.918 7.843 55.793 1.00 0.00 ATOM 2712 H2 H20 512 -14.547 9.270 55.600 1.00 0.00 ATOM 2713 oH2 H20513 -4.825 -3.898 46.077 1.00 26.22 ATOM 2714 Hl H20 513 -4.880 -3.377 46.901 1.00 0.00 ATOM 2715H2 H20 513 -4.485 -3.251 45.428 1.00 0.00 ATOM 2716 OH2 H20514 -22.319 7.998 61.532 1.00 14.50 ATOM 2717 Hl H20 514 -21.517 8.530 61.422 1.00 0.00 ATOM 2718 H2 H20 514 -22.478 8.172 62.465 1.00 0.00 ATOM 2719 OH2 H20515 -10.803 5.341 41.005 1.00 25.05 ATOM 2720Hl H20 515 -10.171 5.135 40.303 1.00 0.00 ATOM 2721 H2 H20 515 -10.270 5.263 41.804 1.00 0.00 ATOM 2722 OH2 H20516 0.902 5.902 27.902 1.00 36.64 ATOM 2723 Hl H20 516 0.214 6.451 28.280 1.00 0.00 ATOM 2724 H2 H20 516 1.440 6.522 27.390 1.00 0.00 SU~STITUTE SHFE~ ~RULE 2~i~

CA 02226963 l998-02-l2 W O 97/08300 PC~US96/13918 ATOM 2725 OH2 H20517 -4.715 -2.823 48.594 1.00 17.95 ATOM 2726 Hl H20517 -4.476 -1.913 48.357 1.00 0.00 ATOM 2727 H2 H20517 -3.g33 -3.025 49.141 1.00 0.00 ATOM 2728 OH2 H20518 -24.803 12.426 65.782 1.00 40.32 5 ATOM 2729 Hl H20518 -25.338 11.990 66.447 1.00 0.00 ATOM 2730 H2 H20518 -24.368 11.668 65.372 1.00 0.00 ATOM 2731 OH2 H20519 -7.490 -3.895 44.639 1.00 17.54 ATOM 2732 Hl H20519 -7.799 -3.087 45.072 1.00 0.00 ATOM 2733 H2 H20519 -6.561 -3.711 44.492 1.00 0.00 ATOM 2734OH2 H20 520 -12.970 1.075 39.173 1.00 19.76 ATOM 2735 Hl H20520 -12.945 0.105 39.195 1.00 0.00 ATOM 2736 H2 H20520 -12.514 1.300 39.992 1.00 0.00 ATOM 2737 OH2 H20521 -11.261 10.026 31.185 1 00 20.36 ATOM 2738 Hl H20521 -11.026 10.800 30.672 1.00 0 00 ATOM 2739H2 H20 521 -11.878 9.547 30.622 1.00 0.00 ATOM 2740 OH2 H20522 -16.253 9.623 47.575 1.00 22.54 ATOM 2741 Hl H20522 -16.330 10.315 46.911 1.00 0.00 ATOM 2742 H2 H20522 -16.945 9.935 48.191 1.00 0.00 ATOM 2743 OH2 H20 523 -13.184 -18.559 49.110 1.00 32.97 ATOM 2744 Hl H20 523 -13.959 -18.613 48.542 1.00 0.00 ATOM 2745 H2 H20 523 -12.455 -18.533 48.480 1.00 0.00 ATOM 2746 OH2 H20524 6.370 1.830 43.428 1.00 20.14 ATOM 2747 Hl H20524 5.423 1.688 43.475 1.00 0.00 ATOM 2748 H2 H20524 6.738 0.978 43.159 1.00 0.00 ATOM 2749OH2 H20 525 -8.942 6.660 44.772 1.00 32.99 ATOM 2750 Hl H20525 -8.594 7.220 44.081 1.00 0.00 ATOM 2751 H2 H20525 -8.778 7.191 45.563 1.00 0.00 ATOM 2752 OH2 H20526 -15.180 4.706 44.777 1.00 35.71 ATOM 2753 Hl H20526 -15.373 4.421 45.677 1.00 0.00 ATOM 2754H2 H20 526 -14.575 5.433 44.939 1.00 0.00 ATOM 2755 OH2 H20527 4.557 22.831 38.913 1.00 25.19 ATOM 2756 Hl H20527 4.963 22.258 38.254 1.00 0.00 ATOM 2757 H2 H20527 5.249 22.752 39.588 1.00 0.00 ATOM 2758 OH2 H20 528 0.327 -18.441 40.849 1 00 63.62 ATOM 2759 Hl H20 528 0.588 -18.051 40.013 1.00 0.00 ATOM 2760 H2 H20 528 -0.242 -17.781 41.246 1.00 0.00 ATOM 2761 OH2 H20 529 6.903 14.794 51.066 1.00 29.24 ATOM 2762 Hl H20 529 7.219 15.307 50.322 1.00 0.00 ATOM 2763 H2 H20 529 5.950 14.776 50.943 1.00 0.00 - 22i -SUBSTITUTE SHE~ (RULE 26) CA 02226963 l998-02-l2 W 0 97/08300 PCT~US96/13918 ATOM 2764 OH2 H20530 -7.974 -1.103 42.817 1.00 34.83 ATOM 2765 Hl H20 530 -7 354 -0.435 43.127 1.00 0.00 ATOM 2766 H2 H20 530 -8.438 -1.272 43.650 1.00 0.00 ATOM 2767 OH2 H20531 -21.992 6.566 69.376 1.00 33.58 5 ATOM 2768 Hl H20 531 -22.876 6.479 68.981 1.00 O.QO
ATOM 2769 H2 H20 531 -22.202 7.118 70.144 1.00 0.00 ATOM 2770 OH2 H20532 -0.211 -0.329 27.193 1.00 35.34 ATOM 2771 Hl H20 532 -1.107 -0.247 27.545 1 00 0.00 ATOM 2772 H2 H20 532 -0.184 0.393 26.558 1.00 0.00 ATOM 2773OH2 H20 533 -14.231 14.927 55.731 1.00 22.94 ATOM 2774 Hl H20 533 -14.283 14.056 55.341 1.00 0.00 ATOM 2775 H2 H20 533 -13.463 14.883 56.317 1.00 0.00 ATOM 2776 OH2 H20535 -24.946 -4.413 65.364 1.00 21.19 ATOM 2777 Hl H20 535 -24.728 -4.688 64.466 1.00 0.00 ATOM 2778H2 H20 535 -24.390 -5.033 65.854 1.00 0.00 ATOM 2779 OH2 H20536 -25.179 -8.028 64.357 1.00 22.68 ATOM 2780 Hl H20 536 -25.799 -8.497 63.785 1.00 0.00 ATOM 2781 H2 H20 536 -24.887 -7.298 63.794 1.00 0.00 ATOM 2782 OH2 H20537 -1.848 9.665 51.881 1.00 19.01 ATOM 2783Hl H20 537 -2.268 8.825 51.657 1.00 0.00 ATOM 2784 H2 H20 537 -2.023 9.739 52.829 1.00 0.00 ATOM 2785 OH2 H20 538 -20.606 -24.004 46.721 1.00 48.06 ATOM 2786 Hl H20 538 -19.935 -24.681 46.905 1.00 0.00 ATOM 2787 H2 H20 538 -21.387 -24.399 47.126 1.00 0.00 ATOM 2788OH2 H20 539 -6.036 -10.488 42.753 1 00 24.63 ATOM 2789 Hl H20 539 -6.570 -11.253 42.552 1 00 0.00 ATOM 2790 H2 H20 539 -5.637 -10.712 43.597 1.00 0.00 ATOM 2791 OH2 H20540 -20.360 12.924 50.060 1.00 44.45 ATOM 2792 Hl H20 540 -20.542 13.863 50.173 1 00 0.00 ATOM 2793H2 H20 540 -20.438 12.583 50.953 1.00 0.00 ATOM 2794 OH2 H20541 -5.385 -8.053 62.249 1.00 38.68 ATOM 2795 Hl H20 541 -5.543 -7.543 63.043 ~.00 0.00 ATOM 2796 H2 H20 541 -5.697 -7.436 61.567 1.00 0.00 ATOM 2797 oH2 H20542 -0.772 18.789 49.390 1.00 42.13 ATOM 2798Hl H20 542 -1.284 18.533 50.147 1.00 0.00 ATOM 2799 H2 H20 542 -1.010 18.089 48.776 1.00 0.00 ATOM 2800 OH2 H20543 5.290 26.308 37.785 1.00 44.00 ATOM 2801 Hl H20 543 5.875 26.038 38.496 1.00 0.00 ATOM 2802 H2 H20 543 5.853 26.326 37.011 1.00 0.00 SUB5TITUTE ~F~ ~RULE 26~

CA 02226963 l998-02-l2 ATOM 2803 OH2 H20 544 -13.634 -13.651 50.337 1.00 32.32 ATOM 2804 Hl H20 544 -13.622 -14.594 50.588 1.00 0.00 ATOM 2805 H2 H20 544 -14.365 -13.576 49.736 1.00 0.00 ATOM 2806 OH2 H20545 6.675 4.419 46.648 1.00 30.02 ATOM 2807Hl H20 545 7.290 4.690 47.341 1.00 0.00 ATOM 2808 H2 H20 545 6.944 3.519 46.428 1.00 0.00 ATOM 2809 OH2 H20546 -19.308 6.081 75.052 1.00 51.03 ATOM 2810 Hl H20 546 -19.538 6.138 74.117 1.00 0.00 ATOM 2811 H2 H20 546 -18.372 5.871 75.036 1.00 0.00 0 ATOM 2812OH2 H20 547 -0.121 9.589 22.739 1.00 39.87 ATOM 2813 Hl H20 547 0.690 10.066 22.559 1.00 0.00 ATOM 2814 H2 H20 547 -0.740 10.279 23.010 1.00 0.00 ATOM 2815 OH2 H20549 -21.186 -9.641 52.393 1.00 33.61 ATOM 2816 Hl H20 549 -21.706 -9.261 51.676 1.00 0.00 ATOM 2817 H2 H20 549 -20.925 -10.499 52.022 1.00 0.00 ATOM 2818 OH2 H20550 -19.368 -9.513 74.224 1.00 42.38 ATOM 2819 Hl H20 550 -19.314 -8.555 74.189 1.00 0.00 ATOM 2820 H2 H20 550 -18.853 -9.794 73.467 1.00 0.00 ATOM 2821 OH2 H20551 -29.465 1.964 65.682 1.00 30.82 ATOM 2822Hl H20 551 -28.568 1.698 65.445 1.00 0.00 ATOM 2823 H2 H20 551 -29.959 1.156 65.517 1.00 0.00 ATOM 2824 OH2 H20 552 -11.132 -14.092 61.004 1.00 44.69 ATOM 2825 Hl H20 552 -11.162 -13.825 60.080 1.00 0.00 ATOM 2826 H2 H20 552 -10 792 -14.983 60.930 1.00 0.00 ATOM 2827OH2 H20 553 15.549 7.780 43.275 1.00 41.22 ATOM 2828 Hl H20 553 16.001 7.569 42.453 1.00 0 00 ATOM 2829 H2 H20 553 15.451 8.759 43.198 1.00 0.00 ATOM 2830 OH2 H20554 -6.955 -6.005 57.945 1.00 42.99 ATOM 2831 Hl H20 554 -6.261 -6.655 58.193 1.00 0.00 ATOM 2832H2 H20 554 - -6.769 -5.912 57.007 1.00 0.00 ATOM 2833 OH2 H20555 -26.977 -3.406 67.817 1.00 32.14 ATOM 2834 Hl H20 555 -26.901 -2.533 67.411 1.00 0.00 ATOM 2835 H2 H20 SSS -26.567 -3.960 67.122 1.00 0.00 ATOM 2836 OH2 H20556 -28.411 -2.810 64.708 1.00 30.05 ATOM 2837Hl H20 556 -28.703 -3.042 65.597 1.00 0.00 ATOM 2838 H2 H20 556 -27.572 -2.359 64.889 1.00 0.00 ATOM 2839 OH2 H20557 -3.769 0.192 55.470 1.00 36.92 ATOM 2840 Hl H20 557 -3.997 0.505 54.588 1.00 0.00 ATOM 2841 H2 H20 557 -4.594 0.325 55.939 1.00 0.00 SUE~STITUTE S}~E~ ~RULE 26) CA 02226963 l998-02-l2 ATOM 2842 OH2 H20558 -18.369 11.227 49.122 1.00 40.83 ATOM 28g3 Hl H20 558 -19.062 11.911 49.168 1.00 0.00 ATOM 2844 H2 H20 558 -18.590 10.704 49.898 1 00 0.00 ATOM 2845 OH2 H20559 -5.557 1.430 51.259 1.00 37.40 ATOM 2846Hl H20 559 -6.379 0.902 51.227 1.00 0.00 r ATOM 2847 H2 H20 559 -5.811 2.195 50.750 1.00 0.00 ATOM 2848 OH2 H20560 -1.244 -1.789 50.252 1.00 42.03 ATOM 2849 Hl H20 560 -1.114 -2.419 49.540 1.00 0.00 ATOM 2850 H2 H20 560 -0.486 -1.214 50.163 1.00 0.00 ATOM 2851 OH2 H20 561 -13.464 -16.412 50.896 1.00 40.41 ATOM 2852 Hl H20 561 -13.891 -17.167 51.314 1.00 0.00 ATOM 2853 H2 H20 561 -12.907 -16.874 50.251 1.00 0.00 ATOM 2854 OH2 H20563 8.297 7.021 48.013 1.00 45.26 ATOM 2855 Hl H20 563 9.196 6.664 48.079 1.00 0.00 ATOM 2856H2 H20 563 8.400 7.891 48.412 1.00 0.00 ATOM 2857 OH2 H20569 -18.672 9.411 70.985 1.00 42.69 ATOM 2858 Hl H20 569 -18.454 10.301 70.720 1.00 0.00 ATOM 2859 H2 H20 569 -19.299 9.181 70.297 1.00 0.00 ATOM 2860 OH2 H20570 -4.013 16.605 50.811 1.00 50.36 ATOM 2861Hl H20 570 -3.642 15.998 51.464 1.00 0.00 ATOM 2862 H2 H20 570 -4.727 17.023 51.309 1.00 0.00 ATOM 2863 OH2 H20572 -6.268 16.662 44.180 1.00 24.25 ATOM 2864 Hl H20 572 -6.777 16.796 45.000 1.00 0 00 ATOM 2865 H2 H20 572 -5.615 17.379 44.261 1.00 0.00 ATOM 2866 oH2 H20 573 -18.387 -26.644 47.160 1.00 49.62 ATOM 2867 Hl H20 573 -17.586 -26.570 46.621 1.00 0.00 ATOM 2868 H2 H20 573 -18.382 -27.600 47.318 1.00 0.00 ATOM 2869 OH2 H20 574 -11.225 -10.882 43.386 1.00 28.82 ATOM 2870 Hl H20 574 -12.100 -10.489 43.454 1.00 0.00 ATOM 2871 H2 H20 574 -11.400 -11.765 43.056 1.00 0.00 ATOM 2872 OH2 H20575 -7.241 6.911 24.257 1.00 46.54 ATOM 2873 Hl H20 575 -6.378 7.294 24.478 1.00 0.00 ATOM 2874 H2 H20 575 -7.127 6.659 23.334 1.00 0.00 ATOM 2875 OH2 H20576 -2.732 3.489 69.646 1.00 35.00 ATOM 2876Hl H20 576 -2.509 3.272 68.740 1.00 0.00 ATOM 2877 H2 H20 576 -3.201 4.317 69.547 1.00 0.00 ATOM 2878 OH2 H20577 -1.004 -5.395 42.848 1.00 31.83 ATOM 2879 Hl H20 577 -1.718 -5.183 42.244 1.00 0.00 ATOM 2880 H2 H20 577 -0.242 -5,437 42.261 1.00 0.00 SUBSTITUTE S~EET ~RULE ;~6) CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 2881 oH2 H20579 2.618 6.038 53.054 1.00 53.16 ATOM 2882 Hl H20 579 2.206 5.196 53.266 1.00 0.00 ~ ATOM 2883 H2 H20 579 3.530 5.782 52.875 1.00 0.00 ATOM 2884 OH2 H20580 -3.109 1.708 61.212 1.00 32.77 5 ATOM 2885 Hl H20 580 -4.013 1.787 61.547 1.00 0.00 ATOM 2886 H2 H20 580 -3.145 2.263 60.427 1.00 0.00 ATOM 2887 OH2 H20581 -15.517 7.216 36.498 1.00 45.24 ATOM 2888 Hl H20 581 -14.609 7.036 36.239 1.00 0.00 ATOM 2889 H2 H20 581 -15.977 6.404 36.259 1 00 0.00 10 ATOM 2890 OH2 H20582 4.831 21.847 47.571 1.00 53.78 ATOM 2891 Hl H20 582 5.295 22.312 46.821 1.00 0.00 ATOM 2892 H2 H20 582 5.264 20.951 47.474 1.00 0.00 ATOM 2893 OH2 H20583 -7.370 -2.505 28.449 1.00 43.85 ATOM 2894 Hl H20 583 -7.859 -2.031 27.773 1.00 0 00 15 ATOM 2895 H2 H20 583 -8.070 -2.637 29.095 1.00 0.00 ATOM 2896 OH2 H20584 11.021 8.553 47.239 1 00 55.00 ATOM 2897 Hl H20 584 11.035 9.388 47.727 1.00 0.00 ATOM 2898 H2 H20 584 11.358 8.841 46.355 1.00 0.00 ATOM 2899 OH2 H20585 -13.463 4.859 41.287 1.00 51.26 20 ATOM 2900 Hl H20 585 -13.880 5.285 42.041 1.00 0.00 ATOM 2901 H2 H20 585 -12.578 5.274 41.218 1.00 0.00 ATOM 2902 OH2 H20 586 -21.459 -21.141 46.452 1.00 38.96 ATOM 2903 Hl H20 586 -20.860 -20.849 47.150 1.00 0.00 ATOM 2904 H2 H20 586 -21.155 -22.070 46.366 1.00 0.00 25 ATOM 2905 OH2 H20587 9.552 9.085 29.404 1 00 21.31 ATOM 2906 Hl H20 587 10.017 9.328 28.595 1.00 0.00 ATOM 2907 H2 H20 587 8.874 8.487 29.061 1.00 0.00 ATOM 2908 OH2 H20588 -18.589 16.079 53.026 1.00 47.95 ATOM 2909 Hl H20 588 -17.885 16.496 53.527 1.00 0.00 30 ATOM 2910 H2 H20 588 -18.406 15.135 53.154 1.00 0.00 ATOM 2911 OH2 H20589 11.877 9.205 44.689 1.00 37.00 ATOM 2912 Hl H20 589 12.160 9.585 43.847 1.00 0.00 ATOM 2913 ~2 ~20 589 12.543 8.490 44.824 1.00 0.00 ATOM 2914 OH2 H20592 -26.188 -5.587 57.097 1.00 33.07 35 ATOM 2915 Hl H20 592 -26.971 -5.989 57.502 1.00 0.00 ATOM 2916 H2 H20 592 -26.094 -4.777 57.619 ~.00 0.00 ATOM 2917 OH2 H20593 -12.898 10.911 38.656 1.00 46.97 ATOM 2918 HlH20 593 -12.3S4 10.108 38.666 1.00 0.00 ATOM 2919 H2H20 593 -13.273 10.940 39.540 1.00 0.00 .

SUBSTITUTE S}~E~ (RUI_E 2&) CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 2920 oH2 H20594 -2.882 16.968 48.295 }.00 30.83 ATOM 2921 Hl H20 594 -3.396 17.749 48.079 1.00 0.00 ATOM 2922 H2 H20 594 -3.313 16.697 49.134 1.00 0.00 ATOM 2923 OH2 H20595 13.656 7.244 45.221 1.00 39.29 5 ATOM 2924 Hl H20 595 14.189 7.235 44.397 1.00 0.00 ATOM 2925 H2 H20 595 14.368 7.167 45.864 1.00 0.00 ATOM 2926 OH2 H20596 10.754 5.887 46.780 1.00 58.01 ATOM 2927 Hl H20 596 10.942 6.831 46.995 1.00 0.00 ATOM 2928 H2 H20 596 11.653 5.535 46.772 1.00 0.00 ATOM 2929OH2 H20 597 8.570 -1.874 32.277 1.00 42.55 ATOM 2930 Hl H20 597 8.461 -2.699 31.792 1.00 0.00 ATOM 2931 H2 H20 597 7.661 -1.660 32.512 1.00 0.00 ATOM 2932 OH2 H20598 15.043 10.456 42.923 1.00 62.88 ATOM 2933 Hl H20 598 14.279 10.904 43.307 1.00 0.00 ATOM 2934H2 H20 598 15.457 11.173 42.429 1.00 0.00 ATOM 2935 OH2 H20599 -15.660 0.506 40.466 1.00 47.74 ATOM 2936 Hl H20 599 -16.222 0.052 39.836 1.00 0.00 ATOM 2937 H2 H20 599 -15.144 1.096 39.903 1.00 0.00 ATOM 2938 OH2 H20601 10.395 0.423 33.259 1.00 37.60 ATOM 2939Hl H20 601 10.006 0.653 34.105 1.00 0.00 ATOM 2940 H2 H20 601 9.821 -0.291 32.928 1.00 0.00 ATOM 2941 OH2 H20602 -8.774 4.671 74.569 1.00 26.62 ATOM 2942 Hl H20 602 -8.038 4.434 75.158 1.00 0.00 ATOM 2943 H2 H20 602 -8.979 3.782 74.258 1.00 0.00 ATOM 2944 OH2 H20 603 -17.104 -12.783 62.725 1.00 37.86 ATOM 2945 Hl H20 603 -16.954 -13.496 62.099 1.00 0.00 ATOM 2946 H2 H20 603 -16.217 -12.397 62.806 1.00 0.00 ATOM 2947 OH2 H20 604 -18.900 -20.100 39.570 1.00 34.28 ATOM 2948 Hl H20 604 -18.978 -19.931 40.517 1.00 0.00 ATOM 2949 H2 H20 604 -19.834 -20.252 39.318 1.00 0.00 ATOM 2950 OH2 H20605 -5.985 -5.412 60.745 1.00 36.79 ATOM 2951 Hl H20 605 -5.650 -4.512 60.798 i.oo o.oo ATOM 2952 H2 H20 605 -6.609 -5.357 60.001 1.00 0.00 ATOM 2953 OH2 H20606 -7.708 -2.084 36.092 1.00 21.56 ATOM 2954Hl H20 606 -6.902 -1.784 35.650 1.00 0.00 ATOM 2955 H2 H20 606 -8.190 -1.262 36.233 1.00 0.00 ATOM 2956 OH2 H20608 -3.614 10.212 57.878 1.00 65.19 ATOM 2957 Hl H20 608 -3.452 9.262 57.744 1.00 0.00 ATOM 2958 H2 H20 608 -3.027 10.425 58.606 1.00 0.00 SUE~STmJTE ~E~ tRlJLE ~6) CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATOM 2959 OH2 H20 609 -3.860 23.973 29.811 1.00 S0.06 ATOM 2960 Hl H20 609 ~3.959 23.569 28.947 1.00 0.00 ATOM 2961 H2 H20 609 -4.765 24.102 30.103 1.00 0.00 ATOM 2962 OH2 H20 610 -14.484 -29.114 38.149 1.00 37.42 5 ATOM 2963 Hl H20 610 -13.947 -29.402 38.898 1.00 0.00 ATOM 2964 H2 H20 610 -15.333 -29.510 38.352 1.00 0.00 ATOM 2965 OH2 H20611 -21.240 -8.832 S5.096 1.00 28.35 ATOM 2966 Hl H20 611 -21.322 -9.290 54.233 1.00 0.00 ATOM 2967 H2 H20 611 -21.978 -8.198 55.041 1.00 0.00 10 ATOM 2968 OH2 H20612 -28.312 0.830 71.261 1.00 57.03 ATOM 2969 Hl H20 612 -27.631 0.653 70.617 1.00 0.00 ATOM 2970 H2 H20 612 -28.949 0.130 71.091 1.00 0.00 ATOM 2971 OH2 H20613 -12.785 13.825 37.299 1.00 58.02 ATOM 2972 Hl H20 613 -13.581 13.348 37.068 1.00 0.00 15 ATOM 2973 H2 H20 613 -12.320 13.191 37.859 1.00 0.00 ATOM 2974 CH2 H20614 -26.951 9.367 64.841 1 00 44.43 ATOM 2975 Hl H20 614 -27.479 9.463 64.039 1.00 0.00 ATOM 2976 H2 H20 614 -27.225 10.150 65.326 1.00 0.00 ATOM 2977 oH2 H20615 0.669 -5.217 31.942 1.00 34.30 20 ATOM 2978 Hl H20 615 1.054 -5.954 32.433 1.00 0.00 ATOM 2979 H2 H20 615 -0.020 -5.664 31.430 1.00 0.00 ATOM 2980 OH2 H20 616 -21.268 -20.889 38.280 1.00 52.02 ATOM 2981 Hl H20 616 -20.821 -20.660 37 462 1.00 0.00 ATOM 2982 H2 H20 616 -21.549 -21.801 38.127 1.00 0.00 25 ATOM 2983 OH2 H20617 -12.839 10.577 73 g97 1 00 32.65 ATOM 2984 Hl H20 617 -13.386 10.619 73.198 1.00 0.00 ATOM 2985 H2 H20 617 -12.500 9.678 73.936 1.00 0.00 ATOM 2986 OH2 H20618 -16.254 12.102 64.699 1.00 39.97 ATOM 2987 Hl H20 618 -16.278 12.774 65.388 1.00 0.00 30 ATOM 2988 H2 H20 618 -16.940 12.440 64.106 1.00 0 00 ATOM 2989 OH2 H20619 0.609 7.758 53.655 1.00 59.42 ATOM 2990 Hl H20 619 1.450 7.256 53.684 1.00 0.00 ATOM 2991 H2 H20 619 0.683 8.342 54.416 1.00 0.00 ATOM 2992 OH2 H20620 -4.989 -8.010 58.309 1.00 38.58 35 ATOM 2993 Hl H20 620 -5.068 -8.214 59.248 1.00 0.00 r ATOM 2994 H2 H20 620 -4.822 -8.893 57.952 1.00 0.00 ATOM 2995 OH2 H20621 -26.221 -7.530 53.875 1.00 52.25 ATOM 2996 Hl H20 621 -25.549 -8.202 53.730 1.00 0.00 ATOM 2997 H2 H20 621 -26.714 -7.882 54.627 1.00 0.00 ~ 227 ~

SUBSTITUTE ~i~F~ ~RULE 2~) CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 2998 OH2 H20622 -28.638 3.741 68.846 1.00 59.40 ATOM 2999 Hl H20 622 -28.605 3.555 69.794 1.00 0.00 ATOM 3000 H2 H20 622 -28.709 2.848 68.480 1.00 0.00 ATOM 3001 OH2 H20623 -2.090 21.292 26.341 1.00 57.48 ATOM 3002Hl H20 623 -1.329 21.457 26.918 1.00 0.00 ATOM 3003 H2 H20 623 -1.757 21.533 25.471 1.00 0.00 ATOM 3004 OH2 H20624 2.746 10.956 28.128 1.00 62.18 ATOM 3005 Hl H20 624 2.977 11.822 27.786 1.00 0.00 ATOM 3006 H2 H20 624 1.817 10.899 27.885 1.00 0.00 ATOM 3007 OH2 H20 625 -21.125 -12.685 57.962 1.00 56.36 ATOM 3008 Hl H20 625 -22.032 -12.954 57.802 1.00 0.00 ATOM 3009 H2 H20 625 -21.176 -11.723 57.883 1.00 0 00 ATOM 3010 OH2 H20626 -3.498 0.232 28.222 1.00 45.90 ATOM 3011 Hl H20 626 -3.396 -0.544 28.792 1.00 0.00 ATOM 3012H2 H20 626 -4.076 -0.127 27.533 1.00 0.00 ATOM 3013 OH2 H20627 -6.243 -1.618 39.632 1.00 33.00 ATOM 3014 Hl H20 627 -6.546 -0.718 39.813 1.00 0.00 ATOM 3015 H2 H20 627 -6.989 -2.019 39.186 1.00 0.00 END
*Note: See copyright notice on page 1.

SUBSTITUTE ~ RULE ;~fi~

CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 A~pendix lII: Coordinateg ~os tho 3D ~tructure of ZAP-NC:zl "dimer" structure (two mol~ucle~ o~ co~plex ~r unit cell)~

R~MARK FTT~AMR="tzape-zetal-reb7-wat-slow.pdb"
RENARK TOPHl9.pep -MACRO for protein sequence created by user: ma~cos ATOM1 CB ASP 33.0Z3-3.462 13.100 1.00 13.09 ATOM2 CG ASP 33.616-2 223 12.417 1.00 20.07 10 ATOM3 ODl ASP 33.875 -2.263 11.212 1.00 23.94 ATOM4 OD2 ASP 33.795 -1.198 13.066 1.00 20.96 ATOM5 C ASP 33.125-2.930 15.585 1.00 11.37 ATOM6 O ASP 31.915-2.908 15.816 1.00 14.62 ATOM7 HTl ASP 31.919 -4.746 15.191 1.00 0.00 15 ATOM8 HT2 ASP 33.317 -5.471 15.778 1 00 0.00 ATOM9 N ASP 32.872-5.087 14.923 1.00 17.39 ATOM10 HT3 ASP 32.808 -5.797 14.172 1.00 0.00 ATOM11 CA ASP 33.564-3.885 14.482 1.00 13.78 ATOM12 N PRO 43.958-2.177 16.299 1.00 6.97 2~ ATOM13 CD PRO 45,405-2.209 16.150 1.00 10.48 ATOM14 CA PRO 43.556-1.192 17.314 1.00 10.28 ATOM15 CB PRO 44.853-0.568 17.733 1.00 9.59 ATOM16 CG PRO 45.881-1.611 17.455 1.00 10.34 ATOM17 C PRO 42.524-0.151 16.856 1.00 12.09 25 ATOM18 O PRO 41.6650.351 17.601 1 00 15.40 ATOM19 N ALA 52.5680.146 15.556 1.00 14.44 ATOM20 H ALA 53.317-0.168 15.008 1.00 0.00 ATOM21 CA ALA 51.6621.120 14.996 1.00 11.85 ATOM22 CB ALA 52.2911.818 13.819 1.00 11.48 30 ATOM23 C ALA 50.3480.580 14.532 1.00 12.81 ATOM24 O ALA 5-0.5431.361 14.246 1.00 14.41 ATOM25 M ALA 60.126-0.726 14.574 1.00 10.58 ATOM26 H ALA 60.778-1.310 15.006 1.00 0.00 ATOM27 CA ALA 6-1.089-1.294 14.028 1.00 14.14 35 ATOM28 CB ALA 6-1.098-2.784 14.300 1.00 16.49 ,~ ATOM 29 C ALA6-2.394 -0.721 14.540 1.00 16.09 ATOM30 O ALA 6-3.390-0.608 13.844 1.00 21.55 ATOM31 N HIS 7-2.376-0.363 15.806 1.00 17.76 ATOM32 H HIS 7-1.541-0 482 16.284 1.00 0.00 - 229 ~

SUBSTITUTE S~E~ tRULE 2~i) CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATOM 33 CA HIS 7-3.533 0.171 16.488 1.00 16.60 ATOM 34 CB HIS 7-3.352 -0.066 18.009 1.00 22.31 ATOM 35 CG HIS 7-2.219 0.769 18.644 1.00 27.59 ATOM 36 CD2 HIS 7 -2.489 1.750 19.576 1.00 28.93 ATOM 37NDl HIS 7 -0.885 0.783 18.461 1.00 25.24 r ATOM 38 HDl HIS 7 -0.298 0.154 17.994 1.00 0.00 ATOM 39 CEl HIS 7 -0.376 1.717 19.227 1.00 28.14 ATOM 40 NE2 HIS 7 -1.347 2.282 19.884 1.00 26.99 ATOM 41 HE2 HIS 7 -1.204 2.905 20.638 1.00 0.00 ATOM 42 C HIS 7 -3.741 1.658 16.209 1.00 13.37 ATOM 43 OHIS 7 -4.720 2.243 16.644 1.00 14.49 ATOM 44 NLEU 8 -2.817 2.341 15.557 1.00 10.78 ATOM 45 H LEU 8-2.221 1.861 14.946 1.00 0.00 ATOM 46 CA LEU 8-2.871 3.783 15.423 1.00 7.84 ATOM 47CB LEU 8 -1.436 4.278 15.161 1.00 6.56 ATOM 48 CG LEU 8-0.575 4.915 16.234 1.00 3.50 ATOM 49 CDl LEU 8 --1.174 4.730 17.610 1.00 6.85 ATOM 50 CD2 LEU 8 0.801 4.382 16.098 1.00 2.00 ATOM 51 C LEU 8-3.808 4.079 14 265 1.00 8.93 ATOM 52 O LEU 8 -3.580 3.600 13.154 1.00 10.23 ATOM 53 N PRO 9-4.863 4.873 14.434 1.00 9.86 ATOM 54 CD PRO 9-5.197 5.551 15.693 1.00 9.32 ATOM 55 CA PRO 9-5.849 5.081 13.389 1.00 8.41 ATOM 56 CB PRO 9-6.966 5.752 14.144 1.00 10.72 ATOM 57CG PRO 9 -6.309 6.490 15.289 1.00 11.80 ATOM 58 C PRO 9-5.355 5.835 12.149 1.00 12.47 ATOM 59 O PRO 9-6.026 5.867 11.110 1.00 18.23 ATOM 60 N PHE10-4.162 6.430 12.259 1.00 9.59 ATOM 61 H PHE10-3.692 6.342 13.107 1.00 0.00 ATOM 62CA PHE 10 -3.498 7.181 11.203 1.00 7.32 ATOM 63 CB PHE10-3.024 8.538 11.737 1.00 4.10 ATOM 64 CG PHE10-2.321 8.453 13.094 1.00 4.21 ATOM 65 CDl PHE10 -0 943 8.232 13.179 1.00 4.43 ATOM 66 CD2 PHE10 -3.058 8.624 14.267 1.00 2.00 ATOM 67CEl PHE 10 -0.301 8.182 14.416 1.00 2.00 ATOM 68 CE2 PHE10 -2.417 8.580 15.500 1.00 2.51 ATOM 69 CZ PHE10-1.047 8.362 15.583 1.00 2.00 ATOM 70 C PHE10-2.294 6.405 10.696 1.00 7.70 ATOM 71 O PHE10-1.349 7.007 10.175 1.00 7.52 - 23~ -SUBSTITUTE ~ EE~ ~RULE 26~

CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 72 N PHE11-2.2245.088 10.921 1.00 6.80 ATOM 73 H PHE11-2.9654.597 11.332 1.00 0.00 ATOM 74 CA PHE11-1.1204.299 10.415 1.00 7.59 ATOM 7S CB PHE11-0.7053.238 11.425 1.00 5.71 ATOM 76 CGPHE 110.248 2.165 10.884 1.00 7 61 ATOM 77 CDl PHE 111.519 2.510 10.393 1.00 2.06 ATOM 78 CD2 PHE 11-0.165 0.821 10.874 1.00 2.94 ATOM 79 CEl PHE 112.370 1.522 9.895 1.00 2.00 ATOM 80 CE2 PHE 110.700 -0.160 10.373 1.00 3.03 ATOM 81 CZPHE 111.962 0.191 9.888 1.00 4.25 ATOM 82 C PHE11-1.6863.663 9.154 1.00 7.98 ATOM 83 O PHE11-2.7843.126 9.188 1.00 9.38 ATOM 84 N TYR12-1.0003.774 8.025 1.00 4.03 ATOM 85 H TYR12-0.1704.294 8.022 1.00 0.00 ATOM 86 CATYR 12-1.522 3.259 6.774 1.00 7.69 ATOM 87 CB TYR12-1.4554.329 5.714 1.00 4.20 ATOM 88 CG TYR12-2.5825.340 5.795 1.00 3.37 ATOM 89 CDl TYR 12-2.543 6.332 6.766 1.00 2.00 ATOM 90 CEl TYR 12-3.532 7.297 6.818 1.00 2.00 ATOM 91CD2 TYR 12 -3.617 5.301 4.872 1.00 2.00 ATOM 92 CE2 TYR 12-4.609 6.269 4.918 1.00 3.76 ATOM 93 CZ TYR12-4.5577.263 5.891 1.00 5.13 ATOM 94 OH TYR12-5.5218.242 5.911 1.00 6.92 ATOM 95 HH TYR12-5.3798.771 6.713 1.00 0.00 ATOM 96 C TYR 12-0.793 2.041 6 249 1.00 10.10 ATOM 97 O TYR12-1.1541.494 5.206 1.00 10.16 ATOM 98 N GLY130.2901.623 6.899 1.00 4.96 ATOM 99 H GLY130.6762.192 7.592 1.00 0.00 ATOM 100 CA GLY 130.993 0.444 6.465 1.00 5.01 ATOM 101 C GLY 131.962 0.782 5.361 1.00 9.03 ATOM 102 O GLY132.4661.911 5.324 1.00 9.88 ATOM 103 N SER142.248-0.181 4.484 1.00 6.75 ATOM 104 H SER141.835-1.069 4.566 1.00 0.00 ATOM 105 CA SER143.216-0.042 3.425 1.00 6.38 ATOM 106 CBSER 143.761 -1 433 3.160 1.00 12.45 ATOM 107 OG SER144.042-2.137 4.368 1.00 14.84 ATOM 108 HG SER144.988-2.032 4.504 1.00 0.00 ATOM 109 C SER142.6460.592 2.163 1.00 9.03 ATOM 110 O SER142.597-0.003 1.083 1.00 6.91 SUBSTITUTE ~}~EE~ tRULE 2~i) CA 02226963 l998-02-l2 W 0 97/08300 PCT~US96/13918 ATOM111 N ILE 152.1201.8122.312 1.00 12.05 ATOM112 H ILE 152.1882.2383.193 1.00 0.00 ATOM113 CA ILE151.6102.588 1.187 1.00 4.84 ATOM114 CB ILE150.5383.627 1.605 1.00 6.22 5 ATOM115 CG2 ILE 15-0.6802.860 2.116 1.00 2.00 ATOM116 CGl ILE 151.0754.612 2.629 1.00 4.45 ATOM117 CD ILE150.0575.720 2.801 1.00 2.00 ATOM118 C ILE 152.7983.3260.597 1.00 4.88 ATOM119 O ILE 153.8613.3821.221 1.00 9.72 1 0 ATOM 120 N SER 162.707 3.871 -0.603 1.00 2.18 ATOM121 H SER 161.8753.823-1.116 1.00 0.00 ATOM122 CA SER163.7884.641 -1.154 1.00 2.42 ATOM123 CB SER163.7044.505 -2.673 1.00 8.87 ATOM124 OG SER162.3884.754 -3.152 1.00 3.44 1 5 ATOM 25 HGSER 162 047 3.891 -3.426 1.00 0.00 ATOM126 C SER 163.6876.106-0.714 1.00 2.00 ATOM'27 O SER 162.6756.502-0.132 1.00 2.00 ATOM128 N ARG 174.6996.935-0.968 1.00 2.93 ATOM129 H ARG 175.5376.524-1.277 1.00 0.00 20 ATOM130 CA ARG 174.6488.381 -0.757 1.00 7.56 ATOM131 CB ARG 175.9249.017 -1.273 1.00 6.05 ATOMi32 CG ARG 175.86210.510 -1.338 1.00 5.21 ATOM133 CD ARG 177.15411.123 -1.775 1.00 3.35 ATOM134 NE ARG 178.22710.897 -0.825 1.00 4.91 25 ATOM135 HE ARG 178.20810.065 -0 338 1.00 0.00 ATOM36 CZ ARG '79.14011.829 -0.522 1.00 4.06 ATOM37 NHl ARG 179.09013.040 -1.078 1.00 11.79 ATOM '38 HHll ARG178.35113.280 -1.704 1.00 0.00 ATOM '39 HH12 ARG179.76713.730 -0.827 1.00 0.00 30 ATOM 140 NH2 ARG 1710.16011.543 0.279 1.00 2.00 ATOM 141 HH21 ARG1710.26710.623 0.648 1.00 0.00 ATOM 142 HH22 ARG1710.82612.246 0.515 1.00 0.00 ATOM143 C ARG 173.4679.007-1.478 1.00 9.96 ATOM144 O ARG 172.7679.855-0.912 1.00 18.22 35 ATOM145 N ALA 183.2268.597-2.725 1.00 8.79 ATOM146 H ALA 183.8667.978-3.146 1.00 0.00 ATOM-47 CA ALA 182.1279.126 -3.517 1.00 6.30 ATOM148 CB ALA 182.1578.565 -4.946 1.00 6.16 ATOM:4g C ALA 180.7528.856-2.957 1.00 6.92 51J85TITUTE ~tE~ tRULE 2~i~

W O 97/08300 PCTrUS96/13918 ATOM 150 O ALA18-0.1079.754 -2.973 1.00 7.53 ATOM 151 N GLU190.5067.652 -2.443 1.00 7.90 ATOM 152 H GLU191.2096.967 -2.446 1.00 0,00 ATOM 153 CA GLU19-0.7827.381 -1.814 1.00 9.39 ATOM 154 CBGLU 19-0.933 5 916 -1.471 1.00 10.49 ATOM 155 CG GLU19-2.3775.601 -1.128 1.00 19.14 ATOM 156 CD GLU19-2.6454.173 -0.680 1.00 20.65 ATOM 157 OEl GLU19-3.479 3.996 0.201 1.00 17.14 ATOM 158 OE2 GLU19-2.030 3.243 -1.201 1.00 24.68 ATOM 159 C GLU 19-0.919 8.177 -0.532 1.00 3.96 ATOM 160 O GLU19-2.0178.678 -0.270 1.00 8.60 ATOM 161 N ALA200.1588.264 0.270 1.00 7.91 ATOM 162 H ALA200.9667.756 0.027 1.00 0.00 ATOM 163 CA ALA200.2119.052 1 508 1.00 5.76 ATOM 164 CBALA 201.649 9.038 2.045 1.00 2.00 ATOM 165 C ALA20-0.24110.487 1.209 1.00 4.60 ATOM 166 O ALA20-1.20610.973 1.808 1 00 5.16 ATOM 167 N GLU210.37911.097 0.190 1.00 4.13 ATOM 168 H GLU211.11610.617 -0.239 1.00 0.00 ATOM 169 CAGLU 210.040 12.416 -0.312 1.00 2.10 ATOM 170 CB GLU211.02012.792 -1.412 1.00 4.68 ATOM 171 CG GLU212.39713.047 -0.773 1.00 2.00 ATOM 172 CD GLUZl3.51913.499 -1.669 1.00 2.00 ATOM 173 OEl GLU214.557 13.853 -1.142 1.00 5.32 ATOM 174OE2 GLU 21 3.407 13.490 -2.883 1.00 13.97 ATOM 175 C GLU 21-1.380 12.520 -0.818 1.00 6.29 ATOM 176 O GLU ~1-2.019 13.528 -0.527 1 00 10.48 ATOM 177 N GLU 22-1.962 11.533 -1.497 1.00 8.02 ATOM 178 H GLU 22-1.426 10.751 -1.745 1.00 0.00 ATOM 179CA GLU 22 -3.372 11.572 -1.859 1.00 7.52 ATOM 180 CB GLU 22-3.832 10.346 -2.661 1.00 7.05 ATOM 181 CG GLU 22-3.392 10.345 -4.114 1.00 14.40 ATOM 182 CD GLU 22-3.683 11.637 -4.867 1.00 8 48 ATOM 183 OEl GLU22-4.835 11 930 -5.138 1.00 9.34 ATOM 184OE2 GLU 22 -2.752 12.353 -5.183 1.00 11.08 ATOM 185 C GLU22-4.27311.631 -0.641 1.00 6.86 ATOM 186 O GLU22-5.25312.378 -0.613 1.00 5.32 ATOM 187 N HIS23-3.95910.856 0.392 1.00 5.94 ATOM 188 H HIS23-3.14010.318 0.345 1.00 0.00 SlJBSmUTE SH~F~ (RULE 26~

CA 02226963 l998-02-l2 W O 97/08300 PCT~US96/13918 ATOM 189 CA HIS23-4.75510.908 1.612 1.00 5.56 ATOM 190 CB HIS23-4.3219.773 2.499 1.00 2.00 ATOM 191 CG HIS23-4.8678.436 2.044 1.00 2.00 ATOM 192 CD2 HIS23-6.203 8.130 1.947 1.00 2.00 5 ATOM 193 NDl HIS23-4.188 7.361 1.687 1.00 3.99 ATOM 194 HDl HIS23-3.210 7.263 1.722 1.00 0.00 ATOM 195 CEl HIS23-5.036 6.418 1.389 1.00 4.29 ATOM 196 NE2 HIS23-6.245 6.892 1.547 1.00 2.00 ATOM 197 HE2 HIS23-7.054 6.418 1.246 1.00 0.00 10 ATOM 198 C HIS23-4.63512.252 2.349 1.00 4.09 ATOM 199 O HIS23-5.62612.842 2.795 1.00 6.37 ATOM 200 N LEU24-3.42112.790 2.458 1.00 3.53 ATOM 201 H LEU24-2.64612.264 2.177 1.00 0.00 ATOM 202 CA LEU24-3.20614.085 3.063 1.00 5.01 15 ATOM 203 CB LEU24-1.70114.303 3.096 1.00 2.00 ATOM 204 CG LEU24-0.82314.200 4.370 1.00 6.54 ATOM 205 CDl LEU24-1.454 13.379 5.465 1.00 7.05 ATOM 206 CD2 LEU240.498 13.624 3.967 1.00 2.00 ATOM 207 C LEU24-3.97315.138 2.252 1.00 11.01 20 ATOM 208 O LEU24-4.65215.982 2.852 1.00 10.63 ATOM 209 N LYS25-4.00015.036 0.904 1.00 12.49 ATOM 210 H LYS25-3.46214.341 0.474 1.00 0.00 ATOM 211 CA LYS25-4.77415.932 0.043 1.00 7.14 ATOM 212 CB LYS25-4.49615.670 -1.428 1.00 8.00 25 ATOM 213 CG LYS25-3.15316.255 -1.839 1.00 5.27 ATOM 214 CD LYS25-Z.58115.554 -3.051 1.00 3.30 ATOM 215 CE LYS25-3.26015.890 -4.355 1.00 10.38 ATOM 216 NZ LYS25-2.55915.231 -5.444 1.00 11.78 ATOM 217 HZl LYS25-3.027 14.321 -5.634 1.00 0.00 30 ATOM 218 HZ2 LYS25-1.570 15.066 -5.169 1.00 0.00 ATOM 219 HZ3 LYS25-2.588 15.821 -6.298 1.00 0.00 ATOM 220 C LYS25-6.26515.828 0.258 1.00 10.22 ATOM 221 O LYS25-6.89716.878 0.404 1.00 9.54 ATOM 222 N LEU26-6.83814.617 0.301 1.00 11.16 35 ATOM 223 H LEU26-6.27313.839 0.106 1.00 0.00 ATOM 224 CA LEU26-8.25114.406 0.623 1.00 9.37 ATOM 225 CB LEU26-8.62012.933 0.400 1.00 11.52 ATOM 226 CG LEU26-8.86912.403 -1.006 1.00 15.81 ATOM 227 CDl LEU26-8.667 10.906 -1.070 1.00 12.44 SUE~STI~UTE SHE~ tRuLE 2~;3 CA 02226963 l998-02-l2 WO 97/08300 PCTrUS96/13918 ATOM 228 CD2 LEU 26-10.274 12.781 -1.405 1.00 14.24 ATOM 229 C LEU 26-8.631 14.799 2.069 1.00 10.95 ATOM 230 O LEU 26-9.801 15.111 2.355 1.00 14.32 ATOM 231 N ALA 27-7.692 14.822 3.024 1.00 11.08 ATOM 232H ALA 27-6.777 14.533 2.808 1.00 0.00 ATOM 233 CA ALA 27-7.994 15.224 4.386 1.00 11.08 ATOM 234 CB ALA27 -7.036 14.511 5.304 1.00 10.64 ATOM 235 C ALA27 -7,953 16.734 4.652 1.00 7.17 ATOM 236 O ALA27 -8.111 17.181 5.782 1.00 11.67 ATOM 237 N GLY 28-7,739 17.589 3.664 1.00 12.48 ATOM 238 H GLY28 -7.484 17.253 2.781 1 00 0.00 ATOM 239 CA GLY28 -7.896 19.028 3.827 1.00 7.75 ATOM 240 C GLY28 -6.628 19.840 3.923 1.00 4.07 ATOM 241 O GLY28 -6.690 21.035 4.200 1.00 6.51 ATOM 242 N MET 29-5.473 19.214 3.803 1.00 2.00 ATOM 243 H MET29 -5.490 18.237 3.712 1.00 0.00 ATOM 244 CA MET 29-4.190 19.893 3.778 1.00 8.42 ATOM 245 CB MET29 -3.995 20.563 2.387 1.00 10.20 ATOM 246 CG MET29 -3.777 19.617 1.225 1.00 2.00 ATOM 247 SDMET 29-2.291 18.598 1.382 1.00 8.85 ATOM 248 CE MET29 -1.010 19.682 0.859 1.00 2.00 ATOM 249 C MET29 -3.856 20.922 4.854 1.00 10.87 ATOM 250 O MET29 -2.966 21.768 4.665 1 00 10.88 ATOM 251 N ALA30 -4.500 20.905 6.021 1.00 11.57 ATOM 252 H ALA 30-5.182 20.223 6.167 1.00 0.00 ATOM 253 CA ALA30 -4.164 21.845 7.095 1.00 10.40 ATOM 254 CB ALA30 -5.179 21.738 8.228 1.00 6.30 ATOM 255 C ALA30 -2.775 21.578 7.669 1.00 10.33 ATOM 256 O ALA30 -2.295 20.435 7.630 1.00 13.22 ATOM 257 N ASP 31-2.076 22.614 8.163 1.00 12.01 ATOM 258 H ASP31 -2.486 23.499 8.124 1.00 0.00 ATOM 259 CA ASP 31-0.776 22.454 8.823 1.00 12.46 ATOM 260 CB ASP 31-0.288 23.751 9.448 1.00 13.37 ATOM 261 CG ASP 310.098 24.844 8.474 1.00 21 50 ATOM 262ODl ASP 31 0.146 25.992 8.888 1.00 24.55 ATOM 263 OD2 ASP 310.365 24.563 7.309 1.00 20.09 ATOM 264 C ASP31 -0.900 21.447 9.952 1.00 7.22 ATOM 265 O ASP31 -1.895 21.484 10.668 1.00 4.46 ATOM 266 N GLY32 0.048 20.550 10.124 1.00 10.27 SUBS ~ rrUTE ~E~ (RULE 2~'J

CA 02226963 l998-02-l2 ATOM 267 H GLY320.79820.509 9.504 1.00 0.00 ATOM 268 CA GLY32-0.03319.590 11.205 1.00 8.51 ATOM 269 C GLY32-0.82318.338 10.859 1.00 7.26 ATOM 270 O GLY32-0.85417.457 11.714 1.00 8.25 ATOM 271 N LEU 33-1.475 18.224 9.681 1.00 11.32 ATOM 272 H LEU33-1.44718.977 9.055 1.00 0.00 ATOM 273 CA LEU33-2.16317.020 9.241 1.00 7.48 ATOM 274 CB LEU33-2.95817.285 7.952 1.00 6.35 ATOM 275 CG LEU33-3.78216.168 7 277 1.00 6.57 t0 ATOM 276CDl LEU 33 -5.026 15.832 8.081 1.00 2.00 ATOM 277 CD2 LEU 33-4.230 16.632 5.924 1.00 2.00 ATOM 278 C LEU33-1.04016.019 8.975 1.00 6.22 ATOM 279 O LEU33-0.08816.324 8.255 1.00 6.43 ATOM Z80 N PHE34-1.09614.827 9.559 1.00 8.18 ATOM 281 H PHE 34-1.873 14.606 10.113 1.00 0.00 ATOM 282 CA PHE34-0.03113.841 9.449 1.00 6.96 ATOM 283 CB PHE340.90613.955 10.668 1.00 9.24 ATOM 284 CG P~E340.29313.474 12.001 1.00 11.41 ATOM 285 CDl PHE 340.609 12.195 12.511 1.00 10.54 ATOM 286CD2 PHE 34 : -0.598 14.301 12.705 1.00 6.42 ATOM 287 CEl PHE 34 0.036 11.755 13.703 1.00 2.02 ATOM 288 CE2 PHE 34 -1.171 13.850 13.902 1.00 7.27 ATOM 289 CZ PHE 34-0.85112.578 14.396 1.00 6.84 ATOM 290 C PHE 34-0.56712.412 9.374 1.00 5.22 ATOM 291 O PHE 34-1.726 12.147 9 661 1.00 3.39 ATOM 292 N LEU 350.26811.458 9.034 .00 5.72 ATOM 293 H LEU 351.18911.706 8.790 1.00 0.00 ATOM 294 CA LEU 35-0.07210.050 9.046 1.00 4.60 ATOM 295 CB LEU 35-0.7249.614 i.712 1.00 8.73 ATOM 296CG LEU 35-0.088 9.773 6.319 1.00 3.40 ATOM 297 CDl LEU 350.9598 732 5.950 1.00 2.00 ATOM 298 CD2 LEU 35-1.2449.677 5.386 1.00 2.00 ATOM 299 C LEU351.2459.3179.250 1.00 3.92 ATOM 300 O LEU352.3249.9339.225 1.00 2.00 ~-ATOM 301 N LEU 361.1918.005 9.422 1.00 5.92 ATOM 302 H LEU360.3237.5519.390 1.00 0.00 ATOM 303 CA LEU362.3807.1849.594 1.00 8.39 ATOM 304 CB LEU362.3636.596 10.986 1.00 11.32 ATOM 305 CG LEU363.6406.400 11.741 1.00 14.05 .

SUBSTITUTE S~E}~ tRULE 2~i) ATOM 306 CDl LEU 36 4.436 7.705 11.802 1.00 16.00 ATOM 307 CD2 LEU 36 3.265 5.884 13.125 1.00 9.12 ATOM 308 C LEU36 2.337 6.074 8.546 1.00 7.14 ATOM 309 O LEU36 1 281 5.554 8.193 1.00 5.23 ATOM 310 N ARG37 3.451 5.641 8.002 1.00 7.21 ATOM 311 H ARG37 4.319 6.012 8 281 1.00 0.00 ATOM 312 CA ARG 37 3.436 4.601 7.001 1.00 6.63 ATOM 313 CB ARG 37 3.347 5.207 5.570 1.00 6.99 ATOM 314 CG ARG 37 4.431 6.217 5.175 1.00 7.51 1 0 ATOM 315 CD ARG 37 4.133 6.877 3.834 1.00 3.14 ATOM 316 NE ARG37 4.999 7.996 3.521 1.00 2.00 ATOM 317 HE ARG 37 4.751 8.885 3.842 1.00 0.00 ATOM 318 CZ ARG 37 6.090 7.884 2.784 1.00 2.00 ATOM 319 NHl ARG '7 6.467 6.714 2 287 1.00 9.05 1 5 ATOM 320 HHllARG 37 5.927 5.895 2.467 1.00 0.00 ATOM 321 HH12 ARG 37 7.293 6.655 1.729 1.00 0.00 ATOM 322 NH2 ARG 37 6.826 8.967 2.509 1.00 2.00 ATOM 323 HH21 ARG 37 6.527 9.860 2.843 1.00 0.00 ATOM 324 HH22 ARG 37 7.645 8.898 1.946 1.00 0.00 20 ATOM 325 C ARG37 4.742 3.896 7.236 1.00 4.63 ATOM 326 O ARG37 5.673 4.451 7.813 1.00 6.35 ATOM 327 N GLN38 4.774 2.634 6.860 1.00 5.04 ATOM 328 H GLN38 4.022 2.306 6.330 1.00 0.00 ATOM 329 CA GLN 38 5.938 1.799 7.031 1.00 7.58 25 ATOM 330 CB GLN 38 5.595 0.351 6.761 1.00 7.74 ATOM 331 CG GLN 33 6.806 -0.558 6.935 1.00 13.64 ATOM 332 CD GLN -'3 6.483 -2.001 6.637 1.00 14.53 ATOM 333 OEl GLN 33 6.523 -2.458 5.~97 1.00 12.05 ATOM 334 NE2 GLN 38 6.109 -2.747 7.656 1.00 18.12 30 ATOM 335 HE21 GLN 38 6.074 -2.344 8.548 1.00 0.00 ATOM 336 HE22 GLN 38 5.914 -3.686 7.478 1.00 0.00 ATOM 337 C GLN38 6.999 2.228 6.044 1.00 10.26 ATOM 338 O GLN38 6.685 2.463 4.877 1.00 17.97 ATOM 339 N CYS39 =8.249 2.259 6.487 1.00 5.47 35 ATOM 340 H CYS39 8.430 1.978 7.409 1.00 0.00 ATOM 341 CA CYS 39 9.348 2.636 5.640 1.00 5.68 ATOM 342 CB CYS 39 10.486 3.061 6.507 1.00 2.00 ATOM 343 SG CYS 39 11.920 3.657 5.614 1.0Q 7.85 ATOM 344 C CYS39 9.677 1.390 4.861 1.00 8.60 5U85TITUTE S}~EE~ tRULE 2~;) CA 02226963 l998-02-l2 WO 97/~8300 PCT~US96/13918 ATOM 345 o CYS 399.841 0.306 5.419 1.00 7.46 ATOM 346 N LEU 409.732 1.534 3.551 1.00 9.77 ATOM 347 H LEU 409.503 2.417 3.173 1.00 0.00 ATOM 348 CA LEU 4010.016 0.439 2.642 1.00 8.59 5 ATOM 349 CB LEU 409.288 0.734 1.312 1.00 6.71 ATOM 350 CG LEU 407.773 1.006 1.449 1.00 11.30 ATOM 351 CDl LEU 40 7.122 1.289 0.101 1.00 8.08 ATOM 352 CD2 LEU 40 7.140 -0.199 2.108 1.00 11.61 ATOM 353 C LEU 40 11.509 0.271 2.441 1.00 5.73 ATOM 354O LEU40 11.937 -0.688 1 800 1.00 9.26 ATOM 355 N ARG 41 12.309 1.209 2.962 1.00 8.34 ATOM 356 H ARG 41 11.897 1.977 3.405 1.00 0.00 ATOM 357 CA ARG 41 13.763 1.249 2.813 1.00 2.90 ATOM 358 CB ARG 41 14.210 2.666 2.555 1.00 2.00 ATOM 359CG ARG41 13.454 3.361 1.465 1.00 2.98 ATOM 360 CD ARG 41 13.444 4.854 1.636 1.00 2.00 ATOM 361 NE ARG 41 14.799 5.288 1.685 1.00 8.56 ATOM 362 HE ARG 41 15.451 4.892 1.068 1.00 0.00 ATOM 363 CZ ARG 41 15.236 6.186 2.575 1.00 12.54 ATOM 364NHl ARG 41 14.464 6.783 3-503 1.00 5.62 ATOM 365 HHll ARG 4113.491 6.577 3.561 1.00 0.00 ATOM 366 HH12 ARG 4114.875 7.443 4.131 1.00 0.00 ATOM 367 NH2 ARG 4116.541 6.418 2.555 1.00 9.56 ATOM 368 HH21 ARG 4117.122 5.945 1.892 1.00 0.00 ATOM 369 HH22 ARG 41 16.939 7.080 3.189 1.00 0.00 ATOM 370 C ARG 4114.546 0.749 4.026 1.00 3.10 ATOM 371 O ARG 4115.738 0.442 3.924 1.00 6.59 ATOM 372 N SER 4213.886 0.603 5.172 1.00 6.64 ATOM 373 H SER 4212.914 0.695 5.186 1.00 0.00 ATOM 374 CA SER 42 14.523 0.260 6.436 1.00 10.06 ATOM 375 CB SER 4214.450 1.447 7.379 1.00 7.22 ATOM 376 OG SER 4215.317 2.451 6.893 1.00 18.52 ATOM 377 HG SER 4215.130 3.248 7.414 1.00 0.00 ATOM 378 C SER 4213.877 -0.927 7.130 1.00 13.90 ATOM 379 ~ SER 42 12.722 -1.258 6.862 1.00 18.52 ATOM 380 N LEU 4314.615 -1.614 7.985 1.00 14.21 ATOM 381 H LEU 4315.551 -1.367 8.099 1.00 0.00 ATOM 382 CA LEU 4314.096 -2.659 8.842 1.00 12.11 ATOM 383 CB LEU 4315.245 -3.504 9 359 1.00 12.29 SU8STITUTE ~j~F~ (RULE 2fi~

CA 02226963 l998-02-l2 WO 97/08300 PCTrUS96/13918 ATOM 384 CG LEU 4315.525 -4.925 8.908 1 00 14.37 ATOM 385 CDl LEU 4314.425 -5.442 7.984 1.00 15.27 ATOM 386 CD2 LEU 4316.915 -4.921 8.302 1.00 3.04 ATOM 387 C LEU4313.405-1.982 10.027 1.00 11.13 5 ATOM 388 O LEU4314.057-1.224 10.754 1.00 10.97 ATOM 389 N GLY4412.099-2.164 10.184 1.00 7.84 ATOM 390 H GLY4411.625-2.683 9.498 1.00 0.00 ATOM 391 CA GLY4411.327-1.661 11.321 1.00 11.90 ATOM 392 C GLY4411.099-0.147 11.447 1.00 14.98 ATOM 393 O GLY 4410.677 0.352 12.508 1.00 9.21 ATOM 394 N GLY4511.2790.615 10.380 1.00 14.81 ATOM 395 ~ GLY4511.3970.182 9.512 1.00 0.00 ATOM 396 CA GLY4511.1222.047 10.463 1.00 9.74 ATOM 397 C GLY459.7692.464 9.936 1.00 8.20 ~5 ATOM 398 O GLY 458.978 1.687 9 395 1.00 6.62 ATOM 399 N TYR469.5113.752 10.057 1.00 9.51 ATOM 400 H TYR4610.1944.332 10.458 1.00 0.00 ATOM 401 CA TYR468.2954.356 9.555 1.00 4.24 ATOM 402 CB TYR467.3474.752 10.689 1.00 2.68 ATOM 403 CGTYR 466.921 3.588 11.564 1.00 8.82 ATOM 404 CDl TYR 465.812 2.830 11.220 1.00 2.00 ATOM 405 CEl TYR 465.463 1.728 11.982 1.00 7.74 ATOM 406 CD2 TYR 467.684 3.255 12.684 1.00 6.02 ATOM 407 CE2 TYR 467.343 2.147 13.453 1.00 11.00 ATOM 408 CZTYR 466.233 1.388 13 092 1.00 10.98 ATOM 409 O~ TYR465.9050 267 13.825 1.00 8.20 ATOM 410 HH TYR466.725-0.036 14.250 1.00 0.00 ATOM 411 C TYR468.6785.610 8.796 1.00 2.66 ATOM 412 O TYR469.8565.975 8.722 1.00 2.00 ATOM 413 N VAL 477.691 6.266 8.217 1.00 2.00 ATOM 414 H VAL476.7725.925 8.251 1.00 0.00 ATOM 415 CA VAL 47 7.906 7.564 7.655 '1.00 3.35 ATOM 416 CB VAL 477.904 7.582 6 088 1.00 4.68 ATOM 417 CGl VAL 478.233 9.004 5.674 1.00 2.00 ATOM 418CG2 VAL 47 8.969 6.694 5.445 1.00 2.00 ATOM 419 C VAL476.7028.327 8.198 1.00 5.16 ATOM 420 O VAL475.5607.842 8.202 1.00 2.00 ATOM 421 N LEU487.0159.505 8.772 1.00 8.17 ATOM 422 H LEU487.9549.773 8.830 1.00 0.00 SU85TlTUTE ~i~E~ tRULE 2~i3 CA 02226963 l998-02-l2 WO 97/0830~ PCT~US96/13918 ATOM 423 CA LEU486.00110.432 9.273 1.00 6.70 ATOM 424 CB LEU486.54411.178 10.506 1.00 3.33 ATOM 425 CG LEU4B5.85512.460 11.014 1.00 10.59 ATOM 426 CDl LEU 484.443 12.184 11.481 1.00 2.00 ATOM 427CD2 LEU 48 6.688 13.032 12.151 1.00 10.81 ATOM 428 C LEU485.73211.393 8.125 1.00 2.00 ATOM 429 O LEU486.65212.078 7.681 1.00 2.00 ATOM 430 N SER494.51811.432 7.592 1.00 5.52 ATOM 431 H SER493.79510.929 8.028 1.00 0.00 ATOM 432 CASER 494.204 12.312 6.464 1.00 7.99 ATOM 433 CB SER4g3.53311.538 5.339 1.00 5.20 ATOM 434 OG SER494.47210.608 4.804 1.00 4.26 ATOM 435 HG SER494.2589.763 5.230 1,00 0.00 ATOM 436 C SER493.27913.402 6.946 1.00 4.36 ATOM 437 O SER 492.207 13.129 7.476 1.00 2.46 ATOM 438 N LEU503.69214.646 6.740 1.00 11.49 ATOM 439 H LEU504.50014.827 6.218 1.00 0.00 ATOM 440 CA LEU502.98115.773 7.301 1.00 10.89 ATOM 441 CB LEU503.73616.081 8.614 1.00 13.17 ATOM 442 CGLEU 504.269 17.435 9.006 1.00 11.02 ATOM 443 CDl LEU 503.244 18.149 9.876 1.00 15.66 ATOM 444 CD2 LEU 505.557 17.249 9.743 1.00 10.25 ATOM 445 C LEU 502.862 16.965 6.360 1.00 5.13 ATOM 446 O LEU 503.736 17.222 5.517 1.00 5.58 ATOM 447N VAL511.734 17.659 6.517 1.00 5 20 ATOM 448 H VAL 511.077 17.332 7.162 1.00 0.00 ATOM 449 CA VAL 511.444 18.873 5.778 1.00 6.94 ATOM 450 CB VAL 51-0.037 18.938 5.369 1.00 5.57 ATOM 451 CGl VAL 51-0.313 20.171 4.539 1.00 5.27 ATOM 452CG2 VAL 51 -0.363 17.755 4.502 1.00 8.48 ATOM 453 C VAL 511.767 20.115 6.605 1.00 6.19 ATOM 454 O VAL 511.419 20.266 7.779 1.00 6.38 ATOM 455 N HIS 522.496 21.014 5.956 1.00 7.67 ATOM 456 H HIS 522.779 20.789 5.041 1.00 0.00 ATOM 457CA HIS522.805 22.326 6.469 1.00 5.57 ATOM 458 CB HIS 524.074 22.315 7.320 1.00 4.68 ATOM 459 CG HIS 524.302 23.714 7.897 1.00 2.00 ATOM 460 CD2 HIS 525.319 24.547 7.535 1.00 5.06 ATOM 461 MDl HIS 523.552 24.372 8.768 1.00 6.19 SIJBSTITUTE S~E~ (RULE ~

CA 02226963 l998-02-l2 WO 97/0830~ PCT~US96/13918 ATOM 462 HDl HIS 522.809 24.027 9.315 1.00 0.00 ATOM 463 CEl HIS 52 4.076 25.555 8.929 1.00 2.82 ~' ATOM 464 NE2 HIS 52 5.135 25.652 8.189 1.00 2.00 ATOM 465 HE2 HIS 52 5.832 26.325 8.378 1.00 0.00 ATOM 466 C HIS 52 3.011 23.224 5.233 1.00 6.14 ATOM 467 O HIS 52 3.752 22.848 4.326 1.00 7.03 ATOM 468 N ASP 53 2.344 24.398 5.203 1.00 7.04 ATOM 469 H ASP 53 1.756 24.593 5.946 l.D0 0,00 ATOM 470 CA ASP 53 2.319 25.378 4.128 1.00 7.19 ATOM 471 CB ASP 53 3.692 26.074 4.077 1.00 13.83 ATOM 472 CG ASP 53 3.782 27.331 3.203 1.00 19.58 ATOM 473 ODl ASP 53 4.872 27.597 2.695 1.00 24.03 ATOM 474 OD2 ASP 53 2.790 28.048 3.030 1.00 20.95 ATOM 475 C ASP 53 1.944 24.749 2.783 1.00 7.16 ATOM 476 O ASP 53 2.571 24.963 1.752 1.00 4.53 ATOM 477 N VAL 54 0.844 23.980 2.869 1.00 8.53 ATOM 478 H VAL 54 0.390 23.945 3.737 1.00 0.00 ATOM 479 CA VAL 54 0.204 23.208 1.800 1.00 8.93 ATOM 480 CB VAL 54 -0.627 24.166 0.849 1.00 12.04 ATOM 481 CGl VAL 54-1.678 23.357 0.060 1.00 7.47 ATOM 482 CG2 VAL 54-1.419 25.201 1.664 1.00 8.15 ATOM 483 C VAL 54 1.224 22.395 1.006 1.00 9.82 ATOM 484 O VAL 54 1.087 22.119 -0.185 1.00 9.21 ATOM 485 N ARG 55 2.250 21.903 1.704 1.00 8.33 ATOM 486 H ARG 55 2.287 22.011 2.677 1.00 0.00 ATOM 487 CA ARG 55 3.322 21.141 1.094 1.00 9.23 ATOM 488 CB ARG 55 4.611 21.966 1.055 1.00 6.97 ATOM 489 CG ARG 55 4.532 23.059 0.020 1.00 10.44 ATOM 490 CD ARG 55 5.795 23.872 0.061 1.00 12.13 ATOM 491 NE ARG 55 5.926 24.706 -1.136 1.00 18.61 ATOM 492 HE ARG 55 6.452 24.356 -1.888 1.00 0.00 ATOM 493 CZ ARG 55 5.350 25.913 -1.280 1.00 15.59 ATOM 494 NHl ARG 55 4.586 26.464 -0.336 1.00 10.00 ATOM 495 HHll ARG 55 4.408 25.984 0.524 1.00 0.00 ATOM 496 HH12 ARG 55 4.189 27.367 -0.490 1.00 0.00 ATOM 497 NH2 ARG 55 5.584 26.607 -2.390 1.00 14.76 ATOM 498 HH21 ARG 55 6.170 26.232 -3.108 1.00 0.00 ATOM 499 HH22 ARG 55 5.161 27.505 -2.516 1.00 0.00 ATOM 500 C ARG 55 3.524 19.911 1.961 1.00 9.89 SUBSTlTUTE S~ RULE 2~

WO g7/08300 PCT~US96/13918 ATOM 501 ~ ARG55 3.145 19.914 3.136 1.00 7.57 ATOM 502 N PHE56 4.170 18.888 1.41g 1.00 11.16 ATOM 503 H PHE56 4.544 18.997 0.510 1.00 0.00 ATOM 504 CA PHE56 4.340 17.617 2.096 1.00 10.07 ATOM 505 CBPHE 564.098 16.469 1.151 1.00 10.65 ATOM 506 CG PHE56 2.742 16.558 0.505 1.00 5.39 ATOM 507 CDl PHE 562.644 16.978 -0.820 1.00 7.49 ATOM 508 CD2 PHE 561.625 16.180 1.224 1.00 2.00 ATOM 509 CEl PHE 561.397 17.010 -1.440 1.00 2.00 ATOM 510CE2 PHE 56 0.387 16.217 0.593 1.00 4.37 ATOM 511 CZ PHE56 0.271 16.629 -0.735 1.00 3.23 ATOM 512 C PHE56 5.720 i7.453 2 654 1.00 7.33 ATOM 513 O PHE56 6.669 17.846 1.989 1.00 3.76 ATOM 514 N HIS57 5.911 16.893 3.847 1.00 7.78 ~5 ATOM 515 H HIS 575.145 16.575 4.376 1.00 0.00 ATOM 516 CA HIS57 7.243 16.753 4.422 1.00 9.13 ATOM 517 CB HIS57 7.410 17.78i 5.554 1.00 9.13 ATOM 518 CG HIS57 7.101 19.214 5.116 1.00 5.87 ATOM 519 CD2 HIS 575.851 19.759 5.157 1.00 4.86 ATOM 520NDl HIS 57 7.905 20.137 4,602 1.00 5.61 ATOM 521 HDl HIS 578.788 19.977 4.213 1.00 0 00 ATOM 522 CEl HIS 577.208 21.202 4.328 1.00 2.00 ATOM 523 NE2 HIS 575.978 20.952 4.666 1.00 8.92 ATOM 524 HE2 HIS 575.233 21 552 4.438 1 00 0 00 ATOM 525C HIS 577.295 15.330 4.g45 1.00 7 66 ATOM 526 O HIS 576.364 14.882 5.611 1.00 11.39 ATOM 527 N HIS 588.296 14.567 4.535 1.00 9.95 ATOM 528 H HIS 589.012 14.961 3.981 1.00 0.00 ATOM 529 CA HIS 588.411 13 173 4.887 1.00 7.60 ATOM 530CB HIS 588.491 12.344 3.620 1.00 3.50 ATOM 531 CG HIS 587.195 12.474 2.834 1.00 2.00 ATOM 532 CD2 HIS 587.013 13.360 1.813 1.00 2.00 ATOM 533 NDl HIS 586.051 11.828 2.960 1.00 4.99 ATOM 534 HDl HIS 585.844 11.123 3.619 1.00 0.00 ATOM 535CEl HIS 58 5 196 12 273 2 087 1 00 2 00 ATOM 536 NE2 HIS 585,794 13.197 1.403 1.00 2.00 ATOM 537 HE2 HIS 585.390 13.727 0.691 1.00 0.00 ATOM 538 C HIS58 9.639 12.966 5.731 1.00 7.66 ATOM 539 O HIS58 10.756 13.187 5.271 1.00 6.10 SUBSTITUTE Si~ RULE 7~;~
, CA 02226963 l998-02-l2 WO 97/08300 PCT~US96/13918 ATOM 540 NPHE 599.418 12.580 6.985 1.00 4.13 ATOM 541 HPHE 598.490 12.492 7.283 1.00 0.00 ATOM 542 CAPHE 5910.476 12.333 7.958 1.00 5.36 ATOM 543 CBPHE 5910.097 13.014 9.295 1.00 5.09 ATOM 544 CGPHE 5910.111 14.519 9.155 1.00 2.00 ATOM 545 CDl PHE598.934 15.206 8.879 1.00 2.00 ATOM 546 CD2 PHE5911.332 15.182 9.253 1.00 3.34 ATOM 547 CEl PHE598.987 16.571 8.688 1.00 8.91 ATOM 548 CE2 PHE5911.371 16.549 9.060 1.00 2.00 ATOM 549 CZPHE 5910.203 17.246 8.780 1.00 2.00 ATOM 550 CPHE 5910.707 10.846 8.189 1.00 3.82 ATOM 551 OPHE 599.802 10.183 8.724 1.00 4.17 ATOM 552 NPRO 6011.822 10.239 7 802 1.00 4.66 ATOM 553 CDPRO 6012.871 10.838 6.989 1.00 7.48 ATOM 554 CAPRO 6012.139 8.867 8.165 1.00 6.70 ATOM 555 CBPRO 6013.388 8.558 7.392 1.00 4.95 ATOM 556 CGPRO 6013.453 9.621 6.300 1.00 5.79 ATOM 557 CPRO 6012.313 8.715 9.672 1.00 10.66 ATOM 558 OPRO 6012.935 9.532 10.350 1.00 8.35 ATOM 559 NILE 6111.681 7.687 10.217 1.00 11.15 ATOM 560 H ILE6111.1167 128 9.646 1.00 0.00 ATOM 561 CA ILE6111.8077.337 11.621 1.00 7.78 ATOM 562 CB ILE6110.4087.155 12.247 1.00 6.02 ATOM 563 CG2 ILE6110.620 6.819 13.710 1.00 4.07 ATOM 564 CGl ILE619.524 8.398 12.103 1.00 4.03 ATOM 565 CDILE 618.035 8.155 12.396 1.00 2.00 ATOM 566 CILE 6112.563 6.013 11.574 1.00 8.52 ATOM 567 OILE 6112.018 5.034 11.047 1.00 9.02 ATOM 568 NGLU 6213.816 5.975 12.022 1.00 9.62 ATOM 569 HGLU 6214.202 6.797 12.395 1.00 0.00 ATOM 570 CA GLU 6214.612 4.756 12.035 1.00 8.61 ATOM 571 CB GLU 6216.077 5.015 11.900 1.00 8.30 ATOM 572 CG GLU6216.575 5.629 10.615 1.00 29.69 ATOM 573 CD GLU6218.027 6.097 10.749 1.00 43.17 ATOM 574 OEl GLU6218.878 5.304 11.173 1.00 46.59 ATOM 575 OE2 GLU6218.305 7.262 10.441 1.00 47.06 ATOM 576 C GLU6214.4644.023 13.348 1.00 9.33 ~ ATOM 577 O GLU6214.3214.691 14.365 1.00 11.22 ATOM 578 N ARG6314.4602.698 13.370 1.00 9.50 SUBSTITUTE S}~ RULE 2~;) CA 02226963 l998-02-l2 ATOM 579 H ARG 63 14.448 2.228 12.514 1.00 0.00 ATOM 580 CA ARG 63 14 508 1.918 14.597 1.00 11.99 ATOM 581 CB ARG 63 13.851 0.583 14.339 1.00 16.38 ATOM 582 CG ARG 63 13.612 -0.2Q3 15.604 1.00 20.52 ATOM 583 CD ARG 63 12.82S -1.422 15.224 1.00 27.53 ATOM 584 NE ARG 63 12.614 -2.334 16.332 1.00 36.69 ATOM 585 HE ARG 63 11.709 -2.419 16.697 1.00 0.00 ATOM 586 CZ ARG 63 13.596 -3.072 16.878 1.00 39.35 ATOM 587 NHl ARG 63 14.864 -3.031 16.463 1.00 42.71 ATOM 588 HHll ARG 63 15.125 -2.426 15.711 1.00 0.00 ATOM 589 HH12 ARG 6315.553 -3.603 16.909 1.00 0.00 ATOM 590 NH2 ARG 6313.293 -3.916 17.858 1.00 41.76 ATOM 591 HH21 ARG 6312.349 -3.985 18.185 1.00 0.00 ATOM 592 HH22 ARG 6314.009 -4.480 18.269 1.00 0.00 ATOM 593 C ARG63 15.992 1.760 14.998 1 00 14.55 ATOM 594 O ARG 6316.882 1.405 14.210 1.00 15.00 ATOM 595 N GLN 6416.312 2.083 16.247 1.00 13.04 ATOM 596 H GLN 6415.586 2.240 16.876 1.00 0.00 ATOM 597 CA GLN 6417.692 2.150 16.724 1.00 14.92 ATOM 598 CB GLN64 17.809 3.120 17.901 1.00 13.12 ATOM 599 CG GLN 6417.253 4-507 17.632 1.00 20.26 ATOM 600 CD GLN 6418.029 5.26S 16.569 1.00 26.72 ATOM 601 OEl GLN 64 17.579 5.524 15.453 1.00 32.53 ATOM 602 NE2 GLN 64 19.246 5.681 16.873 1.00 31.43 ATOM 603 HE21 GLN 64 19.593 5.484 17.766 1.00 0.00 ATOM o'04 HE22 GLN 6419.721 6.197 16.189 1.00 0.00 ATOM 605 C GLN 6418.196 0.803 17.200 1 00 14.42 ATOM 606 O GLN 6417.384 -0.097 17.379 1.00 15.52 ATOM 607 N LEU 6519.498 0.702 17.519 1.00 19.29 ATOM 608 H LEU65 20.086 1.426 17.230 1.00 0.00 ATOM 609 CA LEU 6520.112 -0.477 18.145 1.00 22.45 ATOM 610 CB LEU 6521.589 -0.172 18.629 i.oo 28.25 ATOM 611 CG LEU 6522.134 0.937 19.638 1.00 36.97 ATOM 612 CDl LEU 6521.972 0.566 21.105 1.00 35.85 t ATOM 613 CD2 LEU 65 23.666 1.012 19.553 1.00 31.59 ATOM 614 C LEU 6519.306 -0.988 19.337 1.00 19.74 ATOM 615 o LEU 6519.098 -2.185 19.514 1.00 22.52 ATOM 616 N ASN 6618.737 -0.082 20.122 1.00 16.94 ATOM 617 H ASN 6618.751 0.854 19.850 1.00 0.00 SUBSTlTUTE ~ t~ULE 2~

CA 02226963 l998-02-l2 W O 97/08300 P~TAUS9~/13918 ATOM 618 CA ASN 66 18.035 -0.443 21.344 1.00 14.28 ATOM 619 CB ASN 66 18.407 0.567 22.433 1.00 17.49 ATOM 620 CG ASN 66 18.149 2.027 22.091 1.00 18.94 ATOM 621 ODl ASN66 17.411 2.357 21.159 1.00 20.48 5 ATOM 622 ND2 ASN66 18.776 2.964 22.771 1.00 26.84 ATOM 623 HD21 ASN 66 19.427 2.694 23.459 1.00 0.00 ATOM 624 HD22 ASN 66 18.577 3.906 22.593 1.00 0.00 ATOM 625 CASN 66 16.531 -0.557 21.223 1.00 13.50 ATOM 626 OASN 66 15.822 -0.693 22.219 1.00 11.14 10 ATOM 627 NGLY 67 16.013 -0.514 19.997 1.00 10.89 ATOM 628 HGLY 67 16.594 -0.368 19.219 1.00 0.00 ATOM 629 CAGLY 67 14.604 _0,731 19.757 1.00 5.16 ATOM 630 CGLY 67 13.780 0.521 19.903 1.00 5.50 ATOM 631 OGLY 67 12.551 0.429 19.953 1.00 4.32 15 ATOM 632 NTHR 68 14.402 1.679 20.083 1.00 5.74 ATOM 633 HTHR 68 15.364 1.730 20.241 1.00 0.00 ATOM 634 CATHR 68 13.602 2.891 20.096 1 00 10.10 ATOM 635 CBTHR 68 14.274 3.962 21.038 1.00 7 70 ATOM 636 OGl THR68 15.602 4.200 20.634 1.00 6.50 20 ATOM 637 HGl THR68 16.204 3.718 21 205 1.00 0.00 ATOM 638 CG2 THR68 14.284 3.486 22.482 1.00 6.39 ATOM 639 CTHR 68 13.465 3.376 18.643 1.00 10.84 ATOM 640 OTHR 68 14.033 2.800 17.706 1.00 8.07 ATOM 641 NTYR 69 12.687 4.417 18.438 1.00 11.31 25 ATOM 642 HTYR 69 12.312 4.893 19.205 1.00 0.00 ATOM 643 CATYR 69 12.398 4.956 17.143 1.00 8.56 ATOM 644 CBTYR 69 10.914 4.793 16.881 1.00 10.27 ATOM 645 CGTYR 69 10.494 3.343 16.804 1.00 9.08 ATOM 646 CDl TYR-'9 10.116 2.661 17.959 1.00 11.62 30 ATOM 647 CEl TYR69 9.769 1.316 17.883 1.00 15.89 ATOM 648 CD2 TYR69 10.525 2.691 15.571 1.00 12.19 ATOM 649 CE2 TYR69 10.178 1.342 15.490 1.00 16.67 ATOM 650 CZTYR 69 9.798 0.654 16.647 1.00 20.73 ATOM 651 OHTYR 69 9.417 -0.682 16.573 1.00 17.13 35 ATOM 652 HHTYR 69 9.258 -0.922 15.649 1.00 0.00 ; ATOM 653 CTYR 69 12.784 6.416 17.202 1.00 10.11 ATOM 654 OTYR 69 12.428 7.111 18.163 1.00 14.34 ~ ATOM 655 NALA 70 13.S10 6.930 16.224 1.00 12.39 ATOM 656 HALA 70 13.836 6.347 15.502 1.00 0.00 SUBS~ITUTE ~tEE~ (RULE 2~;) CA 02226963 l998-02-l2 W O 97/08300 PCTrUS96/13918 ATOM 657 CA ALA 70 13.886 8.334 16.185 1.00 10.82 ATOM 658 CB ALA 70 15.239 8.583 16.848 1.00 2.00 ATOM 659 C ALA 7014.013 8.833 14.753 1.00 12.46 ATOM 660 O ALA 7014.523 8.112 13.875 1.00 13.59 ATOM 661 N ILE71 13.533 10.060 14.503 1.00 12.16 ATOM 662 H ILE 7113.071 10.526 15.230 1.00 0.00 ATOM 663 CA ILE 7113.773 10.777 13.252 1.00 8.89 ATOM 664 CB ILE 7112.896 12.060 13.195 1.00 8.93 ATOM 665 CG2 ILE 71 13.255 12.885 11.969 1.00 7.48 ATOM 666 CGl ILE 71 11.433 11.675 13.158 1.00 2 00 ATOM 667 CD ILE 7110.520 12.881 13.246 1.00 4.76 ATOM 668 C ILE 7115.260 11.117 13.332 1.00 11.20 ATOM 669 O ILE 7115.714 ll.gl2 14.446 1.00 13.25 ATOM 670 N ALA 7216.085 11.069 12.277 1.00 11.89 ATOM 671 H ALA72 15.694 10.895 11.392 1.00 0.00 ATOM 672 CA ALA 72 17.517 11.313 12.436 1.00 14.12 ATOM 673 CB ALA 7218.258 11.340 11.128 1 00 12.87 ATOM 674 C ALA 7217.808 12.650 13.095 1.00 15.57 ATOM 675 O ALA 7217.219 13.669 12.737 1.00 13.25 ATOM 676 N GLY73 18.672 12.625 14.108 1.00 16.33 ATOM 677 H GLY 7319.112 11.771 14.299 1.00 0.00 ATOM 678 CA GLY 7319.052 13.798 14.882 1.00 11.52 ATOM 679 C GLY 7317.960 14.265 15.834 1.00 14.51 ATOM 680 O GLY 7318.049 15.366 16.389 1.00 17.12 ATOM 681 N GLY74 16.920 13.g56 16.033 1.00 13.85 ATOM 682 H GLY 7416.913 12.572 15.613 1 00 0.00 ATOM 683 CA GLY 7415.824 13.787 16.906 1.00 9.77 ATOM 684 C GLY 7415.825 12.895 18.126 1.00 13.72 ATOM 685 O GLY 7416.649 11.983 18.268 1.00 12.11 ATOM 686 N LYS75 14.817 13.150 18.960 1.00 12.83 ATOM 687 H LYS 7514.144 13.806 18.678 1.00 0.00 ATOM 688 CA LYS 7514.668 12.437 20.215 1.00 14.60 ATOM 689 CB LYS 7513.695 13.172 21.136 1.00 15.05 ATOM 690 CG LYS 7514.384 14.383 21.707 1.00 11.11 ATOM 691 CD LYS75 13.518 15.120 22.693 1.00 13.01 ATOM 692 CE LYS 7514.260 16.420 22.919 1.00 12.46 ATOM 693 NZ LYS 7513.448 17.330 23.676 1.00 21.36 ATOM 694 HZl LYS 75 12.515 17.427 23.225 1.00 0.00 ATOM 695 HZ2 LYS 75 13.918 18.257 23.714 1.00 0.00 SU~ST~TUTE ~{E~ ~RIJLE 26~

CA 02226963 l998-02-l2 ATOM 696 HZ3 LYS 75 13.329 16.962 24.643 l.C0 0.00 ATOM 697 C LYS 75 14.178 11.018 20.033 1.00 16.16 ATOM 698 O LYS 75 13.270 10.809 19.220 1.00 17.70 ATOM 699 N ALA 76 14.734 10.048 20.761 1.00 13.81 ATOM 700 H ALA 76 15.503 10.266 21.322 1.00 0.00 ATOM 701 CA ALA 76 14.257 8.684 20.683 1.00 10.95 ATOM 702 CB ALA76lS.291 7.721 21.213 1.00 11.99 ATOM 703 C ALA7612.977 8.477 21.464 1.00 10.10 ATOM 704 O ALA7612.624 9.208 22.399 1.00 11.36 1 0 ATOM 705 N HIS 77 12.180 7.515 21.027 1.00 6.45 ATOM 706 H HIS7712.464 6.969 20.258 1 00 0.00 ATOM 707 CA HIS7710.911 7.205 21.658 1.00 8.09 ATOM 708 CB HIS779.751 7.778 20.879 l.C0 8.53 ATOM 709 CG HIS779,907 9.264 20.582 1.00 8.60 1 5 ATOM 710CD2 HIS 77 9.429 10.268 21 371 1.00 9.12 ATOM 711 NDl HIS 77 10.514 9.833 19.550 1.00 9.19 ATOM 712 HDl HIS 77 11.053 9.394 18.851 1.00 0.00 ATOM 713 CEl HIS 77 10.418 11.122 19.680 1.00 2.93 ATOM 714 NE2 HIS 77 9.768 11.368 20.778 1.00 9.32 20 ATOM 715 HE2 HIS 77 9.596 12.266 21.126 1.00 0.00 ATOM 716 C HIS 77 10.745 5.702 21.692 1.00 11.51 ATOM 717 O HIS 77 11.253 4.990 20.834 1.00 12.04 ATOM 718 N CYS 78 10.033 5.169 22.660 1.00 12.82 ATOM 719 H CYS 78 9.625 5.747 23.326 1.00 0.00 2~ ATOM 720 CACYS 78 9.884 3.735 22.776 1~00 14.28 ATOM 721 C~CYS 78 9.381 3.354 2~.175 1.00 11.77 ATOM 722 SGCYS 78 10.796 3.369 25.280 1.00 9.90 ATOM 723 C CYS 78 8.960 3.126 21.757 1.00 16.98 ATOM 724 O CYS 78 9.005 1.908 21.557 1.00 17.80 30 ATOM 725 N GLY 79 8.128 3.943 21.113 1.00 15.68 ATOM 726 H GLY 79 8.169 4.912 21.228 1.00 0.00 ATOM 727 CA GLY 79 7.212 3.410 20.145 1.00 11.88 ATOM 728 C GLY796.762 4.509 19.210 1.00 14.80 ATOM 729 O GLY797.015 5.682 19.512 1.00 12.62 35 ATOM 730 N PRO806.089 4.186 18.089 1.00 16.78 ATOM 731 CD PRO806.052 2.849 17.491 1.00 13.56 ATOM 732 CA PRO805.496 5.158 17.187 1.00 15.14 ATOM 733 CB PRO805.005 4.318 16.015 1.00 18.70 ATOM 734 CG PRO804.852 2.933 16.571 1.00 14.52 SUBSTITUTE ~ ~ (RULE 2~i) WO 97/08300 PCT~US96/13918 ATOM 735 C PRO 80 4.425 6 013 17.827 1.00 13.25 ATOM 736 O P~O 80 4.390 7.209 17.551 1.00 13.75 ATOM 737 N ALA81 3.5825.470 18.715 1.00 11.81 ATOM 738 H ALA81 3.6484.511 18.927 1.00 0.00 ,, ATOM 739 CA ALA81 2.5606.256 19.378 1.00 8.01 ATOM 740 CB ALA81 1.6965.401 20.259 1.00 10.17 ATOM 741 C ALA81 3.2177.301 20.270 1.00 14.13 ATOM 742 O ALA81 2.7598.447 20.315 1.00 19.64 ATOM 743 N GLU82 4.3176.966 20.950 1.00 8.88 1 0 ATOM 744 H GLU82 4.6756.068 20.827 1.00 0.00 ATOM 745 CA GLU82 4.9987.900 21.810 1.00 8.22 ATOM 746 CB GLU82 6.0557.211 22.673 1.00 12.54 ATOM 747 CG GLU82 5.5106.345 23.801 1.00 15.92 ATOM 748 CD GLU82 5.2484.903 23.391 1.00 21.02 1 5 ATOM 749 OEl GLU82 5.8984.019 23.922 l .00 19.20 ATOM 750 OE2 GLU82 4.4034.643 22.545 1.00 30.40 ATOM 751 C GLU82 5.6838.982 21.007 1.00 7.91 ATOM 752 O GLU82 5.77210.112 21.482 1.00 8.06 ATOM 753 N LEU83 6.1778.672 19.799 1.00 9.05 2 0 ATOM 754 H LEU83 6.0607.759 19.462 1 00 0.00 ATOM 755 CA LEU83 6.8049.659 18.938 1.00 4.91 ATOM 756 CB LEU83 7.5218.966 17.736 1.00 3.58 ATOM 757 CG LEU83 8.2729.829 16.683 1.00 7.47 ATOM 758 CDl LEU83 9.4809.086 16.219 1.00 2.00 ATOM 759 CD2 LEU83 7.35710.216 15.52g 1.00 2.00 ATOM 760 C LEU83 5.75210.640 18.449 1.00 4 63 ATOM 761 ~ LEU83 5.98811.849 18.544 1.00 5.60 ATOM 762 N CYS84 4.60210.164 17.973 1.00 8.55 ATOM 763 H CYS84 4.4949.192 17.890 1.00 0.00 3 0 ATOM 764 CA CYS84 3.54811.027 17.482 1.00 8.64 ATOM 765 CB CYS84 2.50310.168 16.756 1.00 5.54 ATOM 766 SG CYS84 3.1779.486 15.221 1.00 11.42 ATOM 767 C CYS84 2.92611.826 18.615 1.00 12.17 ATOM 768 O CYS84 2.57512.979 18.399 1.00 11.99 ATOM 769 N GLU85 2.806ll.Z94 19.835 1.00 15.31 ATOM 770 H GLU85 3.00410.339 19.935 1.00 0.00 ATOM 771 CA GLU85 2.35012.030 21.007 1.00 12.31 ATOM 772 CB GLU85 2.21211.121 22.207 1.00 19.90 ATOM 773 CG FLU85 0.81510.555 22.406 1.00 31.63 SU85TITUTE S~tE~ ~RlJLE ~i~

CA 02226963 l998-02-l2 W O 97/08300 PCTrus96/l39l8 ATON 774 CD GLU 85 0.658 9.4g5 23.503 1.00 39.27 ATOM 775 OEl GLU 85 -0.477 9.081 23.738 1.00 41.21 ATOM 776 OE2 GLU 85 1.642 9.071 24.118 1.00 42.94 ATOM 777 C GLU85 3.333 13.125 21.372 1.00 6.87 ATOM 778 O GLU 85 2.920 14.260 21.571 1.00 10.13 ATOM 779 N PHE86 4.631 12.861 21.416 1.00 4.59 ATOM 780 H PHE86 4.937 11.944 21.248 1.00 0.00 ATOM 781 CA PHE86 5.603 13.890 21.725 1.00 6.95 ATOM 782 CB PHE86 6.999 13.293 21.764 1.00 4.93 ATOM 783 CGPHE 86 8.114 14.317 21.932 1.00 5.40 ATOM 784 CDl PHE 86 8.400 14.831 23.201 1.00 2.19 ATOM 785 CD2 PHE 86 8.808 14.781 20.807 1.00 2.76 ATOM 786 CEl PHE 86 9.375 15.816 23.336 1.00 2.93 ATOM 787 CE2 PHE 86 9.781 15.765 20.944 1.00 2.30 ATOM 788 CZPHE 86 10.064 16.284 22.212 1.00 5.55 ATOM 789 C PHE86 5.575 15.027 20.720 1.00 9.00 ATOM 790 O PHE86 5.446 16.187 21.109 1.00 14.30 ATOM 791 N TYR87 5.653 14.760 19.418 1.00 11.37 ATOM 792 H TYR87 5.691 13.826 19.113 1.00 0.00 ATOM 793 CATYR 87 5.666 15.833 18.446 1.00 6.03 ATOM 794 CB TYR87 6.110 15.254 17.139 1.00 3.16 ATOM 795 CG TYR87 7.591 14.946 17.117 1.00 2.00 ATOM 796 CDl TYR 87 8.021 13.631 17.046 1.00 5.05 ATOM 797 CEl TYR 87 9.391 13.356 16.974 1.00 8.26 ATOM 798CD2 TYR 87 8.525 15.979 17.117 1.00 2.00 ATOM 799 _CE2 TYR87 9.891 15.713 17.042 1.00 2.00 ATOM 800 CZ TYR87 10.316 14.396 16.974 1.00 6.27 ATOM 801 OH TYR87 11.668 14.102 16.932 1.00 7.53 ATOM 802 HH TYR87 12.181 14.910 17.066 1.00 0.00 ATOM 803 C TYR 87 4.352 16.586 18.305 1.00 3.38 ATOM 804 O TYR87 4.319 17.653 17.702 1.00 5.53 ATOM 805 N SER88 3.248 16.094 18.857 1.00 7.17 ATOM 806 H SER88 3.264 15.179 19.207 1.00 0.00 ATOM 807 CA SER88 2.009 16.852 18.979 1.00 6.67 ATOM 808 CBSER 88 0.860 15.969 19.425 1.00 6.09 ATOM 809 OG SER88 0.561 14.907 18.539 1.00 23.12 ATOM 810 HG SER 88 1.351 14.368 18.429 1.00 0.00 ATOM 811 C SER 88 2.160 17.942 20.036 1.00 9.31 ATOM 812 O SER 88 1.486 18.970 19.995 1.00 5.17 SU~STlTUTE ~}tE~ t~U~E 2~) CA 02226963 l998-02-l2 W O 97/08300 PCTnUS96/13918 ATOM 813 N ARG 89 3.017 17.673 21.027 1.00 15.78 ATOM 814 H ARG 89 3.530 16.838 20.985 1.00 0.00 ATOM 815 CA ARG 89 3.262 18.543 22.175 1.00 19.64 ATOM 816 CB ARG 89 3.587 17.742 23.444 1.00 18.92 ATOM 817 CG ARG 89 2.563 16.693 23.853 1.00 28.31 ATOM 818 CD ARG 89 2.997 15.851 25.067 1.00 36.85 ATOM 819 NE ARG 89 4.239 15.083 24.955 1.00 42.21 ATOM 820 HE ARG 89 5.061 15.540 24.679 1.00 0.00 ATOM 821 CZ ARG 89 4.296 13.764 25.223 1.00 44.61 0 ATOM 822 NHl ARG 89 3.207 13.079 25.601 1.00 46.06 ATOM 823 HHll ARG 89 2.324 13.538 2S.696 1.00 0.00 ATOM 824 HH12 ARG 89 3.280 12.100 25.792 1.00 0.00 ATOM 825 NH2 ARG 89 5.469 13.119 25.157 1.00 44.47 ATOM 826 HH21 ARG 89 6.295 13.619 24.899 1.00 0.00 ATOM 827 HH22 ARG 89 5.518 12.140 25.357 1.00 0.00 ATOM 828 C ARG 89 4.444 19.469 21.928 1.00 18.88 ATOM 829 O ARG 89 4.507 20.553 22.493 1.00 20.00 ATOM 830 N ASP 90 5.421 19.082 21.131: 1.00 18.60 ATOM 831 H ASP 90 5.407 18.181 20.738 1.00 0.00 ATOM 832 CA ASP 90 6.582 19.891 20.903 1.00 16.39 ATOM 833 CB ASP 90 7.626 19.502 21.966 1.00 12.09 ATOM 834 CG ASP 90 8.925 20.286 22.048 1.00 10.44 ATOM 835 ODl ASP 90 9.737 19.962 22.905 1.00 21.16 ATOM 836 OD2 ASP 90 9.156 21.203 21.267 1.00 19.94 ATOM 837 C ASP 90 7.039 19.587 l9.g78 1.00 19.96 ATOM 838 O ASP 90 7.512 18.482 19.202 1.00 20.24 ATOM 839 N PRO 91 6.917 20.560 18.560 1.00 15.46 ATOM 840 CD PRO 91 6.233 21.831 18.781 1.00 17.20 ATOM 841 CA PRO 91 7.434 20.495 17.196 1.00 14.01 ATOM 842 CB PRO 91 7.287 21.916 16.672 1.00 16.08 ATOM 843 CG PRO 91 7.060 22.761 17.913 1.00 12.13 ATOM 844 C PRO 91 8.844 19.968 17.102 1.00 14.28 ATOM 845 O PRO 91 9.173 19.194 16.210 1.00 16.05 ATOM 846 N ASP 92 9.683 20.419 18.028 1.00 12.31 7 ATOM 847 H ASP 92 9.364 21.117 18.631 1.00 0.00 ATOM 848 CA ASP 92 11.043 19.991 18.195 1.00 10.93 ATOM 849 CB ASP 92 11.007 18.818 19.198 1.00 5.10 ATOM 850 CG ASP 92 12.355 18.438 19.826 1.00 8.25 ATOM 851 ODl ASP 92 13.246 19.264 20.003 1.00 14.68 SUBS~tTUTE Si~ EE~ tRuLE 2~i~

~ CA 02226963 1998-02-12~

DEMA~YDES OU ~3R~t l ~; VOLUMINEUX

LA PP~ESE~YTE PARTIE DE C~ I I E DEMANDE OU CE ~REVET
COMPREIYD PLUS D'UN TOME. - . -CECI EST LE TOnnE / D~

NC~ Pour les tomes additicrlels, veuillez c~n~acter le 8ureau canadien desb~evets .
- %~z6 ~3 3~
t JUMBO APPL~CATIONSIPATENTS - .

T}~IS S~CTION OF ~E APPLICA~ION~PATENT ~ONTAINS MOR~
THAN ON~ VOLUME

THIS IS VOLUME~ ~/ OF ~

NO~E: Fc~r additi~na1 v~lumes please c~ntact~~e Canadian Patent ~ff~ce , - .
. ' .

Claims (22)

Claims

1. A composition comprising a protein in crystalline form containing a peptide sequence comprising a tandem SH2 region of a ZAP family protein or a portion thereof.

2. A composition of claim 1 which further comprises one or more heavy metal atoms.

3. A composition of claim 1 wherein the protein comprises a region characterized by the coordinates of Appendix 1, Appendix II, Appendix III, or Appendix IV, or coordinates having a root mean square deviation therefrom, with respect to backbone atoms of the listed amino acids, of not more than 1.5 .ANG..

4. A composition of claim 1 in which the protein is in a complex with one or more ligand molecules.

5. A composition of claim 1 in which the protein comprises the tandem SH2 region of human ZAP-70 (spanning at least amino acid residues 3 through 279) or the tandem SH2 region of human SYK (spanning at least amino acid residues 6 through 265).

6. A composition of any of claims 1-5 which diffracts x-rays to a resolution of greater than about 3.5 .ANG..

7. A method for determining the three-dimensional structure of a protein containing an SH2 domain, or a co-complex of the protein with a ligand therefor, which comprises (a) obtaining x-ray diffraction data for crystals of the protein or co-complex, (b) providing three-dimensional structural coordinates for a composition of any of claims 1-6, and (c) determining the three-dimensional structure of the SH2 domain-containing protein or co-complex by analyzing the x-ray diffraction data with reference to the previous structural coordinates using molecular replacement.

8. A method of claim 7 wherein the protein is a co-complex of ZAP-NC, or a portion thereof, with a ligand other than the ~1 peptide.

9 . A method of claim 7 wherein the protein is a co-complex of SYK-NC, or a portion thereof, with a ligand therefor.

10. A method for determining the three dimensional structure of a protein containing an SH2 domain or co-complex of said protein with a ligand therefor, which method comprises:

(a) providing structural coordinates for a composition of any of claims 1-6, and (b) determining the three-dimensional structure of the SH2 domain-containing protein or co-complex by homology modeling with reference to the previous structural coordinates.

11. A method for selecting a compound capable of binding to a ZAP family protein which comprises:

(a) providing coordinates defining the three dimensional structure of a ZAP family protein or a portion thereof;

(b) characterizing points associated with that three dimensional structure with respect to the favorability of interactions with one or more selected functional groups;

(c) providing a database of one or more candidate compounds; and (d) identifying from the database those compounds having structures which best fit the points of favorable interaction with the three dimensional structure.

12. A method of claim 11 which further comprises testing a compound so identified for its ability to:

(a) bind to a ZAP family protein, (b) inhibit the binding of a ZAP family protein to a natural or non-natural ligand therefor, and/or (c) inhibit a biological function mediated by a ZAP family member.

13. A machine-readable data storage medium, comprising a data storage material encoded with machine readable data which, when using a machine programmed with instructions for using said data is capable of displaying a graphical three-dimensional representation of a molecule or molecular complex comprising a protein of any of claims 1-6, or a portion thereof.

14. A machine-readable data storage medium, comprising a data storage material encoded with machine readable data which when using a machine programmed with instructions for using said data, is capable of displaying a graphical three-dimensional representation of a ZAP
family protein or ZAP family protein:ligand complex or portion thereof based on the coordinates of Appendix I Appendix II, or Appendix III, or based on coordinates having a root mean square deviation therefrom with respect to conserved protein backbone atoms of not more than 1.5 .ANG..

15. A machine-readable data storage medium comprising a data storage material encoded with a first set of machine readable data which when combined with a second set of machine-readable data using a machine programmed with instructions for using said first set of data and said second set of data, can determine at least a portion of the coordinates corresponding to the second set of machine-readable data, wherein: said first set of data comprises a Fourier transform of at least a portion of the coordinates according to Appendix I, Appendix II, Appendix III or Appendix IV; and said second set of data comprises an X-ray diffraction pattern of a molecule or molecular complex.

16. A method for displaying a three dimensional representation of a composition of any of claims 1-6 which comprises:
(a) providing a machine capable of reading data stored on a machine-readable storage medium of claim 13 programmed with instructions for using said data to display agraphical three-dimensional representation of a protein or protein:ligand complex or portion thereof defined by said data, and loaded with a machine-readable storage medium of claim 13; and (b) permitting the machine to read said data and display the three-dimensional representation.

17. A method for designing a compound capable of binding to a ZAP family protein that comprises:

(a) graphically displaying a three-dimensional representation based on coordinates defining the three-dimensional structure of a ZAP family protein or a portion thereof;

(b) characterizing the interactions between portions of a ligand that is known to bind to the protein to identify candidate moieties for replacement;

(c) providing a knowledge base of one or more candidate substitute moieties; and (d) identifying from the knowledge base one or more substitute moieties which may be used to replace one or more selected portions of the ligand and retain at least a portion of the ligand's binding affinity for the protein.

18. A method for designing a compound capable of binding to a ZAP family protein that comprises:

(a) providing coordinates defining the three-dimensional structure of a ZAP family protein or a portion thereof;

(b) characterizing points associated with that three-dimensional structure to identify preferred points with respect to the favorability of interactions of one or more selected functional groups with the protein;

(c) characterizing one or more portions of a ligand that is known to bind to theprotein that are proximal to the characterized points;

(d) providing a knowledge base of one or more molecular fragments or molecules;

(e) identifying from the knowledge base one or more fragments or molecules that permit connection of preferred points identified in (b) to portions of the ligand; and (f) modifying the structure of the ligand by the covalent attachment thereto of one or more such fragments or molecules so identified in an orientation and location selected to permit the modified ligand to bind to the protein.

19. A method for determining the orientation of a ligand bound to a ZAP family protein that comprises:

(a) providing coordinates defining the three-dimensional structure of a ZAP family protein or a portion thereof;

(b) characterizing points associated with that three-dimensional structure to identify preferred points with respect to the favorability of interactions of one or more selected functional groups with the protein;

(c) anchoring one or more functional groups of a ligand known to bind to the protein, the bound conformation of the ligand being unknown, at selected sites consistent with the preferred points of functional group interaction identified in (b); and, (d) performing modeling calculations to generate a series of alternative conformations and/or orientations for the anchored ligand.

20. A method for designing a compound capable of binding to a ZAP family protein that comprises:

(a) selecting a protein:ligand conformation and/or orientation identified by themethod of claim 19;

(b) characterizing the interactions between portions of the ligand and the protein to identify candidate moieties of the ligand for replacement;

(c) providing a knowledge base of one or more candidate substitute moieties; and (d) identifying from the knowledge base one or more substitute moieties which may be used to replace one or more selected portions of the ligand and retain at least a portion of the ligand's binding affinity for the protein.

21. A method for designing a compound capable of binding to a ZAP family protein that comprises:

(a) selecting a protein:ligand conformation and/or orientation identified by themethod of claim 19;

(b) characterizing points associated with the three-dimensional structure of theprotein to identify preferred points with respect to the favorability of interactions of one or more selected functional groups with the protein;

(c) characterizing one or more portions of a ligand that is known to bind to theprotein that are proximal to the characterized points;

(d) providing a knowledge base of one or more molecular fragments or molecules;

(e) identifying from the knowledge base one or more fragments or molecules that permit connection of preferred points identified in (b) to portions of the ligand; and (f) modifying the structure of the ligand by the covalent attachment thereto of one or more such fragments or molecules so identified in an orientation and location selected to permit the modified ligand to bind to the protein.

22. A method for selecting or designing a compound capable of binding to a ZAP family protein that comprises any combination of steps as described in claims 17-21.