WO2003083097A1 - Pleckstrin homology domain structure - Google Patents

Abstract

A method of identifying a compound which modulates the interaction between protein kinase B (PKB) and phosphatidylinositol (3,4,5)-triphosphate (PtdIns(3,4,5)P3) or phosphatidylinositol (3,4)-diphosphate (PtdIns(3,4)P2), the method comprising determining whether, and optionally to what extent, a conformational change in a pleckstrin homology (PH) domain of PKB upon contact with PtdIns(3,4,5)P3 or PtdIns(3,4)P2, is enhanced or disrupted in the presence of the compound. A method of identifying a compound which mimics the effect of PtdIns(3,4,5)P3 or PtdIns(3,4)P2 on PKB, the method comprising determining whether, and optionally to what extent, a conformational change in a PH domain of PKB upon contact with the compound, matches a conformational change in the PH domain upon contact with the PtdIns(3,4,5)P3 or PtdIns(3,4)P2.

Description

PLECKSTRIN HOMOLOGY DOMAIN STRUCTURE

The present invention relates to the structure of protein kinases, and particularly to the structure of protein kinase B.

Stimulation of cells with growth factors or insulin leads to the recruitment of phosphoinositide 3-kinase (PI 3-kinase) to the plasma membrane where it phosphorylates phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P₂) at the D3 hydroxyl group of the inositol ring to generate PtdIns(3,4,5)P₃ (reviewed by [1])- The finding that inhibitors of PI 3-kinase, or the over-expression of dominant negative mutants of PI 3-kinases, inhibited many key cellular processes, such as cell survival and insulin-induced metabolic processes, indicated that PtdIns(3,4,5)P₃ functioned as a key second messenger in regulating these events [2, 3]. Much recent work on the molecular mechanisms by which PtdIns(3,4,5)P₃, as well as its immediate breakdown product PtdIns(3,4)P₂, trigger physiological processes indicated that these lipids exert their effects by interacting with proteins possessing pleckstrin homology (PH) domains [4, 5]. One of the best characterised PtdIns(3,4,5)P₃/PtdIns(3,4)P₂ effector proteins is the serine/threonine protein kinase termed Protein Kinase B (PKB) also known as Akt. PKB is activated downstream of PI 3-kinase and phosphorylates numerous regulatory proteins to enhance insulin-induced metabolic responses such as stimulating glucose uptake and glycogen synthesis in addition to promoting cell proliferation and inhibiting apoptosis [6, 7, 8]. Indeed, in a significant number of cancer cell types, PKB activity is elevated and this has been demonstrated to contribute to the enhanced ability of these cells to survive and proliferate (reviewed in [8]).

PKB possesses a pleckstrin homology domain located at its N-terminus, which binds PtdIns(3,4,5)P₃ and PtdIns(3,4)P₂ with similar affinity, but does not interact with PtdIns(4,5)P₂, PtdIns3P or PtdIns4P [9, 10]. Following stimulation of cells with agonists that activate PI 3-kinase, PKB by virtue of its interaction with PtdIns(3,4,5)P₃/PtdIns(3,4)P₂, is recruited from the cytosol to the plasma membrane where these lipids are located [11, 12, 13]. Interaction of PKB with PtdIns(3,4,5)P₃ does not activate PKB directly, but instead brings it into the vicinity of protein kinases that phosphorylate PKB leading to its activation. The principal activating phosphorylation on PKB occurs at Thr308, a residue which resides in the T- loop of the protein kinase catalytic domain. This is mediated by the 3- Phosphoinositide Dependent Protein Kinase- 1 (PDK1), which like PKB, possesses a PtdIns(3,4,5)P₃/PtdIns(3,4)P₂ binding PH domain [14, 15]. Although the co-localisation of PKB and PDK1 with PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ at the plasma membrane is an important determinant in enabling PDK1 to phosphorylate PKB, the binding of PKB to PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ is also postulated to induce a conformational change in PKB exposing Thr308, thereby permitting it to be phosphorylated by PDK1. The evidence for this is based upon the observation that in the absence of 3-phosphoinositides, PDK1 is unable to phosphorylate wild type PKB under conditions where it is able to efficiently phosphorylate a mutant form of PKB that lacks its PH domain, termed ΔPH-PKB [15, 14]. Moreover, artificially promoting the interaction of PDK1 with wild type PKB and ΔPH-PKB by the attachment of a high affinity PDK1 interaction motif to these enzymes, was sufficient to induce maximal phosphorylation of Thr308 in ΔPH-PKB, but not in wild type PKB in unstimulated cells [16].

Despite the cellular importance of the binding of PtdIns(3,4,5)P₃ and PtdIns(3,4)P₂ to PKB, the mechanism by which these molecules bind to PKB, and the structure of the PKB PH domain (PKB-PH), were hitherto unknown. Previous predicted structures of the PKB PH domain were obtained using homology modelling methods based upon structural information available from the PH domain of Bruton's tyrosine kinase (BTK) [27], or from a hybrid of the PH domains of PLCδ and pleckstrin N [12], together with the PKB-PH domain sequence. These predictions of the PKB PH domain structure were thus biased towards the PH domain from which the structural information was obtained.

In this study, we have determined the crystal structure of the isolated PH domain of PKB alone, and a crystal structure of the PKB PH domain complexed with 3,4-phosphorylated phosphoinositide.

We show that binding of the phosphoinositide results in a surprising and unexpected conformational change in the PH domain, a phenomenon not previously observed in any other PH domain structure

We provide the first molecular insight into the mechanism by which PtdIns(3,4,5)P₃/Ptdms(3,4)P₂ bind to PKB. We also provide a structural understanding of how the binding of 3-phosphoinositides to PKB can induce conformational changes that activate PKB, especially its ability to be phosphorylated by PDK1. We also show how the structure of the PH domain of PKB could be exploited to design or identify compounds, such as inhibitors or activators of PKB, or mimics of 3-phosphoinositides, to affect the normal conformational change of the PH domain on binding of PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ to PKB.

A first aspect of the present invention provides a method of identifying a compound which modulates the interaction between PKB and PtdIns(3,4,5)P or PtdIns(3,4)P₂, the method comprising determining whether, and optionally to what extent, a conformational change in the PH domain of the PKB upon contact with PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂, is enhanced or disrupted in the presence of the compound.

A second aspect of the present invention provides a method of identifying a compound which mimics the effect of PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ on PKB, the method comprising determining whether, and optionally to what extent, a conformational change in a PH domain of the PKB upon contact with the compound, matches a conformational change in the PH domain of the PKB upon contact with the PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂.

The PKB_αPH structure reveals a standard PH domain fold with seven β- strands forming two orthogonal anti-parallel β-sheets closed at one end by a C-terminal α-helix. At the other end of the β-barrel lie three loops (NL1-3). These loops form a bowl lined with basic residues into which the Ins(l,3,4,5)P head group can bind. In the uncomplexed form, the ligand binding pocket of the PH domain was found to have a closed conformation, occupied by a hydrogen bonding network involving several basic residues. The hydrogen bonding network centres around an ionic interaction between Arg86/Lysl4 and Glu 17, and also involving Asn53 and several water molecules. The numbering of residues is based upon the numbering of full- length human PKB_α.

Upon binding of Ins(l,3,4,5)P to the PH domain, the hydrogen bonding network is disrupted and Ins(l,3,4,5)P forms specific interactions with several basic amino acid residues of the PH domain, as well as with other side chains and with the protein backbone. The DI -phosphate interacts with Arg23 and the backbone nitrogen of Ilel9; the D3-phosphate interacts with the side chains of Lysl4, Arg23, Arg25, and Asn53; and the D4-phosphate interacts with Lys 14, Asn53 and Arg86. Surprisingly, the D5-phosphate does not interact with any residue in the PH domain — it is oriented towards the solvent and interacts only with five ordered water molecules. Mutagenesis of basic amino acid residues that form ionic interactions with the D3 and D4 phosphate groups was shown to reduce or abolish the ability of PKB to interact with PtdIns(3,4,5)P₃ and PtdIns(3,4)P₂.

Binding of Ins(l,3,4,5)P₄ to the PH domain was shown to result in a surprising and unexpected conformational change in the variable loops of the PH domain, a phenomenon not previously observed in any other PH domain structure. Displacements of up to 7.6 A in the PKB PH backbone were shown to occur upon ligand binding. Glu 17 is pushed outwards, resulting in a relatively minor conformational change of VL1 with backbone shifts up to 2.5 A, with Arg86 following the movement of Glu 17. Arg86 lies at the base of NL3 and pulls the entire loop closer to the phosphoinositide binding pocket, leading to backbone shifts of up to 7.4 A at Trp80 which is located at the tip of VL3. In VL2, the entire loop is rearranged, with backbone shifts up to 7.6 A on Glu49, and forms an ordered α-helix with 3-4 negative charges (Asp44, Asp46, Glu49 and to a lesser extent Glu40) clustered together facing the solvent.

These changes may explain the molecular activation of PKB. While not intending to be bound by theory, we believe that in the absence of 3- phosphoinositides, NL2 forms an intra-molecular interaction with the PKB kinase domain. Upon 3-phosphoinositide binding, the large conformational change of VL2 together with the clustering of outward facing negative charges on the α-helix may dislodge VL2 from the PKB kinase domain, allowing PDK1 to phosphorylate PKB at Thr308.

The structure of the PH domain as provided herein differs from the previously published predicted structures [12, 27] as the predicted molecular models were based upon structures obtained from different PH domains, and using a ligand having a lipid chain (-OP03CH2CH(OCOC2H5)CH20COC2H4), while the structure provided herein is of the PKB-PH domain complexed with the 3-phosphoinositide headgroup Ins(l,3,4,5)P₄ and no lipid chains.

The most detailed previous model was published by Rong et al. [27], in which:

• There was no mention or suggestion of PKB_αPH forming a hydrogen bonding network with the water molecules in the absence of ligand.

• There is no mention or suggestion of Asn53 having any particular relevance to binding.

• There was no mention or suggestion that upon ligand binding, the VL2 loop forms an ordered alpha helix, or of the possible importance of the

3-4 negatively charged residues sited there (Asp44, Asp46, Glu49 and to a lesser extent Glu40). We have shown that these residues are exposed in the complexed structure when the helix is formed, and that in the absence of ligand, the helix is also absent.

• Glu40 is described as having a role in the binding affinity of the ligand PtdIns3,4,5P₃. Our structure, however, shows this is not the case but that Glu40 could have an effect on binding to the kinase domain.

• There was no mention or suggestion the VL2 region could be the region which interacts with the kinase domain.

• There was no mention or suggestion that the conformation of the PH domain changes upon ligand binding (this is highly unexpected in PH domains and so would not have been predicted).

• There was no mention or suggestion that the basic residues Argl5, Lys20, Arg67 and Arg69 could be used to help orientate the protein onto the lipid membrane. The method of the first and second aspects of the invention may also comprise the step of determining a baseline or normal conformational change in the PH domain of the PKB upon contact with PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ in the absence of the compound. Additionally or alternatively, a previously determined baseline or normal conformational change can be used.

Disrupting a conformational change in the PH domain of the PKB upon contact with PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ in the presence of the compound may comprise reducing the rate at which or extent to which the baseline or normal conformational change occurs.

Alternatively, disrupting a conformational change in the PH domain of the PKB upon contact with PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ in the presence of the compound may comprise abolishing a baseline or normal conformational change.

Additionally, disrupting a conformational change in the PH domain of the PKB upon contact with PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ in the presence of the compound may comprise causing a different conformational change to occur.

Enhancing a conformational change in the PH domain of the PKB upon contact with PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ in the presence of the compound may comprise increasing the rate at which or extent to which the baseline or normal conformational change occurs.

By "mimics the effect" of the interaction of the PtdIns(3,4,5)P₃ or

PtdIns(3,4)P₂ on PKB is meant that the compound has a quantitative or qualitative effect on at least one activity or function or property of PKB, for example on its ability to be phosphorylated by PDK1, or its protein kinase activity, that is the same as the effect of PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ on PKB.

The term PKB as used herein includes a polypeptide comprising the amino acid sequence identified as human PKB_α (NCBI Accession Number P31749); or human PKB_p (NCBI Accession Number P31751); or human PKB_y (NCBI Accession Number Q9Y243) or a variant, fragment, fusion or derivative thereof, or a fusion of a variant or fragment or derivative.

It is preferred that the PKB retains the protein kinase activity of full length human PKB_α. It is further preferred that the PKB is capable of binding PtdIns(3,4,5)P₃/PtdIns(3,4)P₂ and being activated by PDK1.

It is particularly preferred, although not essential, that the variant or fragment or derivative or fusion of the PKB, or the fusion of the variant or fragment or derivative, has at least 30% of the enzyme activity of full- length human PKB_α. It is more preferred if the variant or fragment or derivative or fusion of the PKB, or the fusion of the variant or fragment or derivative, has at least 50%, preferably at least 70% and more preferably at least 90% of the enzyme activity of human PKB_α.

It is also particularly preferred, although not essential, that the variant or fragment or derivative or fusion of the PKB, or the fusion of the variant or fragment or derivative, binds PtdIns(3,4,5)P₃/PtdIns(3,4)P₂ at at least 30% of the rate or extent of full-length human PKB_α. It is more preferred if the variant or fragment or derivative or fusion of the PKB, or the fusion of the variant or fragment or derivative, binds PtdIns(3,4,5)P₃/PtdIns(3,4)P₂ at at least 50%, preferably at at least 70% and more preferably at at least 90% of the rate or extent of human PKB_α. It is also particularly preferred, although not essential, that the variant or fragment or derivative or fusion of the PKB, or the fusion of the variant or fragment or derivative, can be activated by PDK1 at at least 30% of the rate or extent of full-length human PKB_α. It is more preferred if the variant or fragment or derivative or fusion of the PKB, or the fusion of the variant or fragment or derivative, can be activated by PDK1 at at least 50%, preferably at at least 70% and more preferably at at least 90% of the rate or extent of human PKB_α.

PDK1 is a ubiquitously expressed enzyme belonging to the serine/threonine family of protein kinases, which, like PKB, possesses a PH domain. It activates not only PKB, but also PKA, PKC-zeta, p70S6K and p90S6K/RSK, and is believed to play a general role in cellular signalling processes. Thus the term PDK1 as used herein includes a polypeptide comprising the amino acid sequence identified as human PDK1 (NCBI Accession Number 015530), or a variant, fragment, fusion or derivative thereof, or a fusion of a variant or fragment or derivative, and having at least 30% of the ability of full-length human PDK1 to phosphorylate PKB.

It is more preferred if the variant or fragment or derivative or fusion of the

PDK1, or the fusion of the variant or fragment or derivative, has at least 50%), preferably at least 70% and more preferably at least 90% of the ability of full-length human PDK1 to phosphorylate PKB.

The term PKB PH domain as used herein includes a polypeptide comprising the amino acid sequence identified as PKB in Figure 2 as SEQ ID NO: 1, or the equivalent region of PKBβ or PKBγ, or a variant, fragment, fusion or derivative thereof, or a fusion of a variant or fragment or derivative. Preferably, the PKB PH domain has a similar structure to that of PKB_αPH as defined herein, more preferably, the same structure as that of PKB_αPH. Preferably, the PKB PH domain undergoes a similar conformational change upon binding of 3-phosphoinositides as does PKB_αPH, and more preferably, undergoes the same conformational change as that of PKB_αPH. Preferably, the PKB PH domain is capable of binding 3-phosphoinositides at at least 30% of the rate or extent of full-length human PKB_α. It is more preferred if the PKB PH binds 3-phosphoinositides at at least 50%, preferably at at least 70% and more preferably at at least 90% of the rate or extent of human PKB_α.

By "variants" of a polypeptide we include insertions, deletions and substitutions, either conservative or non-conservative. In particular we include variants of the polypeptide where such changes do not substantially alter the activity of PKB, or the PKB PH.

By "variants" of a polypeptide we also include polypeptides comprising the native sequence of homologues of the polypeptide from other organisms.

By "conservative substitutions" is intended combinations such as Gly, Ala; Val, He, Leu; Asp, Glu; Asn, Gin; Ser, Thr; Lys, Arg; and Phe, Tyr.

The one letter or three-letter amino acid code of the IUPAC-IUB Biochemical Nomenclature Commission are used herein.

It is particularly preferred if the PKB or PKB-PH variant has an amino acid sequence which has at least 65% identity with the respective amino acid sequences of PKB or PKB-PH referred to above, more preferably at least 70%, 71%, 72%, 73% or 74%, still more preferably at least 75%, yet still more preferably at least 80%, in further preference at least 85%, in still further preference at least 90% and most preferably at least 95% or 97% identity with the respective amino acid sequences defined above. It is appreciated that percent sequence identity between two polypeptides may be readily identified by a person skilled in the art, for example using sequence comparisons as described below.

The percent sequence identity between two polypeptides may be determined using suitable computer programs, for example the GAP program of the University of Wisconsin Genetic Computing Group and it will be appreciated that percent identity is calculated in relation to polypeptides whose sequence has been aligned optimally.

The alignment may alternatively be carried out using the Clustal W program (Thompson et al (1994) Nucl Acid Res 22, 4673-4680). The parameters used may be as follows:

Fast pairwise alignment parameters: K-tuple(word) size; 1, window size; 5, gap penalty; 3, number of top diagonals; 5. Scoring method: x percent.

Multiple alignment parameters: gap open penalty; 10, gap extension penalty; 0.05.

Scoring matrix: BLOSUM.

It is preferred that the PKB or PKB PH domain are polypeptides which comprise the amino acid sequence of the respective PKB or PKB PH domain sequences referred to above, or naturally occurring allelic variants thereof. It is preferred that the naturally occurring allelic variants are mammalian, preferably human, but may alternatively be homologues from other organisms.

It is appreciated that compounds that modulate the binding of 3- phosphoinositides to PKB-PH may themselves bind to PKB-PH at the 3- phosphoinositide binding site. Such compounds may inhibit the normal or baseline conformational change in the PH domain by preventing 3- phosphoinositide binding to PKB-PH, thus reducing or abolishing the normal or baseline conformational change in the PH domain.

Alternatively, such compounds may bind to the 3-phosphoinositide binding site of the PKB-PH and cause a different conformational change from the normal or baseline conformational change to occur in the PH domain.

It is also appreciated that compounds which bind to the 3-phosphoinositide binding site of the PKB-PH may mimic the normal or baseline conformational change that occurs upon 3-phosphoinositide binding. The mimicked conformational change may occur at a different rate or to a different extent to that of the normal or baseline conformational change that occurs upon 3-phosphoinositide binding to PKB-PH.

It is further appreciated that compounds that modulate the binding of 3- phosphoinositides to PKB-PH may themselves bind to other regions of the PKB PH domain other than the 3-phosphoinositide binding site. Such compounds would typically either inhibit or enhance the normal or baseline conformational change that occurs upon 3-phosphoinositide binding to PKB-PH.

Preferably, measuring the conformational change may include measuring any of the changes to the PKB PH domain structure that occur upon binding of PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂, as described herein. More preferably, the measured conformational change is selected from the following:

• Outwards movement of Glu 17, resulting in a relatively minor conformational change of NL1 with backbone shifts up to 2.5 A, with Arg86 following the movement of Glu 17. • Movement of Arg86 at the base of VL3 pulling the entire VL3 loop closer to the 3-phosphoinositide binding pocket, leading to backbone shifts of up to 7.4 A at Trρ80.

• Rearrangement of the NL2 loop, with backbone shifts up to 7.6 A on Glu49, and formation of an ordered α-helix with the negatively charged

Asp44, Asp46, Glu49 and to a lesser extent Glu40 clustered together facing the solvent.

In a preferred embodiment of the present invention, determining the conformational change comprises using the 3D structural co-ordinates of the PH domain bound to a 3-phosphoinositide or headgroup thereof, and/or the 3D structural co-ordinates of the PH domain alone, or a subset thereof, and a molecular modelling technique, preferably, one of the molecular modelling techniques described herein.

Preferably, using the 3D structural co-ordinates of the PH domain bound to a 3-phosphoinositide or headgroup thereof, or subset thereof, comprises using the 3D structural co-ordinates of PKB_αPH-Ins(l,3,4,5)P₄ as set forth in Table 2, or a subset thereof.

Further preferably, using the 3D structural co-ordinates of the PH domain alone, or a subset thereof, comprises using the 3D structural co-ordinates of apo PKB_αPH as set forth in Table 3, or a subset thereof.

In an alternative preferred embodiment of the present invention, determining the conformational change in the PH domain of PKB comprises directly measuring the conformational change. Preferably, this comprises use of one or more of ΝMR; X-ray crystallography; circular dichroism, (CD) which may be useful in detecting, for example, the degree of presence or absence of the VL2 loop α-helix; or FRET. Such techniques are well known in the art. In a further preferred embodiment of the present invention, determining the conformational change comprises indirectly measuring the conformational change.

It will be appreciated that indirect determination of the conformational change does not encompass measurement of PKB enzymatic activity nor measurement of affinity of binding of a compound, for example a phosphoinositide, to PKB, for example using a protein-lipid overlay technique, as known to those skilled in the art.

In accordance with a preferred embodiment of the present invention, at least one amino acid residue of the PKB PH domain is substituted with a detectably-labelled cysteine residue, and indirectly measuring the conformational change in the PH domain of PKB comprises detecting the label.

Preferably, the detectably-labelled cysteine residue is fluorescently-labelled, and detecting the label comprises detecting a change in fluorescence intensity or frequency. Any thiol-reactive fluorophore, for example BAD AN (see, for example, Wadum et al Fluorescently labeled bovine acyl- CoA binding protein - an acyl-CoA sensor. Interaction with CoA and acyl- CoA esters and its use in measuring free acyl CoA esters and non-esterified fatty acids (NEFA); Hammarstrom et al (2001) Biophys J 80(6), 2867-2885; Schindel et al (2001) Eur J Biochem 268(3), 800-808), could be used to label the cysteine. An alternative suitable fluorophore is Acrylodan (Richieri et al (1992) JBiol Chem 267(33), 23495-23501).

It is preferred that the substituted amino acid residue of the PH domain is not involved in binding to PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂. Preferably, the substituted amino acid residue is selected from residues 1-123 of PKB_αPH as listed in SEQ ID No 1, with the exception of Lysl4, Ilel9, Arg23, Arg25, Asn53 and Arg86.

It is preferred that the substituted amino acid residue of the PH domain is not involved in binding to a negatively charged lipid membrane. Preferably the substituted amino acid residue is selected from residues 1-123 of PKB_αPH as listed in SEQ ID No 1, with the exception of Argl5, Lys20, Arg67 and Arg69.

It is preferred that the substituted amino acid residue of the PH domain is exposed to the solvent, and is located close to the binding pocket such that when a ligand (such as a 3,4 phosphoinositide) is not bound to the PH domain in the binding pocket, the fluorophore is located in the binding pocket.

Preferably, the substituted amino acid residue is selected from a residue located in VL1.

Most preferably, the substituted amino acid residue is selected from Glu 17, Glulδ, and Tyrl9 of SEQ ID NO: 1.

Preferably, the interaction or conformational change can be confirmed using a technique such as isothermal titration calorimetry (ITC) or a protein-lipid overlay binding assay.

In another aspect, the present invention provides a method of selecting or designing a compound to be assessed in the method of identifying compounds that modulate or mimic the effect of 3-phosphoinositides on PKB as described herein. The method comprises the step of using the 3D structural co-ordinates of a PKB PH domain bound to a 3-phosphoinositide or headgroup thereof, and/or the 3D structural co-ordinates of a PKB PH domain alone, or a subset thereof, and a molecular modelling technique, to select the compound from a plurality of test compounds. The compound may be based on or superimposed on the 3-phosphoinositide or headgroup structure.

Preferably, the method also comprises the steps of identifying, in at least one database of chemical structures, a set of test compounds containing a specific structural feature, identifying a subset of test compounds by discarding from the set of test compounds those compounds that are obviously unable to bind to the PKB PH domain based upon their size, charge and/or steric hindrance, and using the 3D structural co-ordinates of a PKB PH domain bound to a 3-phosphoinositide or headgroup thereof, and/or the 3D structural co-ordinates of a PH domain alone, or a subset thereof, and a molecular modelling technique, to identify from the subset of test compounds a compound likely to be able to bind to the PH domain.

Preferably, the method also comprises varying, typically computationally, the possible atoms at each site on the 3-phosphoinositide or headgroup thereof (or test compound, for example based on or superimposed on the 3- phosphoinositide or headgroup structure) that is identified in the 3D structural co-ordinates of the PH domain bound to the 3-phosphoinositide or headgroup thereof as being in contact with the PH domain, and screening for resultant compounds that minimise repulsion or hindrance while keeping the remaining protein co-ordinates and ligand co-ordinates of the PH domain bound to the 3-phosphoinositide or headgroup thereof fixed.

In another embodiment, using the 3D structural co-ordinates of a PH domain bound to a 3-phosphoinositide or headgroup thereof, and/or the 3D structural co-ordinates of a PH domain alone, or a subset thereof, comprises using a molecular model of a PH domain derived from the 3D structural coordinates of the PH domain bound to a 3-phosphoinsotide or headgroup thereof, and/or the 3D structural co-ordinates of the PH domain alone, or a subset thereof.

Preferably, using the 3D structural co-ordinates of a PH domain bound to a 3-phosphoinositide or headgroup thereof, or subset thereof, comprises using the 3D structural co-ordinates of PKB_αPH-Ins(l,3,4,5)P as set forth in Table 2, or a subset thereof.

Further preferably, using the 3D structural co-ordinates of a PH domain alone, or a subset thereof, comprises using the 3D structural co-ordinates of apo PKB_αPH as set forth in Table 3, or a subset thereof.

The 3D structure of a compound to be tested may be compared with the 3D structure of a PKB PH domain such as a 3D structure modelled from the data contained in Table 2 and/or Table 3. The compound structure may be a predicted 3D structure or a previously determined 3D structure. The 3D structures may be displayed by a computer in a 2D form, for example on a computer screen. The comparison may be performed using such 2D displays. A compound predicted to interact with the PKB PH domain and to cause a conformational change in a similar manner to PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ may be selected. Methods of assessing a conformational change are well known to those skilled in the art, and include methods such as CD, NMR, X-ray crystallography and FRET.

Conventional drug docking programmes may not take conformational changes of the binding protein into account. Therefore, the analysis of the binding of drugs to the scaffold structure of the PH domain alone, and to the PH domain in the conformation when bound to 3 -phosphoinositide, would typically be performed separately.

One approach to identify compounds that modulate or mimic the interaction between the PH domain of PKB 3-phosphoinositides is co-crystallisation, followed by determination of the structure of the co-crystals to ascertain any conformational change in the PH domain.

Known compounds that bind the PH domain of PKB, or compounds identified by molecular modelling techniques as described herein, are obtained or synthesised, co-crystallised together with the PKB PH domain, and the structure of the PH domain with the compound determined. From the resulting structure, the compound is modified, typically by adding, subtracting, or changing atoms in the compound, with the aim of improving the binding of the compound to the PH domain. The modified compound is obtained or synthesised, co-crystallised together with the PKB PH domain, and the structure of the PH domain with the modified compound determined. The steps of modification, co-crystallisation and structure determination can be iterated until compounds with the desired effect on the PKB PH domain are obtained.

The following references relate to molecular modelling techniques: Blundell et al (1996) "Structure-based drug design" Nature 384, 23-26; Bohm (1996) "Computational tools for structure-based ligand design" Prog Biophys Mol Biol 66(3), 197-210; Cohen et al (1990) J Med Chem 33, 883-894; Navia et al (1992) Curr Opin Struct Biol 2, 202-210.

The following computer programs, for example, may be useful in carrying out the method of this aspect of the invention: GRID (Goodford (1985) J Med Chem 28, 849-857; available from Oxford University, Oxford, UK); MCSS (Miranker et al (1991) Proteins: Structure, Function and Genetics 11, 29-34; available from Molecular Simulations, Burlington, MA); AUTODOCK (Goodsell et al (1990) Proteins: Structure, Function and Genetics 8, 195-202; available from Scripps Research Institute, La Jolla, CA); DOCK (Kuntz et al (1982) J Mol Biol 161, 269-288; available from the University of California, San Francisco, CA); LUDI (Bohm (1992) J Comp Aid Molec Design 6, 61-78; available from Biosym Technologies, San Diego, CA); LEGEND (Nishibata et al (1991) Tetrahedron 47, 8985; available from Molecular Simulations, Burlington, MA); LeapFrog (available from Tripos Associates, St Louis, MO); Gaussian 92, for example revision C (MJ Frisch, Gaussian, Inc., Pittsburgh, PA ©1992); AMBER, version 4.0 (PA Kollman, University of California at San Francisco, ©1994); QUANT A/CHARMM (Molecular Simulations, Inc., Burlington, MA ©1994); and Insight II/Discover (Biosym Technologies Inc., San Diego, CA ©1994). Programs may be run on, for example, a Silicon Graphics™ workstation, Indigo²™ or IBM RISC/6000™ workstation model 550.

Virtual screening methods are also reviewed in Schneider & Bohm (2002) Reviews Combinatorial Chem DDT 7(1) Virtual screening and fast automated docking methods.

The selected or designed compound may be synthesised (if not already synthesised) and tested further for its effect on PKB, for example its effect on the protein kinase activity or lipid binding activity of PKB. The compound may be tested in one of a variety of screening methods which are well known in the art.

A further aspect of the invention provides a method of modulating an activity, for example the protein kinase activity, of PKB wherein the PKB is exposed to a compound identified by any of the methods disclosed herein.

A yet further aspect of the invention is a compound identified or identifiable by the above selection/design method of the invention.

The ability of the compound to disrupt or enhance normal conformational change upon interaction of PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ with PKB-PH may be measured by detecting/measuring the conformational change using any suitable method and comparing the conformational change detected/measured in the presence of different concentrations of the test compound, for example in the absence and in the presence of the test compound, for example at a concentration of about lOOμM, 30μM, lOμM, 3μM, lμM, 0.1 μM, 0.01 μM and/or 0.001 μM. Suitable methods include methods analogous to those discussed herein.

In another aspect, the present invention provides a PKB, or a fragment, variant, derivative or fusion thereof, having at least one amino acid residue of the PH domain substituted by a detectably-labelled cysteine residue. In another similar aspect, the present invention provides a PKB, or a fragment, variant, derivative or fusion thereof, having at least one amino acid residue of the PH domain substituted by a cysteine residue that can be detectably labelled. Preferably, the substituted amino acid residue is as defined above.

In another aspect, the invention provides for the use of the PKB having at least one amino acid residue of the PH domain substituted by a detectably- labelled cysteine residue, in an assay for detecting conformational change of the PH domain. In still another aspect, the invention provides for a kit of parts comprising the PKB having at least one amino acid residue of the PH domain substituted by a detectably-labelled cysteine residue, or PKB having at least one amino acid residue of the PH domain substituted by a cysteine residue that can be detectably-labelled, and means for carrying out an assay for detecting conformational change of the PH domain.

Means for carrying out an assay may include one or more of phosphoinositides, or headgroups thereof, particularly PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ which can be used as normal or baseline positive controls, and Ins(l,3,4,5)P which can be used as a negative control; PKB mutants, for example Lysl4->Ala, Arg25->Ala or Arg86->Ala as negative controls (ie unable to bind to phosphoinositides); assay buffers; assay instructions; and a fluorophore for labelling the substituted cysteine residue, and reaction buffers for the labelling reaction.

In another aspect, the present invention provides for a nucleic acid encoding the PKB, or a fragment, variant, derivative or fusion thereof, having at least one amino acid residue of the PH domain substituted by a cysteine residue that can be detectably-labelled. In yet another aspect, the invention provides for a vector comprising such a nucleic acid, and in still yet a further aspect, the invention provides for a host cell comprising such a vector.

A compound identified by a method of the invention may, by modulating the conformational change of the PH domain, modulate the ability of the PKB to phosphorylate different substrates to different extents. The compound may inhibit the protein kinase activity in relation to one substrate but may increase or not affect the protein kinase activity in relation to a second substrate. A compound at a given concentration may inhibit phosphorylation of one substrate to a greater extent than another substrate. Thus, a compound may have different IC₅₀S in relation to phosphorylation of different substrates. The term IC₅₀ is well known to those skilled in the art and indicates the concentration of compound necessary to inhibit the observed parameter (i.e. phosphorylation of a particular substrate under particular conditions) to 50% of the value in the absence of the compound. The lower the IC₅₀, the more potent the compound. Methods of calculating IC₅₀ values are well known to those skilled in the art. A similar measure of the effect of the compound may be calculated for compounds that increase phosphorylation of a given substrate (for example the concentration necessary to increase phosphorylation by, for example 20% or 50%).

While indirect determination of the conformational change of the PH domain does not encompass measurement of PKB enzymatic activity, the modulatory effect of a compound identified by any of the methods described herein, may be confirmed by performing an assay of PKB enzymic activity in the presence of the compound.

It is appreciated that the invention provides screening assays for drugs which may be useful in modulating, for example either enhancing or inhibiting, the protein kinase activity of PKB. The compounds identified in the methods may themselves be useful as a drug or they may represent lead compounds for the design and synthesis of more efficacious compounds.

The compound may be a drug-like compound or lead compound for the development of a drug-like compound for each of the above methods of identifying a compound. It will be appreciated that the methods may be useful as screening assays in the development of pharmaceutical compounds or drugs, as well known to those skilled in the art.

The term "drug-like compound" is well known to those skilled in the art, and may include the meaning of a compound that has characteristics that may make it suitable for use in medicine, for example as the active ingredient in a medicament. Thus, for example, a drug-like compound may be a molecule that may be synthesised by the techniques of organic chemistry, less preferably by techniques of molecular biology or biochemistry, and is preferably a small molecule, which may be of less than 5000 Daltons. A drug-like compound may additionally exhibit features of selective interaction with a particular protein or proteins and be bioavailable and/or able to penetrate cellular membranes, but it will be appreciated that these features are not essential.

The term "lead compound" is similarly well known to those skilled in the art, and may include the meaning that the compound, whilst not itself suitable for use as a drug (for example because it is only weakly potent against its intended target, non-selective in its action, unstable, difficult to synthesise or has poor bioavailability) may provide a starting-point for the design of other compounds that may have more desirable characteristics.

It is appreciated that screening assays which are capable of high throughput operation are particularly preferred. Examples may include cell based assays and protein-protein binding assays. An SPA-based (Scintillation Proximity Assay; Amersham International) system may be used. For example, beads comprising scintillant and a substrate polypeptide or interacting polypeptide may be prepared. The beads may be mixed with a sample comprising P- or P-γ-labelled PKB (as defined above) and with the test compound. Conveniently this is done in a 96-well or 384- well format. The plate is then counted using a suitable scintillation counter,

T? 3 ¹? 33 using known parameters for P or P SPA assays. Only P or P that is in proximity to the scintillant, i.e. only that bound to the substrate or interacting polypeptide that is bound to the beads, is detected. Variants of such an assay, for example in which the substrate or interacting polypeptide is immobilised on the scintillant beads via binding to an antibody or antibody fragment, may also be used.

It is appreciated that high throughput crystallography techniques may be utilised as particularly preferred screening assays. High throughput crystallography techniques may include those described in the following publications, each of which is incorporated herein by reference: J. Crystal Growth 90:318-324 (1988); J. Crystal Growth 90:325-339 (1988); PCT Patent Publication WO 00/78445; US Patent No. 5,221,410 and European Patent No. EP 0 553 539.

As it is desirable to identify compounds that may modulate the activity of PKB in vivo, it is understood that reagents and conditions used in the method may be chosen such that the interactions between, for example, the PKB and the compound, are substantially the same as between human PKB and PtdIns(3,4,5)P₃ and PtdIns(3,4)P₂ in vivo.

The compounds tested in screening methods or in other assays in which the ability of a compound to modulate the conformational change in the PKB PH domain is measured, may have been selected and/or designed (including modified) using molecular modelling techniques, for example using computer techniques, as indicated above.

A further aspect of the invention provides a compound identified by any of the methods described herein that modulates or mimics a conformational change in the PH domain of the PKB upon contact with the PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂, for use in medicine.

In another aspect, the invention provides a pharmaceutical composition comprising a compound identified by any of the methods described herein that modulates or mimics a conformational change in the PH domain of the PKB upon contact with the PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂₎ and a pharmaceutically acceptable excipient.

The pharmaceutical composition may be administered in any suitable way, usually parenterally, for example intravenously, intraperitoneally or intravesically, in standard sterile, non-pyrogenic formulations of diluents and carriers. The compound (or polypeptide or polynucleotide) may also be administered topically. The pharmaceutical composition may also be administered in a localised manner, for example by injection.

In one preferred embodiment, the compound identified by the methods described herein may be an inhibitor of PKB. As the binding of PKB-PH to 3-phosphoinositides is a prerequisite for activation of PKB by PDKl, compounds, typically small molecules, that disrupt the normal conformational change of the PH domain upon the interaction of PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ with PKB would decrease or abolish the activity of PKB. Inhibitors of PKB may block binding of PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ to PKB by themselves binding to the 3-phosphoinositide binding site in the PH domain of PKB, without causing the conformational change.

PKB inhibition would be expected to impair growth and promote apoptosis of cancer cells in which PKB activity is elevated. Phosphoinositide derivatives containing a hydroxymethyl group at the D3 position, and/or a carbonate rather than a phosphate group at DI were previously shown to inhibit PDGF-induced PKB phosphorylation and inhibited the growth of four different cancer cell lines [25, 26, 27]. Analysis of the PKB_αPH domain structure provided herein indicates these derivatives may function by binding to PKB-PH, thereby preventing it from interacting with PtdIns(3,4,5)P₃, preventing the conformational change in the PH domain upon contact with PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ and thus decreasing or abolishing the activity of PKB.

There is thus provided in accordance with another preferred embodiment of the present invention, the use of a compound identified by any of the methods described herein, in the preparation of a medicament for the treatment of cancer.

In another aspect, the present invention provides the use of a compound identified by any of the methods described herein, that disrupts the conformational change in the PKB-PH domain on interaction with PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂, in the preparation of a medicament for the treatment of cancer. More preferably, the medicament impairs the growth or promotes apoptosis of cancer cells. Such a compound could disrupt the conformational change in the PKB-PH domain by binding directly to the 3-phosphoinositide ligand binding site of PKB-PH, or to another region of the PKB, or directly to PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂, for example so that the 3-phosphoinositides may bind to PKB but without inducing the conformational change.

In another preferred embodiment, the identified compound may be an activator of PKB. A compound that increases the rate or extent of conformational change of the PH domain upon binding of 3- phosphoinositides, could increase the activity of PKB. Additionally, compounds that bind to the 3-phosphoinositide ligand binding site of PKB- PH and induce a similar or enhanced conformational change on the PH domain as does the binding of Ins(l,3,4,5)P₄, could promote the PtdIns(3,4,5)P₃-independent activation of PKB by PDKl. Such compounds could be useful in treating any disorder characterised in having a PKB deficiency. Particularly, such compounds could be used to stimulate insulin dependent responses in diabetic patients, to promote cellular survival following an ischaemic event, for example the survival of neuronal cells following a stroke, or to reduce apoptosis.

There is thus further provided in accordance with another preferred embodiment of the present invention, the use of a compound identified by any of the methods described herein, in the preparation of a medicament for stimulating insulin dependent responses in diabetic patients, or for promoting cellular survival following an ischaemic event, for example for promoting the survival of neuronal cells following a stroke, or for reducing apoptosis.

Thus in another aspect, the present invention provides the use of a compound identified by any of the methods described herein, that binds to the 3-phosphoinositide ligand binding site of PKB_αPH and induces a conformational change which promotes the PtdIns(3,4,5)P₃-independent activation of PKB, in the preparation of a medicament for stimulating insulin dependent responses in diabetic patients or for promoting cellular survival following an ischaemic event, for example for promoting the survival of neuronal cells following a stroke, or for reducing apoptosis.

In another aspect, the present invention provides the use of a compound identified by any of the methods described herein, that enhances the normal conformational change upon binding of PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ to the PKB PH domain, in the preparation of a medicament for stimulating insulin dependent responses in diabetic patients or for promoting cellular survival following an ischaemic event, for example for promoting the survival of neuronal cells following a stroke, or for reducing apoptosis.

Preferably, enhancing the normal conformational change upon binding of PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ to the PKB PH domain promotes activation of PKB by PDKl.

All of the patents and other documents referred to herein are incorporated herein, in their entirety, by reference.

The invention will now be described by reference to the following Examples and Figures:

Figure 1 consists of three pairs of stereo figures illustrating the structure of PKB_αPH complexed to Ins(l,3,4,5)P , in accordance with a preferred embodiment of the present invention.

In panel A, the experimental electron density map from SOLVE after density modification is shown in grey (contoured at 1.25σ). The final PKB_αPH structure is shown as a sticks model. Ins( 1, 3, 4,5)P is represented by a sticks model. Panel B is a ribbon drawing of the PKB_αPH-Ins(l,3,4,5)P₄ complex, with the seven ^-strands (labelled β\-l) and the α-helices (labelled αl-2) shown. Ins(l,3,4,5)P₄ is also shown. The side chains of residues interacting with this molecule are shown with grey carbons. The basic residues thought to interact with the membrane also have their side chains shown as sticks. The negatively charge residues on VL2 that are hypothesised to interact with the kinase domain are also shown.

Panel C is a ribbon diagram of the Ins(l,3,4,5)P₄ binding site, with the ligand shown. The final 2 | F₀1 - 1 F_c | ,φ_caι_c map is shown, contoured at 2.25 σ. Residues making hydrogen bonds to the ligand are shown as sticks with grey carbons, hydrogen bonds are shown as black dotted lines.

Figure 2 shows a structure-based sequence alignment of four PtdIns(3,4,5)P₃ binding PH domains, constructed by superposition of their structures using the MOTIF option in WHAT IF [37]. Conserved residues are shown in black. Homologous residues are highlighted in grey. Secondary structure is shown as black arrows for ^-strands and as bars for the α-helices. Helix αl one is shown as a shaded bar. Arrows indicate residues in PKB_αPH that interact with the lipid head group. Variable loops 1,2 and 3 are labelled as VL1, VL2 and VL3 respectively. The serine residue immediately prior to the methionine residue at position 1 is the protease cleavage site.

Figure 3 shows the lipid binding properties of various PKB_α mutants. The ability of the wild type and mutant GST-PKB_α fusion proteins to bind to the indicated amounts of PtdIns(3,4,5)P₃/PtdIns(3,4)P₂, was analysed using a protein lipid overlay assay.

Figure 4 is a structural comparison of apo-PKB_αPH and PKB_αPH- Ins(l,3,4,5)P _. Panel A is an illustration of electrostatic surface potential calculated with GRASP. Dark grey areas (+6kT) represent highly positively charged residues, mid-grey areas (-6kT) indicated highly negatively charged residues. The left image shows the structure of the complex, with Ins(l,3,4,5)P₄ shown as a stick model. The right image shows the apo structure.

Panel B is a ribbon diagram highlighting the conformational changes between the aρo-PKB_αPH and PKB_αPH-Ins(l,3,4,5)P₄ structures. The apo- PKB_αPH structure is shown with ?-strands and the C-terminal helix, with the loop regions in grey, and side chains shown as stick models. The hydrogen bonding network between residues Arg86, Asn53, Glul7, Lys 14 and two water molecules (spheres) is also shown. The PKB PH- Ins(l,3,4,5)P₄ complex protein backbone is shown, only showing loops or strands that undergo a conformational change upon ligand binding. The Ins(l,3,4,5)P molecule is shown.

Panel C is a ribbon diagram of the PKB_αPH structure with a stick model of an Ins(l,3,4,5)P₄ derivative described previously [26] that has a hydroxymethyl group at D3 and a carbonate group at DI . Side chains capable of interacting with the inhibitor are shown. Predicted hydrogen bonds are shown in black, including the hydrogen bond between the axial hydroxymethyl group and Arg25, which is mentioned in [26] and the discussion.

EXAMPLE I: Structural Analysis of the PKB PH domain

Cloning ofPKBJΗ

The phosphatidylinositide binding PH domain of protein kinase B (PKB_αPH) was amplified by PCR using the Hi-fidelity PCR system with the full-length human PKB_α cDNA as the template, and 5 '-primer GGATCCATGAGCGACGTGGCTATTGTGAAGGAG and 3 '-primer GGATCCTCAGCCCGACCGGAAGTCCATCTCCTC.

This amplified a length of DNA encoding residues 1 to 123 of human PKB_α with a stop codon immediately after codon 123 which is equivalent in length to the 3-phosphoinositide binding PH domains of DAPP1 [22] and TAPP1 [28] that have been crystallised previously. This fragment was subcloned into the BamHl restriction site of the E. coli expression vector pGEX4T- 1. The resultant construct encodes for the bacterial expression of PKB_αPH with an N-terminal glutathione-S-transferase (GST) tag.

Purification & crystallisation of native and selenomethionine PKB_aPH

E. coli BL21 cells transformed with the pGEX4T-l vector encoding the expression of GST-PKB_αPH were grown at 37°C in 4 1 of Luria-Bertani broth with 50 g/ml ampicillin, until OD₆₀₀ reached 0.7. The expression of GST-PKB_αPH was induced by the addition of 250 M isopropyl- ?-D- thiogalactopyranoside (IPTG), and the bacteria were then grown for a further 16 h at 27°C. The cells were harvested by centrifugation at 3500 g for 15 min, then lysed by resuspension in 200 ml of buffer A (50 mM Tris/HCl, pH 7.5, 1 mM EGTA, 1 mM EDTA, 1 mM NaV0₄ , 10 mM sodium-glycerophosphate, 50 mM NaF, 5 mM dithiothreitol and 'complete' proteinase inhibitor cocktail (one tablet per 25 ml; Roche) containing additional DNAse (1.5-2 mg/ml) and 1 mg/ml lysozyme. The cells were then incubated on ice for 30 min before a final sonication step. The resulting solution was centrifuged at 14500 g for 30 min to remove residual debris and passed through a 0.45 μm filter. The supernatant was incubated for 1 h at 4°C with 4 ml of glutathione-Sepharose beads equilibrated against buffer A. The beads were then washed 4 times with 5 column volumes of buffer A, and subsequently washed 6 times with 5 column volumes of buffer B (50 mM Tris/HCl, pH 7.5, 0.1 mM EGTA, 0.3 M NaCI and 5 mM dithiothreitol). The PKB_αPH domain was then separated from the GST-tag by incubating the glutathione-Sepharose beads conjugated to GST-PKB_αPH in a ratio of 2 units of thrombin to 10 /^1 of resin at 4°C overnight. The resin was centrifuged, washed four times with 10 ml of buffer B and the combined supernatants containing PKB_αPH were applied to a 0.2 ml benzamidine-agarose column to remove the thrombin. The eluate was subsequently applied to a 1 ml glutathione-Sepharose column equilibrated in buffer B to remove trace contamination of GST. The supernatant was then concentrated into a 4 ml volume and loaded onto a Superdex 75 26/60 gel filtration column that was previously equilibrated against buffer B. The yield obtained was approximately 5 mg of PKB_αPH domain per 1 of E. coli culture. PKB_αPH was analysed by SDS/PAGE and was found to be essentially homogeneous. Further analysis by electrospray mass spectrometry, revealed a major single species with a molecular mass of 14842.4, close to the predicted mass of 14752.6 for the PKB_αPH fragment.

Selenomethionine-substituted protein was prepared by expressing protein in the methionine auxotrophic strain B834. Cells were grown overnight in Luria Bertani media and then further amplified in M9 minimal media supplemented with 1 g/1 of amino acid mix [29] lacking methionine. Adenine, guanosine, thymine and uracil were added to 5 g/1, FeS0₄ to 4 mg/1 and ZnCl₂ to 40 mg/ml. The media was then filtered through a 0.22 μm filter and L-selenomethionine was added to a final concentration of 125 mg/1. The cells were then grown to an OD₆₀₀=0.7 at 37°C, induced with IPTG as described above and grown for a further 16 h at 27°C. Purification and crystallisation proceeded as described for the native protein, and selenium incorporation was verified using electrospray mass spectrometry revealing a major single species with a molecular mass of 14944, close to the predicted mass of 14872 for the selenomethionine-substituted PKB PH fragment. PKB_αPH was concentrated to 8.5 mg/ml using a VivaSpin concentrator, with the concentration verified using OD₂₈Q. The hanging drop vapour diffusion method was used for producing crystals. Hanging drops were formed by mixing 1 μl of protein solution with 1 μ\ of a mother liquor solution. Monoclinic (C2) crystals of native PKB_αPH were grown at 20°C from a mother liquor containing 30% PEG 4000, 0.25 M sodium acetate, 0.1 M Tris (pH 8.5), with the addition of 0.25 μl of 30% polypropylene glycol 400 to the 2 μl drop. Crystals appeared after 2 days, growing to 0.2x0.2x0.3 mm over 4 days. Selenomethione PKB_αPH was complexed with PtdIns(l,3,4,5)P₄ by incubation in a 10:1 molar ratio of ligand to protein for 30 min on ice. The complex was crystallised using a mother liquor containing 0.25 M ammonium acetate, 30% PEG 4000, 0.1 M sodium acetate (pH 4.6). Monoclinic crystals appeared after 2 days, growing to approximately 0.2x0.2x0.3 mm after four days. Crystals were frozen in a nitrogen gas stream after being soaked in 10% 2-methyl-2,4- pentanediol for 30 seconds.

Data collection, structure solution, and refinement

Data on PKB_αPH crystals were collected at the European Synchrotron Radiation Facility (Grenoble, France) beamline ID29 , using an ADSC Q210 CCD detector. A multi- wavelength anomalous dispersion (MAD) data set for selenomethionine PKB PH-IP was collected on Station 14.2 at the Daresbury Synchrotron Radiation Source, using an ADSC Q4 CCD detector. The temperature of the crystals was maintained at 100K using a nitrogen cryostream. Data were processed using the HKL package [30], statistics are shown in Table I.

The structure of PKB_αPH domain bound to Ins(l,3,4,5)P₄ was solved by MAD phasing using a three-wavelength experiment. Calculation of an anomalous Patterson using the peak wavelength data revealed a single \5σ peak. Two selenium sites were located and refined with SOLVE [31], resulting in experimental phases to 1.4 A with a figure of merit of 0.5, yielding a readily interpretable electron density map. Phases were further improved by density modification with DM [32], resulting in an electron density map that showed well defined density for the protein and the Ins(l,3,4,5)P₄ molecule (Fig. IA). The map was automatically interpreted using warpNtrace [33], which built 111 of a possible 123 residues, giving an initial protein model with R=0.323 (R - _.=0.324). Iterative protein building in O [34] together with refinement in CNS [35], and incorporation of Ins(l,3,4,5)P₄ improved the model to R=0.277 (R_ree=0.289). Refinement was then continued with SHELX-97, employing atomic anisotropic B- factors, and as a last step riding hydrogens, resulting in the final model with R=0.1551 (R _ee=0.1934) which encompassed residues 1-113.

Table 1 lists details of data collection & structure refinement for a MAD data set collected on PKB_αPH-Ins(l,3,4,5)P₄ crystals, and a native apo PKB_αPH data set. Values between brackets are for the highest resolution shell. All measured data were included in structure refinement.

Table 2 lists the data set of structural co-ordinates collected on PKB_αPH- Ins(l ,3,4,5)P₄ crystals.

Table 1

Structure apo HGp_eak Hginfl " Jnemo

Wave length (A) 0.97949 0.97860 0.97896 0.96124

Space group C2 C2 C2 C2

Unit cell (A) a =84.06 a =82.86 a =82.86 α=82.89

0=33.80 6=34.35 6=34.36 6=34.35 c=42.07 c=44.29 c=44.30 c =44.30 β=\ 19.48° / 15.30⁰ y?=115.22° β=l 15.30°

Resolution (A) 30-1.65 15-1.40 15-1.4 15-1.4

(1.71-1.65) (1.45-1.4) (1.45-1.4) (1.45-1.4)

Observed 37427 83520 83957 86238 reflections

Unique reflections 12409 21933 21953 22212

Redundancy 3.0 (2.7) 3.8 (2.6) 3.8 (2.6) 3.8(2.8)

Completeness (%) 98.69 (97.2) 97.8 (83.3) 97.8 (83.0) 98.9 (90.5)

Emerge 0.048 (0.409) 0.055 (0.231) 0.052 (0.231) 0.058 (0.275)

1/ sig a I 24.3 (4.1) 30.8 (6.7) 30.8 (6.2) 29.77(5.74)

Rf_ree reflections 601 914

K^cryst 0.203 0.155

Rf ee 0.239 0.193

Number of atoms

Protein 998 958

Water 131 160

Ins(l,3,4,5)P₄ 0 27

Wilson B (A²) 21.8 16.9

<B> Protein 20.7 13.3

<B> Water 30.6 24.4

<B> Ins(l,3,4,5)P₄ - 9.1

RMSD from ideal geometry

Bond lengths (A) 0.006 0.010

Bond angles (°) 1.31 2.03 Main chain B (A ) 1.89 3.16

Table 2

CRYSTl 82. 868 34. 351 44. 293 90.00 115.31 90.00

SCALE1 0.012067 0.000000 0.005707 0.000000

SCALE2 0.000000 0.029111 0.000000 0.000000

SCALE3 0.000000 0.000000 0.024974 0.000000

ATOM 1 CA ACE -1 27.217 13, .275 -12 .133 1. .000 13. .04

ANISOU 1 CA ACE -1 1484 1487 1986 -186 -165 403

ATOM 2 c ACE -1 25.827 13, .605 -11 .579 1. ,000 15, .57

ANISOU 2 c ACE -1 3185 1810 923 -841 217 -374

ATOM 3 O ACE -1 25.629 13. ,615 -10 .376 1. .000 19. .66

ANISOU 3 O ACE -1 2039 3289 2141 -582 418 -59

ATOM 4 CB SER 0 22.880 15. ,260 -13 .209 1. ,000 37. .51

ANISOU 4 CB SER 0 10249 1881 2123 -2411 -1555 L335

ATOM 5 OG SER 0 22.588 14, ,334 -14 .224 1. ,000 25, .12

ANISOU 5 OG SER 0 4273 3153 2120 877 491 -342

ATOM 6 c SER 0 22.930 13. .821 -11, .165 1. ,000 18. .49

ANISOU 6 c SER 0 3457 2289 1278 -1559 42 -153

ATOM 7 O SER 0 22.539 14, ,168 -10. .055 1. ,000 18. ,42

ANISOU 7 O SER 0 3084 2187 1727 -457 814 -919

ATOM 8 N SER 0 24.969 14, ,122 -12, .458 1. .000 15. ,98

ANISOU 8 N SER 0 2187 1758 2126 -213 279 87

ATOM 9 CA SER 0 23.734 14. .772 -12, .042 1. .000 15. .50

ANISOU 9 CA SER 0 1709 2117 2062 -356 594 164

ATOM 10 N MSE 1 22.673 12. 617 -11. ,655 1. 000 9. ,13

ANISOU 10 N MSE 1 1455 836 1178 -236 -80 308

ATOM 11 CA MSE 1 21.772 11. 734 -10, .881 1. 000 8. ,48

ANISOU 11 CA MSE 1 1281 1007 933 -253 -13 93

ATOM 12 CB MSE 1 21.121 10. 734 -11. ,853 1. 000 10. ,01

ANISOU 12 CB MSE 1 1727 964 1111 -270 -270 -21

ATOM 13 CG MSE 1 20.170 11. 420 -12. ,846 1. 000 9. ,07

ANISOU 13 CG MSE 1 1146 1426 874 86 -14 -125

ATOM 14 SE MSE 1 18.623 12. 182 -12. ,004 1. ,000 19. ,51

ANISOU 14 SE MSE 1 2406 2631 2375 276 17 -157

ATOM 15 CE MSE 1 19.219 13. 991 -11, .977 1. .000 15. ,81

ANISOU 15 CE MSE 1 2247 666 3092 -585 18 428

ATOM 16 c MSE 1 22.474 11. 071 -9. ,720 1. ,000 9. ,24

ANISOU 16 c MSE 1 1487 914 1111 -201 125 -7

ATOM 17 O MSE 1 21.885 10. 861 -8. ,648 1. 000 12. 07

ANISOU 17 O MSE 1 1831 1693 1063 -60 278 141

ATOM 18 N SER 2 23.757 10. 776 -9. ,858 1. 000 8. 89

ANISOU 18 N SER 2 1198 1183 998 -92 193 -95

ATOM 19 CA SER 2 24.480 10. 116 -8. ,750 1. 000 10. 03

ANISOU 19 CA SER 2 1434 1143 1235 ^' -96 -105 174

ATOM 20 CB SER 2 25.826 9. 602 -9. ,237 1. ,000 12. 56

ANISOU 20 CB SER 2 1329 1667 1776 45 -231 220

ATOM 21 OG SER 2 26.646 10. 666 -9. ,728 1. .000 17. 85

ANISOU 21 OG SER 2 2508 1890 2385 -273 -222 289

ATOM 22 c SER 2 24.614 11. 069 -7, ,575 1. ,000 11. 75

ANISOU 22 c SER 2 1880 1172 1411 16 -345 -137

ATOM 23 O SER 2 24.601 10. 653 -6. .419 1. ,000 14. 21

ANISOU 23 O SER 2 2404 1620 1374 -14 -398 168

ATOM 24 N ASP 3 24.675 12. 373 -7. 844 1. 000 9. 46

ANISOU 24 N ASP 3 1329 1068 1196 78 203 -326

ATOM 25 CA ASP 3 24.776 13. 366 -6. 785 1. 000 10. 83

ANISOU 25 CA ASP 3 1590 1148 1378 -389 255 -234 ATOM 26 CB ASP 3 25.026 14.751 -7.406 1, 000 14.98

ANISOU 26 CB ASP 3 2387 1306 2000 -197 129 -252

ATOM 27 CG ASP 3 26.428 15.036 -7.893 1, 000 17. 72

ANISOU 27 CG ASP 3 2370 1939 2423 26 233 -130

ATOM 28 OD1 ASP 3 27.344 14.245 -7.614 1, 000 20. 06

ANISOU 28 OD1 ASP 3 2046 3047 2528 -593 -273

ATOM 29 OD2 ASP 3 26.562 16.110 -8.552 1, 000 23. 40

ANISOU 29 OD2 ASP 3 3160 2734 2996 -895 18 401

ATOM 30 C ASP 3 23.534 13.460 -5.930 1, 000 10. 39

ANISOU 30 C ASP 3 1575 1209 1162 -39 163 -386

ATOM 31 O ASP 3 23.657 13.824 -4.752 1, 000 11. 17

ANISOU 31 O ASP 3 1206 1695 1342 -218 -87 -433

ATOM 32 N VAL 4 22.360 13.207 -6.497 1.000 9. 67

ANISOU 32 N VAL 4 1656 1186 832 -369 199 -163

ATOM 33 CA VAL 4 21.139 13.301 -5.675 1.000 10. 33

ANISOU 33 CA VAL 4 1472 1608 845 -649 229 -33

ATOM 34 CB VAL 4 19.999 14.063 -6.364 1.000 10. 20

ANISOU 34 CB VAL 4 1665 1379 830 -543 22 -92

ATOM 35 CGI VAL 4 20.423 15.523 -6.521 1.000 14. 30

ANISOU 35 CGI VAL 4 1722 2348 1366 -360 -2 -77

ATOM 36 CG2 VAL 4 19.568 13.487 -7.717 1.000 13. 32

ANISOU 36 CG2 VAL 4 2741 1229 1091 114 -35 -181

ATOM 37 C VAL 4 20.644 11.948 -5.192 1.000 9. 42

ANISOU 37 C VAL 4 1198 1564 817 -11 232 -210

ATOM 38 O VAL 4 19.535 11.771 -4.693 1.000 11. 86

ANISOU 38 O VAL 4 1081 2057 1367 -57 311 691

ATOM 39 N ALA 5 21.498 10.921 -5.280 1.000 9. 34

ANISOU 39 N ALA 5 1177 1642 731 -153 360 -145

ATOM 40 CA ALA 5 21.156 9.643 -4.702 1.000 9. 31

ANISOU 40 CA ALA 5 1366 1403 767 -59 143 -361

ATOM 41 CB ALA 5 22.219 8.599 -4.970 1.000 12. 91

ANISOU 41 CB ALA 5 2476 1315 1114 -366 710 -167

ATOM 42 C ALA 5 20.998 9.761 -3.187 1.000 8. 03

ANISOU 42 C ALA 5 1246 1200 606 149 265 -356

ATOM 43 O ALA 5 21.743 10.482 -2.526 1.000 7.

ANISOU 43 O ALA 5 1350 693 953 -70 192 -211

ATOM 44 N ILE 6 19.997 9.016 -2.687 1.000 8. 03

ANISOU 44 N ILE 6 996 1310 744 -160 255 -182

ATOM 45 CA ILE 19.832 8.915 -1.260 1.000 7. 73

ANISOU 45 CA ILE 916 1151 870 -97 298 -251

ATOM 46 CB ILE 18.368 8.651 -0.897 1.000 9. 85

ANISOU 46 CB ILE 1084 1463 1195 117 286 -173

ATOM 47 CG2 ILE 18.165 8.440 0.601 1.000 12. 51

ANISOU 47 CG2 ILE 2192 1453 1108 -789 439 63

ATOM 48 CGI ILE 17.435 9.758 -1.400 1.000 11. 06

ANISOU 48 CGI ILE 1004 1823 1378 69 353 -205

ATOM 49 CD1 ILE 15.971 9.437 -1.457 1.000 13. 65

ANISOU 49 CD1 ILE 619 2395 2172 -110 -364 903

ATOM 50 C ILE 20.749 7.812 -0.692 1.000 7.

ANISOU 50 C ILE 1068 918 934 210 222 -406

ATOM 51 O ILE 20.567 6.640 -1.002 1.000 11. 51L

ANISOU 51 O ILE 1975 986 1413 83 21 -509

ATOM 52 N VAL 21.715 8.230 0.112 1.000 8. 141

ANISOU 52 N VAL 1311 969 812 7 278 -292

ATOM 53 CA VAL 22.725 7.357 0.704 1.000 8. 39

ANISOU 53 CA VAL 940 1177 1072 269 509 -103

ATOM 54 CB VAL 23.966 8.180 1.147 1.000 9.

ANISOU 54 CB VAL 881 1649 1223 558 362 -131

ATOM 55 CGI VAL 24.998 7.332 1.855 1.000 15. 40 ANISOU 55 CGI VAL 7 2007 2115 1729 130 -170 439

ATOM 56 CG2 VAL 7 24.585 8.895 -0.044 1.000 15. 56

ANISOU 56 CG2 VAL 7 1360 1972 2578 132 -9 -229

ATOM 57 C VAL 7 22.155 6, 622 1 901 1.000 9. 54

ANISOU 57 C VAL 7 1339 1071 1214 312 431 -253

ATOM 58 O VAL 7 22.403 5, 445 2 150 1.000 11. 07

ANISOU 58 O VAL 7 1564 958 1684 273 838 135

ATOM 59 N LYS 8 21.355 7.328 2.689 1.000 9. 20

ANISOU 59 N LYS 8 1474 1087 935 -48 382 -148

ATOM 60 CA LYS 8 20.718 6, 795 3, 883 1.000 8. 14

ANISOU 60 CA LYS 8 1410 779 905 -55 419 67

ATOM 61 CB LYS 8 21.713 6.736 5, 047 1.000 10. 12

ANISOU 61 CB LYS 8 1414 1395 1038 -65 289 131

ATOM 62 CG LYS 8 21.185 5. 843 6, 188 1.000 11. 76

ANISOU 62 CG LYS 8 1467 1869 1132 -38 198 -153

ATOM 63 CD LYS 8 22.192 5. 592 7.270 1.000 11, 90

ANISOU 63 CD LYS 8 1792 1645 1085 -244 41 -118

ATOM 64 CE LYS 8 21.652 5.026 8.566 1.000 12.

ANISOU 64 CE LYS 8 1967 1540 1382 -75 72 229

ATOM 65 NZ LYS 8 21.055 3.676 8.390 1.000 11. 65

ANISOU 65 NZ LYS 8 1783 942 1702 281 -81 395

ATOM 66 C LYS 8 19.491 7.622 4, 257 1.000 8. 46

ANISOU 66 C LYS 8 1225 1266 724 -243 512 -166

ATOM 67 O LYS 8 19.521 8. 844 4. 143 1.000 7. 92

ANISOU 67 O LYS 8 1293 644 1073 -239 70 14

ATOM 68 N GLU 9 18.440 6. 938 4. 681 1.000 9. 19

ANISOU 68 N GLU 9 1441 1152 900 -56 472 -84

ATOM 69 CA GLU 9 17.255 7.645 5. 183 1.000 7. 46

ANISOU 69 CA GLU 9 1029 1006 798 -157 542 -115

ATOM 70 CB GLU 9 16.269 7.914 4, 053 1.000 8. 89

ANISOU 70 CB GLU 9 1326 1045 1007 -142 421 -1

ATOM 71 CG GLU 9 15.787 6.671 3. 319 1.000 11. 25

ANISOU 71 CG GLU 9 1535 1474 1266 -590 347 -304

ATOM 72 CD GLU 9 14.709 6.985 2. 287 1.000 13. 64

ANISOU 72 CD GLU 9 1893 2064 1226 -543 239 -512

ATOM 73 OE1 GLU 9 13.590 7.453 2. 659 1.000 17. 12

ANISOU 73 OE1 GLU 9 1564 3534 1409 -167 532 -869

ATOM 74 OE2 GLU 9 14.932 6.781 1. 088 1.000 14. 22

ANISOU 74 OE2 GLU 9 2145 1953 1306 -635 490 -573

ATOM 75 C GLU 9 16.645 6.840 6. 313 1.000 8. 19

ANISOU 75 C GLU 9 1311 926 876 -79 345 -183

ATOM 76 O GLU 9 16.753 5.613 6. 346 1.000 11. 31

ANISOU 76 O GLU 9 2003 992 1303 32 498 -91

ATOM 77 N GLY 10 16.020 7, 557 7. 231 1.000 7.

ANISOU 77 N GLY 10 1506 807 683 -245 278 60

ATOM 78 CA GLY 10 15.359 6.880 8. 334 1.000 8. 00

ANISOU 78 CA GLY 10 1536 776 727 -245 293 2

ATOM 79 C GLY 10 15.003 7.832 9. 444 1.000 6.

ANISOU 79 C GLY 10 959 605 784 -95 433 -58

ATOM 80 O GLY 10 15.382 9.008 9. 434 1.000 7. 44

ANISOU 80 O GLY 10 1287 665 875 -195 173 121

ATOM 81 N TRP 11 14.220 7.306 10. 392 1.000 7. 39

ANISOU 81 N TRP 11 1484 642 683 -436 346 40

ATOM 82 CA TRP 11 13.811 8.071 11. 549 1.000 7. 24

ANISOU 82 CA TRP 11 1242 973 535 -121 416 24

ATOM 83 CB TRP 11 12.640 7.377 12. 219 1.000 7. 84

ANISOU 83 CB TRP 11 1416 879 683 -137 112 32

ATOM 84 CG TRP 11 11.322 7.544 11. 531 1.000 8. 72

ANISOU 84 CG TRP 11 1320 1046 947 -191 166 ^•178 ATOM 85 CD2 TRP 11 10.416 8.654 11.596 1.000 8.08

ANISOU 85 CD2 TRP 11 1124 1020 926 -301 64 222

ATOM 86 CE2 TRP 11 9.321 8.332 10.777 1.000 10.66

ANISOU 86 CE2 TRP 11 1583 1292 1175 -647 61 443

ATOM 87 CE3 TRP 11 10.449 9.864 12.271 1.000 8.97

ANISOU 87 CE3 TRP 11 850 1398 1160 -231 271 339

ATOM 88 CD1 TRP 11 10.742 6.635 10.706 1.000 9.96

ANISOU 88 CD1 TRP 11 1518 1106 1162 -310 128 -343

ATOM 89 NE1 TRP 11 9.550 7.092 10.243 1.000 10.62

ANISOU 89 NE1 TRP 11 1521 1391 1121 -561 59 24

ATOM 90 CZ2 TRP 11 8.245 9.202 10.614 1.000 10.06

ANISOU 90 CZ2 TRP 11 1277 1221 1324 -377 -76 274

ATOM 91 CZ3 TRP 11 9.385 10.726 12.105 1.000 8.90

ANISOU 91 CZ3 TRP 11 758 1555 1069 -210 259 59

ATOM 92 CH2 TRP 11 8.309 10.382 11.287 1.000 10.89

ANISOU 92 CH2 TRP 11 1106 1656 1374 -121 11 41

ATOM 93 C TRP 11 14.934 8.179 12.594 1.000 7.85

ANISOU 93 C TRP 11 1399 742 840 110 43 -125

ATOM 94 O TRP 11 15.748 7.264 12.745 1.000 8.73

ANISOU 94 O TRP 11 1266 879 1172 161 8 78

ATOM 95 N LEU 12 14.904 9.278 13.325 1.000 7.76

ANISOU 95 N LEU 12 1495 795 660 -317 49 -164

ATOM 96 CA LEU 12 15.715 9.445 14.515 1.000 8.87

ANISOU 96 CA LEU 12 1207 1159 1006 43 94 -190

ATOM 97 CB LEU 12 17.115 9.890 14.141 1.000 10.60

ANISOU 97 CB LEU 12 1226 1492 1310 -204 43 -162

ATOM 98 CG LEU 12 17.249 10.952 13.037 1.000 11.48

ANISOU 98 CG LEU 12 1305 1105 1952 -686 -67 419

ATOM 99 CD1 LEU 12 16.813 12.317 13.543 1.000 14.48

ANISOU 99 CD1 LEU 12 982 1897 2624 -361 144 583

ATOM 100 CD2 LEU 12 18.654 10.987 12.468 1.000 14.58

ANISOU 100 CD2 LEU 12 1610 2563 1368 108 488 -442

ATOM 101 C LEU 12 15.028 10.441 15.455 1.000 6.72

ANISOU 101 C LEU 12 941 800 813 97 352 -186

ATOM 102 O LEU 12 14.020 11.043 15.094 1.000 9.11

ANISOU 102 O LEU 12 1526 1089 845 119 -93 -130

ATOM 103 N HIS 13 15.667 10.667 16.584 1.000 6.37

ANISOU 103 N HIS 13 1055 751 615 -19 277 -183

ATOM 104 CA HIS 13 15.262 11.797 17.418 1.000 6.14

ANISOU 104 CA HIS 13 763 727 844 -281 102 -30

ATOM 105 CB HIS 13 15.038 11.440 18.891 1.000 7.27

ANISOU 105 CB HIS 13 789 983 992 -186 -96 23

ATOM 106 CG HIS 13 13.853 10.566 19.114 1.000 7.80

ANISOU 106 CG HIS 13 1014 972 979 -174 -250 16

ATOM 107 CD2 HIS 13 13.842 9.230 19.278 1.000 5.77

ANISOU 107 CD2 HIS 13 501 609 1083 107 -62 68

ATOM 108 ND1 HIS 13 12.539 10.966 19.181 1.000 9.97

ANISOU 108 ND1 HIS 13 1558 1095 1135 -379 -111 402

ATOM 109 CE1 HIS 13 11.824 9.867 19.376 1.000 5.24

ANISOU 109 CE1 HIS 13 495 654 843 48 489 275

ATOM 110 NE2 HIS 13 12.557 8.796 19.436 1.000 10.39

ANISOU 110 NE2 HIS 13 1521 999 1429 -356 65 125

ATOM 111 C HIS 13 16.351 12.883 17.333 1.000 6.80

ANISOU 111 C HIS 13 1105 540 937 -108 -166 173

ATOM 112 O HIS 13 17.550 12.603 17.300 1.000 7.96

ANISOU 112 O HIS 13 811 825 1390 -2 -83 147

ATOM 113 N LYS 14 15.893 14.119 17.326 1.000 6.42

ANISOU 113 N LYS 14 869 681 890 177 75 127

ATOM 114 CA LYS 14 16.710 15.320 17.190 1.000 5.41 ANISOU 114 CA LYS 14 688 792 575 -23 337 127

ATOM 115 CB LYS 14 16.377 16 003 15 S79 1.000 4.

ANISOU 115 CB LYS 14 630 726 495 253 71

ATOM 116 CG LYS 14 17.117 17 287 15 620 1, 000 6. 96

ANISOU 116 CG LYS 14 1009 860 777 -25 183 -92

ATOM 117 CD LYS 14 16.877 17.787 14 207 1, 000 7. 53

ANISOU 117 CD LYS 14 1412 693 755 -146 166 -2

ATOM 118 CE LYS 14 17.547 19, 106 13 909 1, 000 7. 04

ANISOU 118 CE LYS 14 800 1026 849 31 335 264

ATOM 119 NZ LYS 14 16.787 20 235 14 505 1.000 7. 97

ANISOU 119 NZ LYS 14 986 1026 1015 41 183 131

ATOM 120 C LYS 14 16.403 16 198 18, 398 1.000 5. 12

ANISOU 120 C LYS 14 781 776 388 249 173 68

ATOM 121 O LYS 14 15.242 16 479 18 660 1.000 6. 55

ANISOU 121 O LYS 14 940 881 670 81 151 59

ATOM 122 N ARG 15 17.439 16 599 19 118 1, 000 5. 74

ANISOU 122 N ARG 15 602 892 173 213 -93

ATOM 123 CA ARG 15 17.235 17 333 20 356 1.000 6.

ANISOU 123 CA ARG 15 856 823 914 537 -61 -264

ATOM 124 CB ARG 15 18.428 17 128 21, 311 1, 000 9. 02

ANISOU 124 CB ARG 15 1894 659 875 808 -250 -248

ATOM 125 CG AARG 15 18.143 17 511 22, 747 0.500 12. 16

ANISOU 125 CG AARG 15 2507 1069 1042 955 -262 -79

ATOM 126 CG BARG 15 18.157 17 515 22, 743 0.500 12. 11

ANISOU 126 CG BARG 15 2495 1066 1042 969 -255

ATOM 127 CD AARG 15 19.327 17 216 23.650 0.500 15. 32

ANISOU 127 CD AARG 15 3107 1378 1337 942 -437 -129

ATOM 128 CD BARG 15 19.430 17 420 23.572 0.500 15. 44

ANISOU 128 CD BARG 15 3124 1394 1349 938 -445 -144

ATOM 129 NE AARG 15 18.921 17 087 25.044 0.500 16. 52

ANISOU 129 NE AARG 15 3369 1481 1425 738 -387 -38

ATOM 130 NE BARG 15 19.128 17 627 24.977 0.500 17. 34

ANISOU 130 NE BARG 15 3511 1605 1472 847 -468 -23

ATOM 131 CZ AARG 15 19.622 17 477 26.110 0.500 16. 04

ANISOU 131 CZ AARG 15 3087 1572 1435 727 -222 231

ATOM 132 CZ BARG 15 18.448 16 810 25.766 0.500 16. 68

ANISOU 132 CZ BARG 15 3200 1551 1587 831 -223 42

ATOM 133 NH1AARG 15 20.815 18 053 26.027 0.500 15. 68

ANISOU 133 NH1AARG 15 1479 2025 2452 530 191 521

ATOM 134 NH1BARG 15 17.961 15 675 25.300 0.500 21. 60

ANISOU 134 NH1BARG 15 3392 2784 2030 141 183 220

ATOM 135 NH2AARG 15 19.117 17 293 27.325 0.500 17. 46

ANISOU 135 NH2AARG 15 2825 1939 1872 1071 -154 318

ATOM 136 NH2BARG 15 18.251 17 133 27.035 0.500 15. 24

ANISOU 136 NH2BARG 15 2513 1856 1423 807 704 731

ATOM 137 C ARG 15 17.056 18 817 20.090 1.000 6. 02

ANISOU 137 C ARG 15 788 769 732 131 137 -169

ATOM 138 O ARG 15 17.806 19.456 19.332 1.000 7. 20

ANISOU 138 O ARG 15 890 905 940 77 237 202

ATOM 139 N GLY 16 16.045 19.435 20.704 1.000 6. 61

ANISOU 139 N GLY 16 894 810 806 113 58 -212

ATOM 140 CA GLY 16 15.860 20.870 20.607 1.000 6. 15

ANISOU 140 CA GLY 16 717 826 793 100 161 -178

ATOM 141 C GLY 16 17.074 21.647 21.048 1.000 5.

ANISOU 141 C GLY 16 851 794 590 103 314 -84

ATOM 142 O GLY 16 17.850 21.239 21.923 1.000 8. 58

ANISOU 142 O GLY 16 1304 1134 823 116 -46 67

ATOM 143 N GLU 17 17.244 22 830 20.457 1.000 7. 55

ANISOU 143 N GLU 17 1157 1044 667 -63 193 102 ATOM 144 CA GLU 17 18 . 330 23.698 20.820 1, 000 6.91

ANISOU 144 CA GLU 17 1012 847 764 -158 267

ATOM 145 CB GLU 17 18 . 600 24.702 19, 683 1, 000 8. 70

ANISOU 145 CB GLU 17 1245 1004 1057 143 197 -162

ATOM 146 CG GLU 17 19 . 188 24.044 18, 462 1, 000 10. 13

ANISOU 146 CG GLU 17 1245 1396 1207 -432 521 -403

ATOM 147 CD GLU 17 20 . 449 23.237 18, 736 1, 000 11. 93

ANISOU 147 CD GLU 17 1226 1870 1436 -252 1098 -509

ATOM 148 OE1 GLU 17 21.371 23.799 19, 353 1.000 14. 91

ANISOU 148 OE1 GLU 17 1567 2292 1806 85 529 -46

ATOM 149 OE2 GLU 17 20.469 22.056 18.327 1.000 19. 21

ANISOU 149 OE2 GLU 17 2611 2111 2576 -418 1765 -489

ATOM 150 C GLU 17 18.077 24.483 22.090 1, 000 7. 61

ANISOU 150 C GLU 17 1029 865 996 -112 239 -144

ATOM 151 O GLU 17 19.063 24.792 22.782 1.000 11. 28

ANISOU 151 O GLU 17 1063 1612 1610 -29 -51 -89

ATOM 152 N TYR 18 16.830 24.802 22, 428 1.000 5. L

ANISOU 152 N TYR 18 706 616 885 -220 456 -106

ATOM 153 CA TYR 18 16.528 25.588 23.613 1.000 7.

ANISOU 153 CA TYR 18 1128 692 1174 -40 190 -116

ATOM 154 CB TYR 18 15.847 26.892 23.200 1.000 8. 79

ANISOU 154 CB TYR 18 1357 783 1200 80 195 86

ATOM 155 CG TYR 18 16.779 27.798 22.453 1, 000 9.82

ANISOU 155 CG TYR 18 1589 754 1389 -296 -20 207

ATOM 156 CD1 TYR 18 17.595 28.678 23.161 1.000 11.37

ANISOU 156 CD1 TYR 18 2040 862 1417 -374 -79 71

ATOM 157 CE1 TYR 18 18.468 29.523 22.486 1.000 12.27

ANISOU 157 CE1 TYR 18 1837 1398 1428 -603 -118 164

ATOM 158 CD2 TYR 18 16.881 27.781 21.075 1.000 9.32

ANISOU 158 CD2 TYR 18 1417 847 1278 -222 101 365

ATOM 159 CE2 TYR 18 17.743 28.612 20.412 1.000 10.20

ANISOU 159 CE2 TYR 18 1543 1057 1277 -411 -80 425

ATOM 160 CZ TYR 18 18.542 29.477 21.120 1.000 11.

ANISOU 160 CZ TYR 18 1899 1119 1491 -455 -154 514

ATOM 161 OH TYR 18 19.415 30.327 20.491 1.000 16. 14

ANISOU 161 OH TYR 18 2686 2063 1383 -1118 226 182

ATOM 162 C TYR 18 15.634 24.836 24.586 1.000 7. 13

ANISOU 162 C TYR 18 1002 617 1090 -37 147 120

ATOM 163 O TYR 18 15.857 24.797 25.806 1.000 9. 28

ANISOU 163 O TYR 18 1417 1071 1037 -28 174 -34

ATOM 164 N ILE 19 14.578 24.258 24.030 1.000 6. 26

ANISOU 164 N ILE 19 788 769 821 33 206 182

ATOM 165 CA ILE 19 13.693 23.323 24.710 1.000 6. 96

ANISOU 165 CA ILE 19 1122 781 742 149 143 -151

ATOM 166 CB ILE 19 12.253 23.534 24.315 1.000 6. 93

ANISOU 166 CB ILE 19 1279 766 588 -108 Ill 74

ATOM 167 CG2 ILE 19 11.307 22.560 25.030 1.000 8. 43

ANISOU 167 CG2 ILE 19 856 1130 1218 99 536 -78

ATOM 168 CGI ILE 19 11.804 24.988 24.545 1.000 7. 72

ANISOU 168 CGI ILE 19 1110 768 1054 35 148 164

ATOM 169 CD1 ILE 19 10.416 25.320 24.085 1.000 10. 22

ANISOU 169 CD1 ILE 19 1179 1308 1397 250 325 -17

ATOM 170 C ILE 19 14.237 21.935 24.358 1.000 6. 70

ANISOU 170 C ILE 19 915 794 838 57 112 19

ATOM 171 O ILE 19 13.945 21.442 23.279 1.000 7. 47

ANISOU 171 O ILE 19 1025 1191 621 -100 87 -136

ATOM 172 N LYS 20 15.029 21.408 25.262 1.000 7. 441

ANISOU 172 N LYS 20 1071 860 894 222 -101 -192

ATOM 173 CA LYS 20 15.962 20.327 24.914 1.000 9. 19 ANISOU 173 CA LYS 20 1072 994 1425 24 -99 -279

ATOM 174 CB LYS 20 17.218 20.407 25.818 1.000 10.80

ANISOU 174 CB LYS 20 1074 1034 1995 51 -408 -298

ATOM 175 CG LYS 20 17.965 21.703 25.524 1.000 13.66

ANISOU 175 CG LYS 20 1612 1277 2301 215 -891 -432

ATOM 176 CD LYS 20 19.367 21.710 26.094 1.000 17.62

ANISOU 176 CD LYS 20 1873 1880 2942 -243 -1075 -209

ATOM 177 CE LYS 20 20.044 23.041 25.818 1.000 20.26

ANISOU 177 CE LYS 20 2508 2099 3092 -341 -1297 -61

ATOM 178 NZ LYS 20 21.428 23.085 26.388 1.000 31.24

ANISOU 178 NZ LYS 20 4351 2845 4674 -125 -2319 10

ATOM 179 C LYS 20 15.314 18.957 24.976 1.000 7.99

ANISOU 179 C LYS 20 1043 821 1173 360 179 -82

ATOM 180 O LYS 20 15.834 18.024 25.553 1.000 12.66

ANISOU 180 O LYS 20 1669 1357 1784 157 -328 353

ATOM 181 N THR 21 14.173 18.857 24.318 1.000 7.84

ANISOU 181 N THR 21 1204 787 987 82 99 126

ATOM 182 CA THR 21 13.450 17.624 24.179 1.000 7.56

ANISOU 182 CA THR 21 1175 910 789 224 165 331

ATOM 183 CB THR 21 11.941 17.877 24.104 1.000 8.39

ANISOU 183 CB THR 21 1047 948 1193 253 402 13

ATOM 184 OG1 THR 21 11.731 18.876 23.095 1.000 9.11

ANISOU 184 OG1 THR 21 1571 807 1084 212 395 56

ATOM 185 CG2 THR 21 11.389 18.389 25.414 1.000 10.52

ANISOU 185 CG2 THR 21 1573 1001 1422 355 559 23

ATOM 186 C THR 21 13.901 16.890 22.917 1.000 7.16

ANISOU 186 C THR 21 1024 809 887 4 263 179

ATOM 187 O THR 21 14.371 17.488 21.967 1.000 8.27

ANISOU 187 O THR 21 1010 1222 912 60 433 146

ATOM 188 N TRP 22 13.716 15.590 22.906 1.000 6.83

ANISOU 188 N TRP 22 983 828 784 139 226 32

ATOM 189 CA TRP 22 13.940 14.704 21.789 1.000 6.77

ANISOU 189 CA TRP 22 834 905 833 -216 283 172

ATOM 190 CB TRP 22 14.262 13.328 22.318 1.000 6.86

ANISOU 190 CB TRP 22 868 887 853 220 175 -45

ATOM 191 CG TRP 22 15.599 13.227 22.958 1.000 6.31

ANISOU 191 CG TRP 22 575 1091 733 137 376 168

ATOM 192 CD2 TRP 22 16.891 13.290 22.361 1.000 8.09

ANISOU 192 CD2 TRP 22 859 1137 1079 -177 -19 441

ATOM 193 CE2 TRP 22 17.824 13.132 23.396 1.000 11.60

ANISOU 193 CE2 TRP 22 1109 2170 1131 -84 31 440

ATOM 194 CE3 TRP 22 17.365 13.473 21.066 1.000 7.45

ANISOU 194 CE3 TRP 22 1087 671 1072 -27 125 83

ATOM 195 CD1 TRP 22 15.796 13.029 24.283 1.000 10.93

ANISOU 195 CD1 TRP 22 1047 2163 944 -373 -26 386

ATOM 196 NE1 TRP 22 17.131 12.972 24.557 1.000 14.86

ANISOU 196 NE1 TRP 22 1591 2941 1115 -308 -285 631

ATOM 197 CZ2 TRP 22 19.187 13.148 23.160 1.000 13.18

ANISOU 197 CZ2 TRP 22 1410 1950 1649 -122 -216 513

ATOM 198 CZ3 TRP 22 18.737 13.486 20.850 1.000 9.75

ANISOU 198 CZ3 TRP 22 1576 1067 1060 90 227 276

ATOM 199 CH2 TRP 22 19.657 13.324 21.888 1.000 10.43

ANISOU 199 CH2 TRP 22 1153 1475 1335 -15 370 488

ATOM 200 C TRP 22 12.700 14.686 20.892 1.000 7.82

ANISOU 200 C TRP 22 1141 956 875 38 0 18

ATOM 201 O TRP 22 11.620 14.308 21.319 1.000 9.45

ANISOU 201 O TRP 22 798 1410 1384 68 80 92

ATOM 202 N ARG 23 12.865 15.102 19.662 1.000 5.94

ANISOU 202 N ARG 23 874 760 622 -62 134 -62 ATOM 203 CA ARG 23 11.769 15.196 18.718 1 000 5.75

ANISOU 203 CA ARG 23 535 675 974 341 211 •125

ATOM 204 CB ARG 23 11.646 16.642 18.238 1 000 8 38

ANISOU 204 CB ARG 23 1216 806 1160 427 110 -263

ATOM 205 CG ARG 23 11.628 17.619 19.396 1.000 7 13

ANISOU 205 CG ARG 23 1065 574 1068 -16 381 -455

ATOM 206 CD ARG 23 11.690 19.047 18.973 1 000 9 91

ANISOU 206 CD ARG 23 1580 1043 1144 -184 122 -407

ATOM 207 NE ARG 23 11.916 19.925 20.126 1 000 8 74

ANISOU 207 NE ARG 23 1441 863 1015 -267 422 -334

ATOM 208 CZ ARG 23 12.088 21.232 20.015 1 000 7 55

ANISOU 208 CZ ARG 23 1365 548 954 -36 173 -279

ATOM 209 NH1 ARG 23 12.058 21.785 18.809 1, 000 8 .98

ANISOU 209 NH1 ARG 23 1330 968 1115 -103 48 •127

ATOM 210 NH2 ARG 23 12.274 21.973 21.073 1.000 7. 16

ANISOU 210 NH2 ARG 23 1417 552 753 84 361 -255

ATOM 211 C ARG 23 11.962 14.250 17.546 1.000 5. 35

ANISOU 211 C ARG 23 644 849 539 205 120 117

ATOM 212 O ARG 23 13.052 14.191 16.979 1, 000 6. 83

ANISOU 212 O ARG 23 856 888 853 -26 131 -49

ATOM 213 N PRO 24 10.918 13.503 17.216 1.000 5. 48

ANISOU 213 N PRO 24 517 901 666 -63 357 231

ATOM 214 CD PRO 24 9.563 13.483 17.791 1.000 6. 58

ANISOU 214 CD PRO 24 675 906 918 -243 307 19

ATOM 215 CA PRO 24 11.068 12.538 16.130 1.000 6. 24

ANISOU 215 CA PRO 24 908 1029 433 -104 232 ^■129

ATOM 216 CB PRO 24 9.842 11.648 16. 277 1.000 8. 48

ANISOU 216 CB PRO 24 1199 1084 939 -272 -54 -207

ATOM 217 CG PRO 24 8.808 12.595 16. 832 1.000 9. 12

ANISOU 217 CG PRO 24 1249 1213 1005 -537 163 •136

ATOM 218 C PRO 24 11.141 13.261 14.780 1.000 7. 19

ANISOU 218 C PRO 24 1165 940 627 -4 52 -160

ATOM 219 O PRO 24 10.333 14.150 14.507 1.000 7. 37

ANISOU 219 O PRO 24 1109 743 950 184 316 183

ATOM 220 N ARG 25 12.106 12.847 13.964 1.000 6. 62

ANISOU 220 N ARG 25 979 1141 397 66 248 -77

ATOM 221 CA ARG 25 12.302 13.461 12.682 1.000 5. 76

ANISOU 221 CA ARG 25 705 904 581 19 283 -70

ATOM 222 CB ARG 25 13.397 14. 528 12.686 1.000 8. 12

ANISOU 222 CB ARG 25 835 1198 1053 103 -7 -176

ATOM 223 CG ARG 25 13.245 15. 684 13.657 1.000 8. 52

ANISOU 223 CG ARG 25 815 1374 1047 368 235 -119

ATOM 224 CD ARG 25 12.307 16.722 13.084 1.000 8. 12

ANISOU 224 CD ARG 25 958 1097 1031 26 306 -194

ATOM 225 NE ARG 25 12.023 17.829 14.022 1.000 6. 78

ANISOU 225 NE ARG 25 681 845 1050 -77 416 -26

ATOM 226 CZ ARG 25 10.940 17.903 14.767 1.000 6. 04

ANISOU 226 CZ ARG 25 550 995 750 23 483 -151

ATOM 227 NH1 ARG 25 9.969 16.982 14.801 1.000 8. 09

ANISOU 227 NH1 ARG 25 903 879 1291 -164 -199 -252

ATOM 228 NH2 ARG 25 10.760 18.956 15.586 1.000 7. 27

ANISOU 228 NH2 ARG 25 942 935 885 98 64

ATOM 229 C ARG 25 12.735 12.388 11.671 1.000 6. 75

ANISOU 229 C ARG 25 1151 706 706 80 12

ATOM 230 O ARG 25 13.471 11.466 12.049 1.000 7. 57

ANISOU 230 O ARG 25 1164 913 798 128 38 -11

ATOM 231 N TYR 26 12.273 12. 529 10.449 1.000 6. 11

ANISOU 231 N TYR 26 998 720 602 136 107 102

ATOM 232 CA TYR 26 12.653 11. 612 9.367 1.000 6. 62 ANISOU 232 CA TYR 26 1040 736 738 -205 50 20

ATOM 233 CB TYR 26 11.474 11.233 8.469 1 000 6 62

ANISOU 233 CB TYR 26 808 1045 663 -169 278 -58

ATOM 234 CG TYR 26 11.851 10.095 7.534 1, 000 8 .52

ANISOU 234 CG TYR 26 1049 1462 727 -510 256 -213

ATOM 235 CD1 TYR 26 12.364 10.310 6.261 1 000 10 61

ANISOU 235 CD1 TYR 26 1616 1613 803 -684 248 45

ATOM 236 CEl TYR 26 12.706 9.272 5.426 1, 000 10 49

ANISOU 236 CEl TYR 26 1413 1715 858 -620 481 -99

ATOM 237 CD2 TYR 26 11.700 8.782 7.949 1, 000 9 54

ANISOU 237 CD2 TYR 26 1309 1399 917 -658 260 -71

ATOM 238 CE2 TYR 26 12.036 7.726 7.121 1, 000 10 51

ANISOU 238 CE2 TYR 26 1462 1477 1053 -592 380 -4

ATOM 239 CZ TYR 26 12.536 7.985 5, 865 1, 000 10 10

ANISOU 239 CZ TYR 26 1500 1497 840 -643 412 -352

ATOM 240 OH TYR 26 12.878 6.928 5, 055 1, 000 13 .11

ANISOU 240 OH TYR 26 2077 1824 1081 -821 454 -563

ATOM 241 C TYR 26 13.775 12.291 8.572 1, 000 7 10

ANISOU 241 C TYR 26 915 791 992 -166 66 103

ATOM 242 O TYR 26 13.537 13.372 8.058 1, 000 6 78

ANISOU 242 O TYR 26 796 715 1067 241 32 85

ATOM 243 N PHE 27 14.961 11.687 8.521 1, 000 6 55

ANISOU 243 N PHE 27 862 807 818 14 176 71

ATOM 244 CA PHE 27 16.072 12.339 7.867 1.000 6 48

ANISOU 244 CA PHE 27 913 701 846 291 325 214

ATOM 245 CB PHE 27 17.270 12.486 8.812 1, 000 8.43

ANISOU 245 CB PHE 27 1104 861 1237 150 13 -82

ATOM 246 CG PHE 27 17.288 13.853 9.459 1.000 6 94

ANISOU 246 CG PHE 27 971 797 868 101 207 35

ATOM 247 CD1 PHE 27 16.497 14.105 10.566 1, 000 7 63

ANISOU 247 CD1 PHE 27 667 1077 1153 -236 235 131

ATOM 248 CD2 PHE 27 18.088 14.851 8.929 1.000 6 73

ANISOU 248 CD2 PHE 27 675 933 951 -134 229

ATOM 249 CEl PHE 27 16.498 15.366 11.120 1.000 8 54

ANISOU 249 CEl PHE 27 819 1237 1187 -272 236 25

ATOM 250 CE2 PHE 27 18.088 16.125 9.479 1.000 7 67

ANISOU 250 CE2 PHE 27 895 814 1206 -318 155 192

ATOM 251 CZ PHE 27 17.286 16.372 10.587 1.000 6 90

ANISOU 251 CZ PHE 27 624 818 1181 -139 169 71

ATOM 252 C PHE 27 16.520 11.575 6.625 1.000 6 85

ANISOU 252 C PHE 27 717 802 1085 -128 180 169

ATOM 253 O PHE 27 16.381 10.355 6.529 1.000 8 22

ANISOU 253 O PHE 27 1342 683 1100 -313 190 140

ATOM 254 N LEU 28 17.086 12.322 5.704 1.000 7 33

ANISOU 254 N LEU 28 857 835 1091 -169 587 -62

ATOM 255 CA LEU 28 17.537 11.823 4.409 1.000 8 84

ANISOU 255 CA LEU 28 899 1281 1177 -212 555

ATOM 256 CB LEU 28 16.472 12.192 3.432 1.000 14 58

ANISOU 256 CB LEU 28 1447 2273 1822 -564 121 101

ATOM 257 CG LEU 28 16.325 11.684 2.035 1. 000 17 45

ANISOU 257 CG LEU 28 1775 2715 2142 -739 87 57

ATOM 258 CD1 LEU 28 14.842 11.655 1.647 1. 000 19 94

ANISOU 258 CD1 LEU 28 1587 4585 1403 339 317 -578

ATOM 259 CD2 LEU 28 17.135 12.575 1.109 1.000 20 26

ANISOU 259 CD2 LEU 28 2856 3055 1786 -817 726 40

ATOM 260 C LEU 28 18.879 12.469 4.061 1.000 8 15

ANISOU 260 C LEU 28 1068 1061 967 116 445 -380

ATOM 261 O LEU 28 18.954 13.708 4.124 1.000 7 87

ANISOU 261 O LEU 28 1005 943 1043 -23 407 -322 ATOM 262 N LEU 29 19.853 11.660 3.725 1.000 7.89

ANISOU 262 N LEU 29 1103 953 941 -91 252 -218

ATOM 263 CA LEU 29 21.185 12.084 3.374 1.000 7.14

ANISOU 263 CA LEU 29 779 839 1095 -68 207 -281

ATOM 264 CB LEU 29 22.234 11.360 4.225 1.000 7.83

ANISOU 264 CB LEU 29 1171 903 902 -52 127 -143

ATOM 265 CG LEU 29 23.712 11.581 3.891 1.000 7.51

ANISOU 265 CG LEU 29 960 1085 808 -11 156 41

ATOM 266 CD1 LEU 29 24.111 13.006 4.231 1.000 8.65

ANISOU 266 CD1 LEU 29 1144 1245 899 -193 -70 -24

ATOM 267 CD2 LEU 29 24.591 10.556 4.582 1.000 9.73

ANISOU 267 CD2 LEU 29 830 1638 1231 501 -73 -336

ATOM 268 C LEU 29 21.420 11.785 1.893 1.000 7.38

ANISOU 268 C LEU 29 783 974 1049 -212 172 -83

ATOM 269 O LEU 29 21.248 10.631 1.491 1.000 7.29

ANISOU 269 O LEU 29 1060 840 869 -91 137 -3

ATOM 270 N LYS 30 21.842 12.807 1.153 1.000 7.18

ANISOU 270 N LYS 30 838 1033 857 -7 452 -195

ATOM 271 CA LYS 30 22.135 12.595 -0.256 1.000 6.70

ANISOU 271 CA LYS 30 1040 761 746 -119 527 -26

ATOM 272 CB LYS 30 21.347 13.567 -1.124 1.000 8.82

ANISOU 272 CB LYS 30 1023 1187 1142 118 259 -146

ATOM 273 CG LYS 30 19.860 13.259 -1.064 1.000 11.70

ANISOU 273 CG LYS 30 1122 1523 1799 -82 -59 479

ATOM 274 CD LYS 30 19.106 13.835 -2.259 1.000 14.16

ANISOU 274 CD LYS 30 1509 1739 2132 -42 62 208

ATOM 275 CE LYS 30 19.095 15.351 -2.212 1.000 13.30

ANISOU 275 CE LYS 30 1115 1525 2412 -249 -53 190

ATOM 276 NZ LYS 30 18.248 15.820 -1.077 1.000 16.49

ANISOU 276 NZ LYS 30 2119 1901 2245 -52 -177 175

ATOM 277 C LYS 30 23.629 12.766 -0.557 1.000 6.25

ANISOU 277 C LYS 30 872 785 718 202 405 -19

ATOM 278 O LYS 30 24.360 13.384 0.220 1.000 7.84

ANISOU 278 O LYS 30 1039 1385 554 -15 6 -146

ATOM 279 N ASN 31 24.057 12.250 -1.708 1.000 6.79

ANISOU 279 N ASN 31 1007 947 626 63 324 1

ATOM 280 CA ASN 31 25.464 12.295 -2.077 1.000 8.72

ANISOU 280 CA ASN 31 1281 1269 763 280 404 -11

ATOM 281 CB ASN 31 25.726 11.510 -3.362 1.000 10.00

ANISOU 281 CB ASN 31 1708 1022 1071 227 491 -291

ATOM 282 CG ASN 31 26.163 10.089 -3.141 1.000 16.27

ANISOU 282 CG ASN 31 2955 1654 1573 845 -249 -366

ATOM 283 OD1 ASN 31 26.805 9.807 -2.118 1.000 18.29

ANISOU 283 OD1 ASN 31 2743 2667 1538 1252 369 197

ATOM 284 ND2 ASN 31 25.779 9.256 -4.100 1.000 18.49

ANISOU 284 ND2 ASN 31 2687 1946 2394 -169 748 -227

ATOM 285 C ASN 31 25.978 13.709 -2.263 1.000 9.91

ANISOU 285 C ASN 31 1375 1547 841 122 307 -70

ATOM 286 O ASN 31 27.192 13.911 -2.258 1.000 14.04

ANISOU 286 O ASN 31 1185 2496 1655 -272 189 -271

ATOM 287 N ASP 32 25.072 14.665 -2.398 1.000 8.18

ANISOU 287 N ASP 32 921 1274 911 -150 299 -89

ATOM 288 CA ASP 32 25.497 16.041 -2.605 1.000 10.23

ANISOU 288 CA ASP 32 1555 1371 962 -485 216 46

ATOM 289 CB ASP 32 24.494 16.785 -3.467 1.000 13.01

ANISOU 289 CB ASP 32 2153 1655 1134 -610 -330 17

ATOM 290 CG ASP 32 23.129 16.953 -2.854 1.000 13.52

ANISOU 290 CG ASP 32 1875 1576 1687 -449 -593 -93

ATOM 291 OD1 ASP 32 22.933 16.628 -1.663 1.000 12.92 ANISOU 291 OD1 ASP 32 1823 1625 1461 -232 -467 137

ATOM 292 OD2 ASP 32 22.235 17.404 -3.580 1.000 20.87

ANISOU 292 OD2 ASP 32 3640 1489 2802 -302 -1683 511

ATOM 293 C ASP 32 25.732 16.774 -1.285 1.000 9.47

ANISOU 293 C ASP 32 1260 1201 1137 -108 347 -218

ATOM 294 O ASP 32 25.992 17.982 -1.264 1.000 11.19

ANISOU 294 O ASP 32 1706 1119 1426 -455 568 -160

ATOM 295 N GLY 33 25.655 16.049 -0.187 1.000 9.14

ANISOU 295 N GLY 33 1270 1222 981 -173 352 -216

ATOM 296 CA GLY 33 25.995 16.601 1.112 1.000 10.19

ANISOU 296 CA GLY 33 1337 1386 1148 -395 236 -189

ATOM 297 C GLY 33 24.792 17.155 1.845 1.000 9.01

ANISOU 297 C GLY 33 1114 1386 924 -348 434 -249

ATOM 298 O GLY 33 24.900 17.544 3.009 1.000 9.40

ANISOU 298 O GLY 33 1426 1254 893 28 121 -435

ATOM 299 N THR 34 23.611 17.188 1.203 1.000 8.90

ANISOU 299 N THR 34 1210 1244 928 -102 319 -76

ATOM 300 CA THR 34 22.434 17.668 1.907 1.000 7.24

ANISOU 300 CA THR 34 870 968 912 118 356 61

ATOM 301 CB THR 34 21.303 18.079 0.940 1.000 10.13

ANISOU 301 CB THR 34 1119 1281 1450 84 31 91

ATOM 302 OGl THR 34 20.928 16.993 0.102 1.000 18.28

ANISOU 302 OGl THR 34 2309 2454 2182 -229 -1080 601

ATOM 303 CG2 THR 34 21.806 19.212 0.060 1.000 12.68

ANISOU 303 CG2 THR 34 852 2135 1829 -315 -304 784

ATOM 304 C THR 34 21.901 16.609 2.876 1.000 7.95

ANISOU 304 C THR 34 1053 925 1042 -51 41 -249

ATOM 305 O THR 34 21.792 15.438 2.548 1.000 9.15

ANISOU 305 O THR 34 1640 691 1147 39 357 -174

ATOM 306 N PHE 35 21.569 17.090 4.072 1.000 7.34

ANISOU 306 N PHE 35 913 1063 813 123 389 -151

ATOM 307 CA PHE 35 21.055 16.256 5.165 1.000 7.42

ANISOU 307 CA PHE 35 1025 809 984 -28 106 -311

ATOM 308 CB PHE 35 22.091 16.153 6.272 1.000 8.70

ANISOU 308 CB PHE 35 1177 1124 1005 -46 107 -123

ATOM 309 CG PHE 35 21.794 15.205 7.415 1.000 9.17

ANISOU 309 CG PHE 35 1292 1137 1054 401 25 -167

ATOM 310 CD1 PHE 35 21.351 13.916 7.166 1.000 9.80

ANISOU 310 CD1 PHE 35 1425 1092 1206 110 -119 -191

ATOM 311 CD2 PHE 35 21.966 15.613 8.728 1.000 12.37

ANISOU 311 CD2 PHE 35 1941 1490 1268 192 -230 -208

ATOM 312 CEl PHE 35 21.082 13.043 8.222 1.000 9.60

ANISOU 312 CEl PHE 35 1169 1025 1453 100 110 -311

ATOM 313 CE2 PHE 35 21.723 14.743 9.776 1.000 12.29

ANISOU 313 CE2 PHE 35 1685 1693 1291 149 69 -162

ATOM 314 CZ PHE 35 21.304 13.456 9.507 1.000 10.33

ANISOU 314 CZ PHE 35 1303 1359 1262 387 204 32

ATOM 315 C PHE 35 19.765 16.906 5.630 1.000 7.29

ANISOU 315 C PHE 35 816 790 1164 -184 223 -369

ATOM 316 O PHE 35 19.828 17.969 6.283 1.000 8.38

ANISOU 316 O PHE 35 1115 1020 1047 -105 129 -133

ATOM 317 N ILE 36 18.652 16.319 5.225 1.000 6.27

ANISOU 317 N ILE 36 658 778 946 -54 300 -251

ATOM 318 CA ILE 36 17.378 17.041 5.372 1.000 7.26

ANISOU 318 CA ILE 36 837 1043 879 -237 317 97

ATOM 319 CB ILE 36 16.755 17.339 4.011 1.000 11.52

ANISOU 319 CB ILE 36 1673 1552 1153 -17 25 557

ATOM 320 CG2 ILE 36 17.644 18.311 3.237 1.000 16.39

ANISOU 320 CG2 ILE 36 3009 2278 939 -190 -320 480 ATOM 321 CGI ILE 36 16.460 16.093 3.193 1.000 15 36

ANISOU 321 CGI ILE 36 2208 2316 1315 -548 -307 969

ATOM 322 CD1 ILE 36 15.715 16.453 1.904 1. 000 20 .59

ANISOU 322 CD1 ILE 36 2418 3542 1864 -483 639 357

ATOM 323 C ILE 36 16.413 16.244 6.244 1.000 6

ANISOU 323 C ILE 36 998 896 694 -236 159 17

ATOM 324 O ILE 36 16.346 15.016 6.200 1.000 8 .65

ANISOU 324 O ILE 36 1429 745 1113 -175 373 47

ATOM 325 N GLY 37 15.672 16.958 7. 074 1. 000 5.80

ANISOU 325 N GLY 37 811 721 672 -105 18

ATOM 326 CA GLY 37 14.743 16 ,364 7. 995 1. 000 7.16

ANISOU 326 CA GLY 37 933 874 912 179 -5 ^•150

ATOM 327 C GLY 37 13.330 16 ,864 7.836 1. 000 6.38

ANISOU 327 C GLY 37 979 705 738 11 66 -79

ATOM 328 O GLY 37 13.079 17.979 7.405 1. 000 6.69

ANISOU 328 O GLY 37 773 642 1127 133 -74 -107

ATOM 329 N TYR 38 12.393 16 ,022 8.207 1. 000 7.06

ANISOU 329 N TYR 38 884 751 1046 52 13 -46

ATOM 330 CA TYR 38 10.975 16 ,219 8. 075 1. 000 7.63

ANISOU 330 CA TYR 38 488 1192 1218 105 152 -24

ATOM 331 CB TYR 38 10.408 15 382 6. 939 1. 000 7.40

ANISOU 331 CB TYR 38 615 935 1263 -75 93 -39

ATOM 332 CG TYR 38 11.093 15 485 5.606 1. 000 7.42

ANISOU 332 CG TYR 38 726 989 1104 -52 180 -53

ATOM 333 CD1 TYR 38 10.588 16 ,302 4.608 1. 000 7.65

ANISOU 333 CD1 TYR 38 815 1105 987 73 56 -122

ATOM 334 CEl TYR 38 11.207 16 394 3.388 1. 000 8.53

ANISOU 334 CEl TYR 38 741 1409 1092 87 128 -149

ATOM 335 CD2 TYR 38 12.237 14 770 5.331 1. 000 10.79

ANISOU 335 CD2 TYR 38 1124 1533 1441 43 84 280

ATOM 336 CE2 TYR 38 12.855 14 862 4.110 1. 000 11.95

ANISOU 336 CE2 TYR 38 1134 1912 1495 698 136 ^•139

ATOM 337 CZ TYR 38 12.346 15 679 3.140 1.000 10.83

ANISOU 337 CZ TYR 38 745 2199 1170 210 309 164

ATOM 338 OH TYR 38 12.957 15 772 1.912 1.000 19.43

ANISOU 338 OH TYR 38 1564 4404 1415 976 527 20

ATOM 339 C TYR 38 10.237 15 839 9.349 1.000 7.30

ANISOU 339 C TYR 38 609 945 1222 93 103 57

ATOM 340 O TYR 38 10.655 14 901 10.022 1.000 8.08

ANISOU 340 O TYR 38 835 1153 1081 136 167 -113

ATOM 341 N LYS 39 9.155 16 556 9.658 1.000 8.05

ANISOU 341 N LYS 39 595 1026 1436 -8 138 -141

ATOM 342 CA LYS 39 8.346 16 178 10.806 1.000 8.84

ANISOU 342 CA LYS 39 663 1295 1401 -87 394 -1

ATOM 343 CB LYS 39 7.312 17 243 11.093 1.000 11.06

ANISOU 343 CB LYS 39 852 1662 1690 197 482 -246

ATOM 344 CG LYS 39 6.613 17 114 12.435 1.000 11.39

ANISOU 344 CG LYS 39 1383 1589 1355 -87 602 -323

ATOM 345 CD LYS 39 5.633 18 252 12.663 1.000 12.35

ANISOU 345 CD LYS 39 1791 1645 1255 0 351 -550

ATOM 346 CE LYS 39 4.982 18 206 14.031 1.000 12.19

ANISOU 346 CE LYS 39 1681 1478 1474 8 253 -411

ATOM 347 NZ LYS 39 5.993 18 413 15.118 1.000 12.09

ANISOU 347 NZ LYS 39 1372 1782 1438 -376 275 -280

ATOM 348 C LYS 39 7.632 14 853 10.549 1.000 11.51

ANISOU 348 C LYS 39 1333 1606 1434 -247 251

ATOM 349 O LYS 39 7.498 13 996 11. 407 1.000 14.14

ANISOU 349 O LYS 39 1860 1949 1562 -529 113 15

ATOM 350 N GLU 40 7.173 14 716 9. 307 1.000 11.58 ANISOU 350 N GLU 40 1197 1892 1312 -364 402 186

ATOM 351 CA GLU 40 6.514 13.486 8 .882 1.000 12. 27

ANISOU 351 CA GLU 40 1075 2193 1394 -506 619 154

ATOM 352 CB GLU 40 5.051 13.717 8 .511 1.000 16. 60

ANISOU 352 CB GLU 40 1517 2812 1980 -534 425 277

ATOM 353 CG GLU 40 4.286 14..691 9 .408 1.000 19. 33

ANISOU 353 CG GLU 40 1758 3338 2247 -726 114 526

ATOM 354 CD GLU 40 4.053 14..115 10 .788 1.000 21. 68

ANISOU 354 CD GLU 40 2628 3310 2300 -240 308 496

ATOM 355 OE1 GLU 40 4.337 12..910 10 .926 1.000 25. 45

ANISOU 355 OE1 GLU 40 3408 3357 2903 602 207 521

ATOM 356 OE2 GLU 40 3.595 14..826 11 .715 1.000 25. 64

ANISOU 356 OE2 GLU 40 3616 3457 2667 -83 996 917

ATOM 357 C GLU 40 7.283 12..892 7 ,704 1.000 11.

ANISOU 357 C GLU 40 1334 1750 1428 -891 263 247

ATOM 358 O GLU 40 7.826 13..617 6 .863 1.000 12. 69

ANISOU 358 O GLU 40 1392 2137 1291 -732 378 -147

ATOM 359 N ARG 41 7.330 11..560 7 .660 1.000 11. 61

ANISOU 359 N ARG 41 1431 1658 1322 -573 -23 471

ATOM 360 CA ARG 41 7.963 10..953 6 ,494 1.000 12. 86

ANISOU 360 CA ARG 41 1510 1818 1558 -480 -122 251

ATOM 361 CB ARG 41 7.910 9..443 6 ,650 1.000 14. 81

ANISOU 361 CB ARG 41 1964 2126 1537 -495 -319 342

ATOM 362 CG ARG 41 8.687 8..783 5 ,514 1.000 14. 76

ANISOU 362 CG ARG 41 2098 1934 1576 -386 -359 167

ATOM 363 CD ARG 41 8.847 7..307 5 774 1.000 16. 63

ANISOU 363 CD ARG 41 2739 1739 1843 -744 -448 242

ATOM 364 NE ARG 41 9.539 6..670 4 661 1.000 19. 06

ANISOU 364 NE ARG 41 3860 1686 1697 -386 -500 -10

ATOM 365 CZ ARG 41 9.938 5..402 4 745 1.000 22. 14

ANISOU 365 CZ ARG 41 4642 1672 2097 -278 -563 -107

ATOM 366 NH1 ARG 41 9.703 4..710 5 851 1.000 28. 35

ANISOU 366 NH1 ARG 41 6290 1805 2675 -779 -954 357

ATOM 367 NH2 ARG 41 10.558 4..870 3 713 1.000 28. 26

ANISOU 367 NH2 ARG 41 5567 2253 2918 -260 -740 -241

ATOM 368 C ARG 41 7.281 11..367 5 191 1.000 12. 31

ANISOU 368 C ARG 41 1665 1607 1405 -341 72 367

ATOM 369 O ARG 41 6.058 11..184 5 052 1.000 15. 14

ANISOU 369 O ARG 41 2216 1859 1677 -724 -334 160

ATOM 370 N PRO 42 7.994 11.,930 4 231 1.000 12. 55

ANISOU 370 N PRO 42 1810 1578 1382 -108 82 406

ATOM 371 CD PRO 42 9.428 12..279 4 200 1.000 13. 68

ANISOU 371 CD PRO 42 1998 1909 1289 -547 -1 475

ATOM 372 CA PRO 42 7.338 12..380 2 992 1.000 14. 05

ANISOU 372 CA PRO 42 2099 1940 1298 -457 128 466

ATOM 373 CB PRO 42 8.445 13..023 2 154 1.000 16. 56

ANISOU 373 CB PRO 42 2310 2229 1754 -281 156 363

ATOM 374 CG PRO 42 9.490 13.350 3 142 1.000 17. 62

ANISOU 374 CG PRO 42 2529 2216 1949 -751 -357 499

ATOM 375 C PRO 42 6.736 11.229 2 189 1.000 16. 30

ANISOU 375 C PRO 42 2649 2116 1428 -416 -70 -92

ATOM 376 O PRO 42 7.356 10.191 2 056 1.000 23. 20

ANISOU 376 O PRO 42 4413 1937 2463 314 -1236 -371

ATOM 377 N GLN 43 5.548 11.515 1 691 1.000 19. 95

ANISOU 377 N GLN 43 3455 2573 1551 -927 -355 -23

ATOM 378 CA GLN 43 4.708 10.545 0 995 1.000 23. 64

ANISOU 378 CA GLN 43 3826 3349 1809 -1532 -447 79

ATOM 379 CB GLN 43 3.329 10.528 1 663 1.000 26. 28

ANISOU 379 CB GLN 43 3435 4093 2456 -1221 -79 -257 ATOM 380 CG GLN 43 3.364 9.994 3.097 1.000 30.96

ANISOU 380 CG GLN 43 3697 4807 3260 -1111 -37 -33

ATOM 381 CD GLN 43 3.329 8.479 3.106 1.000 37.27

ANISOU 381 CD GLN 43 4375 5761 4025 -796 -214 87

ATOM 382 OE1 GLN 43 4.361 7.822 2.926 1.000 48.13

ANISOU 382 OE1 GLN 43 5726 7215 5345 -369 -583 556

ATOM 383 NE2 GLN 43 2.150 7.906 3.305 1.000 46.60

ANISOU 383 NE2 GLN 43 6123 7017 4568 -908 -1374 -364

ATOM 384 C GLN 43 4.589 10.850 -0.487 1.000 25.96

ANISOU 384 C GLN 43 4646 3389 1827 -1588 -696 161

ATOM 385 O GLN 43 4.096 10.018 -1.249 1.000 31.71

ANISOU 385 O GLN 43 6531 3665 1851 -2853 -1470 376

ATOM 386 N ASP 44 5.042 12.027 -0.891 1.000 24.47

ANISOU 386 N ASP 44 4548 3076 1675 -1707 -681 361

ATOM 387 CA ASP 44 5.017 12.331 -2.332 1.000 25.59

ANISOU 387 CA ASP 44 4571 3036 2116 -1188 -947 392

ATOM 388 CB ASP 44 3.666 12.888 -2.726 1.000 24.88

ANISOU 388 CB ASP 44 3838 3276 2340 -965 -577 20

ATOM 389 CG ASP 44 3.226 14.168 -2.069 1.000 26.64

ANISOU 389 CG ASP 44 3375 4028 2720 -928 -458 96

ATOM 390 OD1 ASP 44 4.078 15.001 -1.710 1.000 24.74

ANISOU 390 OD1 ASP 44 2374 4377 2649 -1003 -225 337

ATOM 391 OD2 ASP 44 1.996 14.351 -1.918 1.000 29.71

ANISOU 391 OD2 ASP 44 2231 5201 3856 -695 -379 46

ATOM 392 C ASP 44 6.225 13.226 -2.606 1.000 21.68

ANISOU 392 C ASP 44 3943 2540 1755 -1075 -600 631

ATOM 393 O ASP 44 6.922 13.604 -1.657 1.000 20.14

ANISOU 393 O ASP 44 3363 2493 1794 -733 -1117 255

ATOM 394 N VAL 45 6.468 13.547 -3.875 1.000 22.26

ANISOU 394 N VAL 45 4139 2505 1813 -530 -850 184

ATOM 395 CA VAL 45 7.620 14.399 -4.196 1.000 21.34

ANISOU 395 CA VAL 45 3443 2919 1748 -163 -355 309

ATOM 396 CB VAL 45 7.866 14.395 -5.719 1.000 22.52

ANISOU 396 CB VAL 45 3389 3193 1973 309 -16 78

ATOM 397 CGI VAL 45 8.752 15.557 -6.127 1.000 25.16

ANISOU 397 CGI VAL 45 3831 3582 2144 -241 188 744

ATOM 398 CG2 VAL 45 8.486 13.065 -6.145 1.000 27.41

ANISOU 398 CG2 VAL 45 3967 3728 2721 860 -747 -715

ATOM 399 C VAL 45 7.442 15.812 -3.638 1.000 17.64

ANISOU 399 C VAL 45 2387 2409 1909 111 -269 319

ATOM 400 O VAL 45 8.383 16.477 -3.204 1.000 15.93

ANISOU 400 O VAL 45 1936 1962 2157 195 16 365

ATOM 401 N ASP 46 6.225 16.355 -3.608 1.000 16.77

ANISOU 401 N ASP 46 2295 2355 1721 -189 -145 759

ATOM 402 CA ASP 46 5.983 17.680 -3.080 1.000 17.53

ANISOU 402 CA ASP 46 1687 2990 1982 218 -38 585

ATOM 403 CB ASP 46 4.504 18.033 -3.227 1.000 23.69

ANISOU 403 CB ASP 46 2299 4105 2597 542 -211 706

ATOM 404 CG ASP 46 4.089 18.534 -4.588 1.000 28.07

ANISOU 404 CG ASP 46 2665 4920 3080 1037 -432 660

ATOM 405 OD1 ASP 46 2.877 18.811 -4.747 1.000 36.47

ANISOU 405 OD1 ASP 46 3732 6312 3813 1092 -1373 1152

ATOM 406 OD2 ASP 46 4.909 18.667 -5.512 1.000 31.78

ANISOU 406 OD2 ASP 46 3919 5551 2604 533 -56 1361

ATOM 407 C ASP 46 6.403 17.748 -1.618 1.000 15.22

ANISOU 407 C ASP 46 1381 2494 1906 -140 -172 559

ATOM 408 O ASP 46 7.006 18.711 -1.147 1.000 16.99

ANISOU 408 O ASP 46 1856 2127 2472 110 292 158

ATOM 409 N GLN 47 6.062 16.706 -0.885 1.000 15.59 ANISOU 409 N GLN 47 1796 2099 2031 -248 -599 401

ATOM 410 CA GLN 47 6.456 16.625 0, 524 1.000 12. 17

ANISOU 410 CA GLN 47 1082 1898 1643 19 66 409

ATOM 411 CB GLN 47 5.786 15.438 1, 190 1.000 15. 65

ANISOU 411 CB GLN 47 1374 2383 2188 -133 -168 373

ATOM 412 CG GLN 47 4.326 15.801 1, 522 1.000 17. 67

ANISOU 412 CG GLN 47 1436 2469 2810 -503 -432 769

ATOM 413 CD GLN 47 3.521 14.572 1. 899 1.000 19. 99

ANISOU 413 CD GLN 47 1864 2648 3083 -201 -335 537

ATOM 414 OE1 GLN 47 4.043 13.622 2, 472 1.000 21. 70

ANISOU 414 OE1 GLN 47 2616 2878 2753 -109 -234 706

ATOM 415 NE2 GLN 47 2.240 14.605 1, 556 1.000 23. 20

ANISOU 415 NE2 GLN 47 1934 2979 3901 119 -16 355

ATOM 416 C GLN 47 7.970 16.547 0. 636 1.000 12. 06

ANISOU 416 C GLN 47 1211 2063 1307 -27 319 268

ATOM 417 O GLN 47 8.596 17.155 1.490 1.000 11. 82

ANISOU 417 O GLN 47 1592 1632 1267 151 53

ATOM 418 N ARG 48 8.591 15.783 -0. 256 1.000 12. 15

ANISOU 418 N ARG 48 1417 1829 1369 -66 -54 118

ATOM 419 CA ARG 48 10.035 15.642 -0. 257 1.000 12. 39

ANISOU 419 CA ARG 48 2053 1614 1041 367 31 187

ATOM 420 CB ARG 48 10.292 14.614 -1. 347 1.000 17. 28

ANISOU 420 CB ARG 48 2866 2169 1532 778 -502 11

ATOM 421 CG ARG 48 11.720 14.375 -1.656 1.000 16. 26

ANISOU 421 CG ARG 48 2446 2113 1620 449 -487 -32

ATOM 422 CD ARG 48 11.990 13.085 -2.395 1.000 15. 04

ANISOU 422 CD ARG 48 2302 2003 1411 494 33 -435

ATOM 423 NE ARG 48 11.956 11.926 -1.537 1.000 16. 12

ANISOU 423 NE ARG 48 2075 2484 1567 537 172 -424

ATOM 424 CZ ARG 48 12.316 10.701 -1.878 1.000 15. 41

ANISOU 424 CZ ARG 48 2351 1885 1618 535 22 ^■174

ATOM 425 NHl ARG 48 12.764 10.452 -3.110 1.000 13. 33

ANISOU 425 NHl ARG 48 2093 1120 1852 159 -158 -307

ATOM 426 NH2 ARG 48 12.246 9.698 -1.010 1.000 23. 61

ANISOU 426 NH2 ARG 48 2221 3537 3213 -67 -177 1395

ATOM 427 C ARG 48 10.711 16.985 -0.455 1.000 11. 62

ANISOU 427 C ARG 48 1488 1696 1232 191 194 49

ATOM 428 O ARG 48 11.778 17.319 0.082 1.000 12. 97

ANISOU 428 O ARG 48 1501 2164 1262 -34 -13 187

ATOM 429 N GLU 49 10.088 17.853 -1.242 1.000 13. 49

ANISOU 429 N GLU 49 1906 1808 1410 321 9 24

ATOM 430 CA GLU 49 10.713 19.131 -1.575 1.000 14. 04

ANISOU 430 CA GLU 49 2138 1756 1439 351 85 97

ATOM 431 CB GLU 49 10.138 19.581 -2.926 1.000 14. 91

ANISOU 431 CB GLU 49 2436 1718 1511 175 284 -11

ATOM 432 CG GLU 49 10.645 18.715 -4.078 1.000 18. 17

ANISOU 432 CG GLU 49 3287 2149 1468 343 -66 -396

ATOM 433 CD GLU 49 9.992 18.926 -5.416 1.000 18. 69

ANISOU 433 CD GLU 49 3004 2376 1721 422 -68 -291

ATOM 434 OE1 GLU 49 8.966 19.618 -5.484 1.000 19. 64

ANISOU 434 OE1 GLU 49 2400 2767 2294 319 41 -121

ATOM 435 OE2 GLU 49 10.530 18.372 -6.419 1.000 19. 34

ANISOU 435 OE2 GLU 49 2993 2506 1848 276 38 140

ATOM 436 C GLU 49 10.532 20.194 -0.509 1.000 14. 80

ANISOU 436 C GLU 49 2710 1549 1365 -73 -186 388

ATOM 437 O GLU 49 10.980 21.340 -0.638 1.000 20. 68

ANISOU 437 O GLU 49 4018 1556 2281 -574 -708 342

ATOM 438 N ALA 50 9.882 19.860 0.593 1.000 13. 65

ANISOU 438 N ALA 50 2138 1719 1331 312 -68 171 ATOM 439 CA ALA 50 9.631 20 848 1.641 1.000 15.40

ANISOU 439 CA ALA 50 2292 1982 1579 443 -168 -129

ATOM 440 CB ALA 50 8.139 21 181 1.664 1.000 19.91

ANISOU 440 CB ALA 50 2071 2900 2593 566 -761 -553

ATOM 441 C ALA 50 10.086 20 397 3.022 1.000 14.22

ANISOU 441 C ALA 50 2004 1855 1545 572 -168 -468

ATOM 442 O ALA 50 9.266 20 245 3.940 1.000 16.28

ANISOU 442 O ALA 50 1499 2732 1957 336 57 -86

ATOM 443 N PRO 51 11.377 20 160 3.207 1.000 10.80

ANISOU 443 N PRO 51 1427 1557 1120 142 22 -223

ATOM 444 CD PRO 51 12.474 20 234 2.217 1.000 12.97

ANISOU 444 CD PRO 51 1811 1691 1426 -44 -159 219

ATOM 445 CA PRO 51 11.867 19 736 4.519 1.000 9.49

ANISOU 445 CA PRO 51 1492 1173 942 -84 2 -13

ATOM 446 CB PRO 51 13.346 19 421 4.267 1.000 10.07

ANISOU 446 CB PRO 51 1593 1254 977 -246 71 -58

ATOM 447 CG PRO 51 13.712 20 217 3.076 1.000 12.66

ANISOU 447 CG PRO 51 1884 1563 1364 35 -15 -161

ATOM 448 C PRO 51 11.722 20 814 5.580 1.000 9.33

ANISOU 448 C PRO 51 1388 1026 1131 -27 42 -37

ATOM 449 O PRO 51 11.685 22 012 5.329 1.000 12.39

ANISOU 449 O PRO 51 2397 997 1314 249 66 50

ATOM 450 N LEU 52 11.659 20 311 6.810 1.000 8.41

ANISOU 450 N LEU 52 1188 900 1107 141 86 43

ATOM 451 CA LEU 52 11.730 21 114 8.022 1.000 7.22

ANISOU 451 CA LEU 52 892 843 1007 274 108 -201

ATOM 452 CB LEU 52 11.181 20 303 9.193 1.000 8.88

ANISOU 452 CB LEU 52 977 1263 1134 23 145 -346

ATOM 453 CG LEU 52 11.073 21. 013 10.529 1.000 11.06

ANISOU 453 CG LEU 52 1200 1556 1446 -306 -108 -515

ATOM 454 CD1 LEU 52 10.118 22. 214 10.501 1.000 13.41

ANISOU 454 CD1 LEU 52 1547 1259 2290 260 269 -938

ATOM 455 CD2 LEU 52 10.585 20.052 11.613 1.000 13.05

ANISOU 455 CD2 LEU 52 1786 1686 1488 -154 -12 123

ATOM 456 C LEU 52 13.145 21.566 8.350 1.000 8.12

ANISOU 456 C LEU 52 1055 837 1193 107 74 -112

ATOM 457 O LEU 52 13.406 22.727 8.706 1.000 10.28

ANISOU 457 O LEU 52 1416 1103 1389 349 -125 -380

ATOM 458 N ASN 53 14.093 20.649 8.240 1.000 7.67

ANISOU 458 N ASN 53 1399 744 771 102 66 10

ATOM 459 CA ASN 53 15.485 20.864 8.521 1.000 7.61

ANISOU 459 CA ASN 53 1257 800 835 -76 109 85

ATOM 460 CB ASN 53 16.022 19.874 9.569 1.00 6.58

ANISOU 460 CB ASN 53 942 668 891 -101 209 -283

ATOM 461 CG ASN 53 15.111 19.796 10.783 1.00 7.76

ANISOU 461 CG ASN 53 1084 623 1242 -307 61 -107

ATOM 462 OD1 ASN 53 14.352 18.839 11.042 1.00 10.21

ANISOU 462 OD1 ASN 53 1688 1098 1095 -36 -160 -131

ATOM 463 ND2 ASN 53 15.200 20.850 11.552 1.00 6.29

ANISOU 463 ND2 ASN 53 797 966 626 133 443 -283

ATOM 464 C ASN 53 16.332 20.664 7.263 1.000 5.48

ANISOU 464 C ASN 53 640 661 783 203 351 64

ATOM 465 O ASN 53 16.014 19.755 6.469 1.000 6.52

ANISOU 465 O ASN 53 1165 560 754 -69 219 -185

ATOM 466 N ASN 54 17.382 21.465 7.146 1.000 6.47

ANISOU 466 N ASN 54 811 787 862 -56 439 35

ATOM 467 CA ASN 54 18.284 21.302 6.003 1.000 6.97

ANISOU 467 CA ASN 54 813 735 1102 -49 158 0

ATOM 468 CB ASN 54 17.733 22.088 4.838 1.000 12.46 ANISOU 468 CB ASN 54 1795 1860 1078 203 -124 -347

ATOM 469 CG ASN 54 18.495 21.905 3.543 1.000 15.02

ANISOU 469 CG ASN 54 2044 2250 1413 675 3 -230

ATOM 470 OD1 ASN 54 19.530 21.241 3.500 1.000 19.06

ANISOU 470 OD1 ASN 54 2224 2118 2900 189 101 337

ATOM 471 ND2 ASN 54 17.928 22.526 2.528 1.000 23.58

ANISOU 471 ND2 ASN 54 4238 3025 1699 589 -686 244

ATOM 472 C ASN 54 19.685 21.729 6.409 1.000 6.90

ANISOU 472 C ASN 54 1048 731 843 -179 142 34

ATOM 473 O ASN 54 19.908 22.877 6.765 1.000 9.09

ANISOU 473 O ASN 54 1162 604 1688 68 -172 -217

ATOM 474 N PHE 55 20.588 20.749 6.366 1.000 6.05

ANISOU 474 N PHE 55 726 753 820 -46 189 -80

ATOM 475 CA PHE 55 21.991 20.997 6.639 1.000 6.64

ANISOU 475 CA PHE 55 840 534 1150 15 -4 -80

ATOM 476 CB PHE 55 22.440 20.225 7.892 1.000 7.36

ANISOU 476 CB PHE 55 674 938 1184 -102 150 147

ATOM 477 CG PHE 55 21.460 20.469 9.043 1.000 6.95

ANISOU 477 CG PHE 55 586 1166 889 73 451 67

ATOM 478 CD1 PHE 55 21.370 21.717 9.615 1.000 9.19

ANISOU 478 CD1 PHE 55 1303 1331 857 202 319 -13

ATOM 479 CD2 PHE 55 20.649 19.453 9.511 1.000 7.31

ANISOU 479 CD2 PHE 55 254 1472 1052 72 645 -89

ATOM 480 CEl PHE 55 20.449 21.948 10.614 1.000 9.47

ANISOU 480 CEl PHE 55 1266 1345 987 -53 79 -106

ATOM 481 CE2 PHE 55 19.751 19.686 10.527 1.000 7.00

ANISOU 481 CE2 PHE 55 444 1120 1094 -349 335 116

ATOM 482 CZ PHE 55 19.659 20.934 11.097 1.000 8.16

ANISOU 482 CZ PHE 55 1069 1056 975 -246 8 -112

ATOM 483 C PHE 55 22.845 20.560 5.473 1.000 6.82

ANISOU 483 C PHE 55 791 710 1089 -215 214 -118

ATOM 484 O PHE 55 22.407 19.834 4.575 1.000 10.30

ANISOU 484 O PHE 55 832 1481 1602 -443 345 -590

ATOM 485 N SER 56 24.087 21.003 5.489 1.000 6.31

ANISOU 485 N SER 56 500 773 1125 -6 290 -125

ATOM 486 CA SER 56 25.085 20.552 4.545 1.000 8.00

ANISOU 486 CA SER 56 671 1212 1157 -168 480 -97

ATOM 487 CB ASER 56 25.573 21.702 3.671 0.500 10.78

ANISOU 487 CB ASER 56 1225 1482 1390 -28 217 24

ATOM 488 CB 1 BSER 56 25.701 21.635 3.662 0.500 10.30

ANISOU 488 CB 1 BSER 56 1094 1461 1357 -45 297 44

ATOM 489 OG ASER 56 24.472 22.367 3.043 0.500 12.00

ANISOU 489 OG ASER 56 1624 1208 1728 -55 420 438

ATOM 490 OG 1 BSER 56 26.943 21.108 3.208 0.500 11.21

ANISOU 490 OG 1 BSER 56 1124 1846 1288 564 1140 180

ATOM 491 C SER 56 26.248 19.940 5.325 1.000 9.46

ANISOU 491 C SER 56 750 1369 1474 190 -5 -321

ATOM 492 0 SER 56 26.764 20.580 6.263 1.000 12.11

ANISOU 492 0 SER 56 981 1703 1915 -34 -88 -1101

ATOM 493 N VAL 57 26.634 18.723 4.927 1.000 10.42

ANISOU 493 N VAL 57 1203 1296 1458 413 -335 -635

ATOM 494 CA VAL 57 27.595 18.015 5.777 1.000 10.17

ANISOU 494 CA VAL 57 998 1530 1336 299 -165 -410

ATOM 495 CB VAL 57 27.231 16.529 5.940 1.000 9.71

ANISOU 495 CB VAL 57 821 1628 1240 179 50 -270

ATOM 496 CGI VAL 57 25.840 16.440 6.554 1.000 14.86

ANISOU 496 CGI VAL 57 1067 2451 2127 296 261 -423

ATOM 497 CG2 VAL 57 27.320 15.771 4.616 1.000 11.60

ANISOU 497 CG2 VAL 57 1428 1361 1619 70 -178 -61 ATOM 498 C VAL 57 29.024 18.133 5.277 1, 000 9 51

ANISOU 498 C VAL 57 1041 1392 1179 507 137 -409

ATOM 499 O VAL 57 29.888 17.462 5.843 1.000 10 18

ANISOU 499 O VAL 57 912 1480 1477 374 271 -285

ATOM 500 N ALA 58 29.283 18.923 4.244 1, 000 11 21

ANISOU 500 N ALA 58 1324 1585 1349 284 164 ^■134

ATOM 501 CA ALA 58 30.658 19.103 3.756 1.000 11 .5.

ANISOU 501 CA ALA 58 1408 1706 1285 207 123 220

ATOM 502 CB ALA 58 30.738 20.131 2.643 1.000 15 .22

ANISOU 502 CB ALA 58 2255 2402 1127 346 370 185

ATOM 503 C ALA 58 31.574 19.484 4.921 1.000 10 72

ANISOU 503 C ALA 58 1243 1693 1136 237 251 16

ATOM 504 O ALA 58 31.243 20.378 5.683 1.000 12 03

ANISOU 504 O ALA 58 1643 1650 1276 -118 384 102

ATOM 505 N GLN 59 32.706 18.812 5.037 1.000 11 .38

ANISOU 505 N GLN 59 1383 1798 1142 103 347 -22

ATOM 506 CA GLN 59 33.701 19.121 6.047 1.000 12 34

ANISOU 506 CA GLN 59 1393 1914 1381 -189 273 218

ATOM 507 CB GLN 59 34.316 20.512 5.779 1.000 17 50

ANISOU 507 CB GLN 59 2026 2695 1929 -477 179 582

ATOM 508 CG GLN 59 35.023 20.530 4.421 1.000 21 65

ANISOU 508 CG GLN 59 2894 3167 2164 -638 155 710

ATOM 509 CD GLN 59 35.642 21.876 4.120 1, 000 25 07

ANISOU 509 CD GLN 59 3108 3690 2727 -556 520 505

ATOM 510 OE1 GLN 59 35.370 22.896 4.773 1. 000 32 31

ANISOU 510 OE1 GLN 59 4344 3895 4035 -1285 -461 311

ATOM 511 NE2 GLN 59 36.505 21.899 3.111 1. 000 33 10

ANISOU 511 NE2 GLN 59 5207 4107 3263 -403 510 624

ATOM 512 C GLN 59 33.186 19.075 7.479 1.000 11 27

ANISOU 512 C GLN 59 1212 1701 1368 -78 187 -39

ATOM 513 O GLN 59 33.736 19.683 8.398 1.000 12 28

ANISOU 513 O GLN 59 1344 1485 1836 -104 -34 -101

ATOM 514 N CYS 60 32.108 18.325 7. 709 1.000 10 75

ANISOU 514 N CYS 60 1362 1711 1014 -46 173 ^■97

ATOM 515 CA CYS 60 31.569 18.259 9. 062 1.000 10 42

ANISOU 515 CA CYS 60 1302 1423 1235 -293 -37 223

ATOM 516 CB CYS 60 30.198 17.618 9. 026 1. 000 12 44

ANISOU 516 CB CYS 60 1967 1527 1232 -319 -269 277

ATOM 517 SG CYS 60 30.233 15.847 8. 746 1. 000 15 37

ANISOU 517 SG CYS 60 2096 1780 1962 -377 -169 -62

ATOM 518 C CYS 60 32.472 17.461 9. 993 1. 000 10 26

ANISOU 518 C CYS 60 1403 1214 1281 1 74 162

ATOM 519 O CYS 60 33.358 16.731 9. 594 1. 000 11 74

ANISOU 519 O CYS 60 1536 1622 1303 473 278 98

ATOM 520 N GLN 61 32.178 17.651 11. 269 1.000 8 74

ANISOU 520 N GLN 61 1045 1081 1193 85 337 20

ATOM 521 CA GLN 61 32.700 16.829 12. 335 1.000 9.82

ANISOU 521 CA GLN 61 1192 1175 1366 115 213

ATOM 522 CB GLN 61 33.324 17.673 13. 428 1. 000 12 19

ANISOU 522 CB GLN 61 1478 1414 1741 -173 -122 359

ATOM 523 CG GLN 61 34.648 18.269 13. 023 1. 000 14 45

ANISOU 523 CG GLN 61 1721 1760 2010 -325 -202 508

ATOM 524 CD GLN 61 35.262 18.972 14. 236 1. 000 17 52

ANISOU 524 CD GLN 61 1934 2059 2662 -929 -738 349

ATOM 525 OE1 GLN 61 35.849 18.372 15. 151 1. 000 23 75

ANISOU 525 OE1 GLN 61 2979 3170 2875 -263 -746 -586

ATOM 526 NE2 GLN 61 35.069 20.278 14. 163 1. 000 27 08

ANISOU 526 NE2 GLN 61 2982 2474 4832 -575 -2000 -412

ATOM 527 C GLN 61 31.574 15.985 12. 931 1. 000 8 79 ANISOU 527 C GLN 61 1385 957 997 10 131 48

ATOM 528 O GLN 61 30.443 16 .467 12 .993 1, .000 9.

ANISOU 528 O GLN 61 1488 909 1351 281 340 -73

ATOM 529 N LEU 62 31.926 14 .784 13 .330 1. .000 7. 90

ANISOU 529 N LEU 62 1115 885 1003 42 239 121

ATOM 530 CA LEU 62 30.965 13, .820 13, .835 1. .000 7. 68

ANISOU 530 CA LEU 62 1323 917 680 122 454 125

ATOM 531 CB LEU 62 30.785 12, .637 12, .874 1. .000 8. 62

ANISOU 531 CB LEU 62 1301 1087 888 61 114 ^■ 11

ATOM 532 CG LEU 62 30.239 13, .095 11, .515 1. .000 11. 02

ANISOU 532 CG LEU 62 1425 1702 1059 344 -108 -82

ATOM 533 CD1 LEU 62 30.622 12, .137 10, .429 1. .000 10. . 72

ANISOU 533 CD1 LEU 62 739 2171 1162 485 -106 -427

ATOM 534 CD2 LEU 62 28.727 13, .275 11, .626 1. .000 11. 98

ANISOU 534 CD2 LEU 62 1404 1788 1359 341 183 -239

ATOM 535 C LEU 62 31.429 13, .302 15, .203 1, .000 6. 86

ANISOU 535 C LEU 62 966 927 713 294 375 112

ATOM 536 O LEU 62 32.470 12, .681 15. .304 1, .000 9. 62

ANISOU 536 O LEU 62 996 1475 1184 566 11 -243

ATOM 537 N MSE 63 30.593 13, .571 16, .180 1. .000 6. 37

ANISOU 537 N MSE 63 565 1094 762 102 317 126

ATOM 538 CA MSE 63 30.985 13. .282 17. .571 1, .000 9. 00

ANISOU 538 CA MSE 63 1248 1116 1057 12 -Ill 486

ATOM 539 CB AMSE 63 31.033 14, ,505 18. .462 0. .500 10. 98

ANISOU 539 CB AMSE 63 2310 834 1026 348 -542

ATOM 540 CB BMSE 63 31.119 14. .659 18. .226 0. .500 11. 65

ANISOU 540 CB BMSE 63 2526 875 1024 249 -740 87

ATOM 541 CG AMSE 63 32.171 15. .491 18, .152 0. .500 14. 43

ANISOU 541 CG AMSE 63 3668 701 1114 314 -1372 265

ATOM 542 CG BMSE 63 32.333 15. ,531 17, .858 0. ,500 12.

ANISOU 542 CG BMSE 63 3535 510 847 362 -1293 433

ATOM 543 SE AMSE 63 31.660 16. ,548 16. .643 0. ,500 36. 72

ANISOU 543 SE AMSE 63 5081 4614 4258 -1729 -1356 469

ATOM 544 SE BMSE 63 32.243 17. ,374 18. .488 0. ,500 21. 19

ANISOU 544 SE BMSE 63 3197 2154 2702 -61 55 ^■ 685

ATOM 545 CE AMSE 63 30.670 17. ,818 17. .683 0. ,500 37. 23

ANISOU 545 CE AMSE 63 2050 7838 4259 -3876 -1361 3905

ATOM 546 CE BMSE 63 30.907 17. 789 17. ,154 0. ,500 37. 23

ANISOU 546 CE BMSE 63 2049 7837 4258 -3876 -1360 3905

ATOM 547 C MSE 63 29.971 12. 290 18. ,121 1. ,000 8. 95

ANISOU 547 C MSE 63 1167 894 1340 342 -259 285

ATOM 548 O MSE 63 28.752 12. 491 18. ,036 1. ,000 12. 63

ANISOU 548 O MSE 63 706 1858 2233 376 320 1270

ATOM 549 N LYS 64 30.438 11. 190 18. ,715 1. ,000 6. 41

ANISOU 549 N LYS 64 386 975 1075 115 132 286

ATOM 550 CA LYS 64 29.578 10. 255 19. ,406 1. .000 6. 89

ANISOU 550 CA LYS 64 583 1091 944 -66 251 102

ATOM 551 CB LYS 64 29.999 8. 806 19. ,158 1. ,000 8. 19

ANISOU 551 CB LYS 64 695 1271 1145 -44 206 - 159

ATOM 552 CG LYS 64 29.957 8. 399 17. ,676 1. 000 9. 08

ANISOU 552 CG LYS 64 926 1406 1117 -125 5 - 499

ATOM 553 CD LYS 64 30.447 6. 976 17. .421 1. 000 13. 31

ANISOU 553 CD LYS 64 1184 2207 1667 -132 -86 - 474

ATOM 554 CE LYS 64 31.943 6. 797 17. .660 1. ,000 17. 37

ANISOU 554 CE LYS 64 1482 3043 2073 -393 71 -419

ATOM 555 NZ LYS 64 32.680 7. 305 16. ,483 1. ,000 20. 16

ANISOU 555 NZ LYS 64 1756 3550 2353 -166 -116 194

ATOM 556 C LYS 64 2*** 10. 537 20. .898 1. ,000 6. 47

ANISOU 556 C LYS 64 567 1040 850 -28 103 181 ATOM 557 O LYS 64 30.725 10.630 21.496 1.000 9.07

ANISOU 557 O LYS 64 350 1930 1166 187 239 -72

ATOM 558 N THR 65 28.473 10.651 21.524 1.000 7.32

ANISOU 558 N THR 65 831 1153 796 123 -114 88

ATOM 559 CA THR 65 28.422 10.955 22.958 1.000 5.78

ANISOU 559 CA THR 65 380 1039 776 319 144 -34

ATOM 560 CB THR 65 28.020 12.414 23.207 1.000 9.81

ANISOU 560 CB THR 65 1163 1359 1207 573 -46 22

ATOM 561 OGl THR 65 26.720 12.629 22.611 1.000 11.66

ANISOU 561 OGl THR 65 1493 1274 1665 306 -39 155

ATOM 562 CG2 THR 65 28.941 13.402 22.569 1.000 14.52

ANISOU 562 CG2 THR 65 1523 2526 1467 90 178 312

ATOM 563 C THR 65 27.422 10.051 23.646 1.000 5.66

ANISOU 563 C THR 65 684 756 710 191 169 -11

ATOM 564 O THR 65 26.607 9.384 23.005 1.000 8.00

ANISOU 564 O THR 65 937 1238 864 -179 -87 58

ATOM 565 N GLU 66 27.465 9.990 24.959 1.000 7.29

ANISOU 565 N GLU 66 872 1150 746 129 95 -171

ATOM 566 CA GLU 66 26.621 9.104 25.746 1.000 9.81

ANISOU 566 CA GLU 66 1150 1520 1059 -289 -164 2

ATOM 567 CB GLU 66 27.469 8.077 26.494 1.000 9.04

ANISOU 567 CB GLU 66 657 1748 1031 -450 308 203

ATOM 568 CG GLU 66 28.420 7.275 25.625 1.000 9.51

ANISOU 568 CG GLU 66 869 1724 1021 -207 185 69

ATOM 569 CD GLU 66 27.815 6.613 24.398 1.000 10.40

ANISOU 569 CD GLU 66 1243 1781 927 138 3 -227

ATOM 570 OE1 GLU 66 28.494 6.609 23.344 1.000 9.82

ANISOU 570 OEl GLU 66 1136 1521 1075 189 128 110

ATOM 571 OE2 GLU 66 26.686 6.082 24.484 1.000 10.88

ANISOU 571 OE2 GLU 66 1340 1511 1283 -344 -150 5

ATOM 572 C GLU 66 25.755 9.874 26.736 1.000 9.56

ANISOU 572 C GLU 66 875 1570 1188 -154 -3 -35

ATOM 573 O GLU 66 25.059 9.269 27.544 1.000 9.45

ANISOU 573 O GLU 66 944 1579 1067 -207 156 -270

ATOM 574 N ARG 67 25.784 11.193 26.657 1.000 9.07

ANISOU 574 N ARG 67 847 1669 930 101 418 -302

ATOM 575 CA ARG 67 24.956 12.056 27.504 1.000 11.91

ANISOU 575 CA ARG 67 1413 1975 1139 -78 372 -243

ATOM 576 CB ARG 67 25.759 12.767 28.596 1.000 12.31

ANISOU 576 CB ARG 67 1594 2024 1060 -416 608 -315

ATOM 577 CG ARG 67 26.373 11.766 29.560 1.000 12.72

ANISOU 577 CG ARG 67 1571 2193 1070 -458 396 -228

ATOM 578 CD ARG 67 25.292 11.178 30.455 1.000 14.96

ANISOU 578 CD ARG 67 1785 2596 1303 -669 153 99

ATOM 579 NE ARG 67 25.773 10.131 31.342 1.000 15.53

ANISOU 579 NE ARG 67 1858 2763 1280 -710 -123 205

ATOM 580 CZ ARG 67 26.372 10.346 32.516 1.000 16.53

ANISOU 580 CZ ARG 67 1735 3048 1499 -891 -2 145

ATOM 581 NHl ARG 67 26.577 11.561 32.972 1.000 14.78

ANISOU 581 NHl ARG 67 1483 2720 1413 -667 16 -75

ATOM 582 NH2 ARG 67 26.774 9.332 33.260 1.000 18.72

ANISOU 582 NH2 ARG 67 1261 3859 1993 -438 -212 -90

ATOM 583 C ARG 67 24.250 13.057 26.601 1.000 14.46

ANISOU 583 C ARG 67 1998 1669 1826 280 291 -56

ATOM 584 O ARG 67 24.891 13.556 25.677 1.000 17.90

ANISOU 584 O ARG 67 2263 2307 2231 89 437 1012

ATOM 585 N PRO 68 22.980 13.348 26.839 1.000 16.09

ANISOU 585 N PRO 68 1924 1753 2435 276 405 75

ATOM 586 CD PRO 68 22.144 14.195 25.953 1.000 19.15 ANISOU 586 CD PRO 68 2023 2287 2966 511 280 -158

ATOM 587 CA PRO 68 22.248 12.872 28.013 1, 000 12 .93

ANISOU 587 CA PRO 68 1195 1660 2058 232 718 -205

ATOM 588 CB PRO 68 21.019 13.785 28.018 1.000 16 68

ANISOU 588 CB PRO 68 1615 2258 2463 600 516 -459

ATOM 589 CG PRO 68 20.777 14.101 26.583 1.000 19 .84

ANISOU 589 CG PRO 68 2228 2359 2950 651 131 -117

ATOM 590 C PRO 68 21.758 11.428 27.916 1, 000 10 .96

ANISOU 590 C PRO 68 1137 1461 1565 533 580 -54*

ATOM 591 O PRO 68 21.317 10.858 28.922 1.000 16 04

ANISOU 591 O PRO 68 2430 2484 1179 -825 -33 -138

ATOM 592 N ARG 69 21.829 10.860 26. 729 1, 000 9 96

ANISOU 592 N ARG 69 1005 1642 1137 109 491 -284

ATOM 593 CA ARG 69 21.463 9.503 26. 440 1.000 11 94

ANISOU 593 CA ARG 69 998 1958 1580 39 218 ^■613

ATOM 594 CB ARG 69 20.281 9.424 25.443 1. 000 16 15

ANISOU 594 CB ARG 69 1585 2379 2171 406 -232 -823

ATOM 595 CG ARG 69 18.907 9.826 25.887 1. 000 21 10

ANISOU 595 CG ARG 69 2511 2772 2733 -302 -677 -322

ATOM 596 CD ARG 69 17.841 9.194 24.973 1. 000 18 03

ANISOU 596 CD ARG 69 1991 2265 2595 -994 -230 29

ATOM 597 NE ARG 69 17.654 7.761 25.206 1. 000 18 01

ANISOU 597 NE ARG 69 2200 2133 2509 -793 -62 -37

ATOM 598 CZ ARG 69 16.692 7.052 24.619 1. 000 15 03

ANISOU 598 CZ ARG 69 1769 1587 2356 -1045 72 -142

ATOM 599 NHl ARG 69 15.866 7.676 23.783 1. 000 13 57

ANISOU 599 NHl ARG 69 1171 1885 2099 -143 533 -718

ATOM 600 NH2 ARG 69 16.531 5.747 24.837 1.000 17 51

ANISOU 600 NH2 ARG 69 1641 2510 2504 -788 304 249

ATOM 601 C ARG 69 22.590 8.737 25. 745 1.000 9 48

ANISOU 601 C ARG 69 783 1621 1197 -83 364 -377

ATOM 602 O ARG 69 23.254 9.362 24. 934 1.000 8 47

ANISOU 602 O ARG 69 810 1237 1172 -11 256 -64

ATOM 603 N PRO 70 22.740 7.459 26. 035 1.000 9.56

ANISOU 603 N PRO 70 1163 1516 953 -304 83 -145

ATOM 604 CD PRO 70 22.136 6.671 27.120 1.000 12 48

ANISOU 604 CD PRO 70 1426 2184 1132 -329 375 -83

ATOM 605 CA PRO 70 23.613 6.649 25.190 1.000 9.22

ANISOU 605 CA PRO 70 1271 1359 872 -44 -59 -122

ATOM 606 CB PRO 70 23.372 5.234 25. 730 1.000 9. 75

ANISOU 606 CB PRO 70 1040 1812 854 95 427 -36

ATOM 607 CG PRO 70 23.097 5.491 27. 186 1.000 12. 08

ANISOU 607 CG PRO 70 1530 2078 984 -304 230 196

ATOM 608 C PRO 70 23.208 6.740 23.728 1.000 7.

ANISOU 608 C PRO 70 1118 1001 838 204 -122 -171

ATOM 609 O PRO 70 22.020 6.952 23.434 1.000 9. 67

ANISOU 609 O PRO 70 847 1694 1133 141 -6 -142

ATOM 610 N ASN 71 24.158 6.505 22.833 1.000 7. 20

ANISOU 610 N ASN 71 737 981 1017 -84 -36 119

ATOM 611 CA ASN 71 23.903 6.376 21.393 1.000 7. 22

ANISOU 611 CA ASN 71 1101 737 907 3 -91 -37

ATOM 612 CB ASN 71 22.840 5.307 21.140 1.000 6. 99

ANISOU 612 CB ASN 71 926 817 915 -5 189 141

ATOM 613 CG ASN 71 23.296 3.986 21.733 1.000 8. 09

ANISOU 613 CG ASN 71 1276 747 1050 41 -64 129

ATOM 614 OD1 ASN 71 24.430 3.563 21.484 1.000 9. 42

ANISOU 614 OD1 ASN 71 1233 1138 1207 345 -261

ATOM 615 ND2 ASN 71 22.452 3.337 22.521 1.000 9. 15

ANISOU 615 ND2 ASN 71 1312 885 1279 -90 -29 488 ATOM 616 C ASN 71 23.513 7 688 20.749 1.000 7 54

ANISOU 616 C ASN 71 1220 675 969 -68 -444 13

ATOM 617 O ASN 71 22.819 7 747 19. 726 1.000 8. 69

ANISOU 617 O ASN 71 1047 979 1276 -138 -245 -38

ATOM 618 N THR 72 24.010 8 768 21. 343 1.000 7, 76

ANISOU 618 N THR 72 1120 897 930 160 -346 59

ATOM 619 CA THR 72 23.814 10 112 20.801 1.000 7, 11

ANISOU 619 CA THR 72 708 953 1040 -13 -90 16

ATOM 620 CB THR 72 23.682 11 091 21.974 1.000 7, 67

ANISOU 620 CB THR 72 704 794 1418 314 -198 -179

ATOM 621 OGl THR 72 22.508 10 791 22.745 1.000 9, 52

ANISOU 621 OGl THR 72 703 1408 1506 174 51 ^■101

ATOM 622 CG2 THR 72 23.618 12.538 21.481 1.000 11. 29

ANISOU 622 CG2 THR 72 1714 1216 1361 309 -650 -340

ATOM 623 C THR 72 24.940 10, 435 19.826 1.000 7. 35

ANISOU 623 C THR 72 909 782 1100 244 29 53

ATOM 624 O THR 72 26.075 9 961 19.949 1.000 7. 26

ANISOU 624 O THR 72 941 823 996 235 -80 42

ATOM 625 N PHE 73 24.626 11 233 18. 813 1.000 8. 52

ANISOU 625 N PHE 73 913 814 1510 126 -206 311

ATOM 626 CA PHE 73 25.692 11 782 17. 987 1.000 8. 14

ANISOU 626 CA PHE 73 771 1021 1302 150 98 206

ATOM 627 CB PHE 73 25.905 10 984 16. 726 1.000 9. 53

ANISOU 627 CB PHE 73 1302 947 1373 2 -95 -79

ATOM 628 CG PHE 73 24.817 10 865 15. 688 1.000 9. 14

ANISOU 628 CG PHE 73 1119 952 1403 255 127 23

ATOM 629 CD1 PHE 73 23.848 9 895 15.812 1.000 10. 39

ANISOU 629 CD1 PHE 73 1438 896 1613 125 -392 -43

ATOM 630 CD2 PHE 73 24.775 11 711 14.591 1.000 10. 56

ANISOU 630 CD2 PHE 73 1613 933 1468 607 -186 -306

ATOM 631 CEl PHE 73 22.873 9 772 14.842 1.000 11. 42

ANISOU 631 CEl PHE 73 1460 1108 1772 403 -274 -322

ATOM 632 CE2 PHE 73 23.799 11.603 13.617 1.000 9. 58

ANISOU 632 CE2 PHE 73 1386 1054 1202 392 254

ATOM 633 CZ PHE 73 22.848 10.617 13.758 1.000 12. 32

ANISOU 633 CZ PHE 73 1830 1180 1669 519 -318 -504

ATOM 634 C PHE 73 25.410 13.254 17.680 1.000 8. 74

ANISOU 634 C PHE 73 1024 1101 1197 -13 -33 412

ATOM 635 O PHE 73 24.261 13.679 17. 612 1.000 9.

ANISOU 635 O PHE 73 789 751 1941 81 -32 437

ATOM 636 N ILE 74 26.491 13.994 17. 526 1.000 8. 07

ANISOU 636 N ILE 74 799 1105 1162 241 304 326

ATOM 637 CA ILE 74 26.486 15. 413 17. 224 1.000 8. 36

ANISOU 637 CA ILE 74 857 1101 1218 -155 153 32

ATOM 638 CB ILE 74 27.178 16. 256 18. 307 1.000 8. 84

ANISOU 638 CB ILE 74 1092 1075 1191 -222 -159 50

ATOM 639 CG2 ILE 74 27.135 17.737 17. 978 1.000 11. 50

ANISOU 639 CG2 ILE 74 1720 865 1785 -434 -417 294

ATOM 640 CGI ILE 74 26.618 15.961 19. 706 1.000 11. 58

ANISOU 640 CGI ILE 74 1910 1188 1303 -392 -498 277

ATOM 641 CD1 ILE 74 27.480 16.507 20. 814 1.000 12. 67

ANISOU 641 CD1 ILE 74 2370 1234 1209 129 -463 280

ATOM 642 C ILE 74 27.190 15.640 15. 891 1.000 8. 33

ANISOU 642 C ILE 74 1018 900 1246 71 237 347

ATOM 643 O ILE 74 28.275 15.094 15. 676 1.000 10. 59

ANISOU 643 O ILE 74 959 1532 1533 288 315 516

ATOM 644 N ILE 75 26.540 16. 414 15.035 1.000 7. 14

ANISOU 644 N ILE 75 1120 523 1068 103 116 287

ATOM 645 CA ILE 75 27.196 16. 903 13.832 1.000 9. 13 ANISOU 645 CA ILE 75 1528 902 1040 -135 -16 297

ATOM 646 CB AILE 75 26.363 16 .728 12 .560 0 .500 9. 67

ANISOU 646 CB AILE 75 1375 1151 1148 -16 25 277

ATOM 647 CB BILE 75 26.321 16 .728 12 .591 0. .500 9. . 53

ANISOU 647 CB BILE 75 1352 1146 1124 -17 56 277

ATOM 648 CG2AILE 75 25.082 17, .537 12 .673 0, .500 12. 16

ANISOU 648 CG2AILE 75 2070 1133 1416 153 -509 460

ATOM 649 CG2BILE 75 27.128 17, .042 11 .333 0, .500 12. 16

ANISOU 649 CG2BILE 75 1700 1503 1417 -594 -305 404

ATOM 650 CG1AILE 75 27.096 17. .059 11 .255 0, .500 11. 10

ANISOU 650 CG1AILE 75 1574 1406 1238 -219 -87 321

ATOM 651 CG1BILE 75 25.647 15, .353 12 .457 0. .500 7. 42

ANISOU 651 CG1BILE 75 939 960 921 260 546 112

ATOM 652 CD1AILE 75 26.466 16, .532 9 .982 0, .500 11. 87

ANISOU 652 CD1AILE 75 1188 2372 951 208 805 288

ATOM 653 CD1BILE 75 24.536 15, .318 11 .430 0. .500 9. 86

ANISOU 653 CD1BILE 75 954 956 1838 147 335 135

ATOM 654 C ILE 75 27.524 18. .373 14 .076 1, .000 8. 32

ANISOU 654 C ILE 75 1334 1111 714 -71 167 255

ATOM 655 O ILE 75 26.688 19. .142 14 .544 1. .000 8. 54

ANISOU 655 O ILE 75 940 882 1425 276 264 108

ATOM 656 N ARG 76 28.768 18. .691 13. .753 1. .000 8. 24

ANISOU 656 N ARG 76 1092 1004 1035 145 90 256

ATOM 657 CA ARG 76 29.228 20. .077 13, .718 1. ,000 8.

ANISOU 657 CA ARG 76 1148 953 1159 -76 6 218

ATOM 658 CB ARG 76 30.465 20. ,303 14, .582 1. ,000 9. 57

ANISOU 658 CB ARG 76 1036 1318 1282 -184 -75 ^■180

ATOM 659 CG ARG 76 31.098 21. ,671 14. .494 1. ,000 12. 40

ANISOU 659 CG ARG 76 1158 1737 1817 -485 -43 -47

ATOM 660 CD ARG 76 32.489 21. 643 15. .141 1. ,000 18. 61

ANISOU 660 CD ARG 76 2273 2189 2611 -740 -658 - 114

ATOM 661 NE ARG 76 32.368 21. 469 16. .564 1. 000 20. 22

ANISOU 661 NE ARG 76 2674 2490 2516 -293 -893 -653

ATOM 662 CZ ARG 76 33.218 21. 289 17. .544 1. 000 22. 02

ANISOU 662 CZ ARG 76 2781 2985 2602 37 -910 -711

ATOM 663 NHl ARG 76 34.539 21. 194 17, .520 1. 000 22. 30

ANISOU 663 NHl ARG 76 2525 2778 3169 -56 -1194 -722

ATOM 664 NH2 ARG 76 32.726 21. 172 18. .777 1. 000 26. 33

ANISOU 664 NH2 ARG 76 3870 2988 3148 822 -1387 -1249

ATOM 665 C ARG 76 29.488 20. 442 12. .254 1. 000 9. 37

ANISOU 665 C ARG 76 1312 1046 1203 -68 78 228

ATOM 666 O ARG 76 30.318 19. 815 11. ,605 1. 000 11. 03

ANISOU 666 O ARG 76 1532 1360 1300 118 168 331

ATOM 667 N CYS 77 28.731 21. 428 11. ,770 1. 000 9. 57

ANISOU 667 N CYS 77 1688 948 998 407 -32 48

ATOM 668 CA CYS 77 28.778 21. 705 10. ,332 1. 000 10. 32

ANISOU 668 CA CYS 77 1609 1202 1109 286 -193 33

ATOM 669 CB CYS 77 27.734 20. 889 9. 591 1. 000 12. 16

ANISOU 669 CB CYS 77 2053 1262 1304 -120 -470 25

ATOM 670 SG CYS 77 26.053 20. 971 10. .234 1. 000 16. 76

ANISOU 670 SG CYS 77 2428 1723 2219 -231 -1018 126

ATOM 671 C CYS 77 28.572 23. 183 10. 108 1. 000 7. 78

ANISOU 671 C CYS 77 863 1077 1017 -18 161 212

ATOM 672 O CYS 77 28.214 23. 939 11. 000 1. 000 9. 79

ANISOU 672 O CYS 77 1638 1019 1064 -18 322

ATOM 673 N LEU 78 28.807 23. 592 8. ,884 1. 000 8. 03

ANISOU 673 N LEU 78 921 1117 1013 163 136 -196

ATOM 674 CA LEU 78 28.667 24. 987 8. ,495 1. 000 7. 90

ANISOU 674 CA LEU 78 1103 791 1109 178 33 -136 ATOM 675 CB LEU 78 29.774 25,.324 7.498 1.000 9.83

ANISOU 675 CB LEU 78 1479 1017 1239 215 -36 ^■ 102

ATOM 676 CG LEU 78 29.835 26. .756 7 .004 1. .000 11. . 86

ANISOU 676 CG LEU 78 1657 1386 1465 45 162 ^■ 174

ATOM 677 CDl LEU 78 30.140 27. .685 8 .182 1, .000 11. 99

ANISOU 677 CDl LEU 78 1504 1472 1578 -85 848 43

ATOM 678 CD2 LEU 78 30.889 26. .959 5 .921 1, .000 13. 30

ANISOU 678 CD2 LEU 78 1645 1785 1623 -86 688 163

ATOM 679 C LEU 78 27.307 25, .221 7 .871 1, .000 7. 66

ANISOU 679 C LEU 78 1075 984 852 106 235 -35

ATOM 680 O LEU 78 26.989 24. ,539 6, .892 1. .000 9. 04

ANISOU 680 O LEU 78 1194 1051 1191 -212 -132 -39

ATOM 681 N GLN 79 26.542 26. ,155 8. .415 1, .000 7. 10

ANISOU 681 N GLN 79 910 1006 781 112 184 25

ATOM 682 CA GLN 79 25.292 26, .621 7 .885 1. .000 7. 90

ANISOU 682 CA GLN 79 1255 1014 734 206 -73 152

ATOM 683 CB GLN 79 24.219 26. ,627 8, .955 1, .000 7. 99

ANISOU 683 CB GLN 79 1195 950 892 -150 -167 209

ATOM 684 CG GLN 79 22.800 26. ,752 8, .490 1. .000 8. 01

ANISOU 684 CG GLN 79 957 1020 1067 172 -40 - 96

ATOM 685 CD GLN 79 22.227 25. ,522 7. .811 1. .000 9. 42

ANISOU 685 CD GLN 79 1116 1198 1264 186 -241 -166

ATOM 686 OEl GLN 79 22.905 24. ,743 7, .150 1, .000 12. 27

ANISOU 686 OEl GLN 79 1302 1619 1742 29 163 - 634

ATOM 687 NE2 GLN 79 20.929 25. 296 7. .965 1. .000 11. 28

ANISOU 687 NE2 GLN 79 1002 1391 1894 -326 -95 - 34 1

ATOM 688 C GLN 79 25.494 28. ,042 7. .349 1. .000 8. 00

ANISOU 688 C GLN 79 1214 1049 778 190 73 47

ATOM 689 O GLN 79 25.480 28. ,996 8. .117 1. .000 8. 53

ANISOU 689 O GLN 79 987 1218 1035 -80 169 - 61

ATOM 690 N TRP 80 25.688 28. 107 6, .042 1. ,000 8. 46

ANISOU 690 N TRP 80 1329 1070 817 199 -50 14

ATOM 691 CA TRP 80 26.006 29. 312 5. .282 1. .000 9. 62

ANISOU 691 CA TRP 80 1492 1016 1147 -47 -210 123

ATOM 692 CB TRP 80 24.811 30. 264 5. .305 1. ,000 10. 15

ANISOU 692 CB TRP 80 1380 1204 1271 103 -70 26

ATOM 693 CG TRP 80 25.095 31. 625 4. .764 1. .000 13. 69

ANISOU 693 CG TRP 80 1775 1727 1699 172 -350 596

ATOM 694 CD2 TRP 80 25.617 31. 959 3. .487 1. ,000 14. 09

ANISOU 694 CD2 TRP 80 1324 2054 1976 183 -126 737

ATOM 695 CE2 TRP 80 25.716 33. 365 3. .429 1. ,000 14. 66

ANISOU 695 CE2 TRP 80 1826 1952 1793 -26 42 800

ATOM 696 CE3 TRP 80 26.001 31. ,197 2. .399 1. .000 13. 28

ANISOU 696 CE3 TRP 80 1465 2011 1572 160 83 781

ATOM 697 CDl TRP 80 24.902 32. 809 5. .424 1. ,000 16. 79

ANISOU 697 CDl TRP 80 2579 1641 2158 -Ill -729 932

ATOM 698 NE1 TRP 80 25.271 33. 853 4. .623 1. ,000 18. 83

ANISOU 698 NE1 TRP 80 2885 1953 2317 -401 -798 768

ATOM 699 CZ2 TRP 80 26.187 34. 069 2. .335 1. ,000 18. 19

ANISOU 699 CZ2 TRP 80 2357 2438 2118 114 -16 611

ATOM 700 CZ3 TRP 80 26.475 31. 894 1. .290 1. ,000 15. 96

ANISOU 700 CZ3 TRP 80 1619 2235 2209 42 -4 796

ATOM 701 CH2 TRP 80 26.563 33. 284 1. .266 1. ,000 17. 26

ANISOU 701 CH2 TRP 80 1792 2529 2239 348 27 474

ATOM 702 C TRP 80 27.336 29. 836 5. .813 1. ,000 9. 13

ANISOU 702 C TRP 80 1397 1053 1020 -122 71 104

ATOM 703 O TRP 80 28.362 29. 405 5. .275 1. ,000 10. 57

ANISOU 703 O TRP 80 1246 1424 1347 52 -42 179

ATOM 704 N THR 81 27.388 30. 690 6. .814 1. ,000 10. 05 ANISOU 704 N THR 81 1566 1182 1070 -260 -52 68

ATOM 705 CA THR 81 28.642 31.223 7 .350 1 .000 9 .64

ANISOU 705 CA THR 81 1340 1090 1232 -335 91 128

ATOM 706 CB THR 81 28.806 32.740 7 .060 1 .000 12 19

ANISOU 706 CB THR 81 1803 1418 1409 16 10 -237

ATOM 707 OGl THR 81 27.735 33.484 7 .641 1 .000 13 53

ANISOU 707 OGl THR 81 1688 1437 2016 -381 -45

ATOM 708 CG2 THR 81 28.778 32.990 5 .564 1 .000 13 . l i

ANISOU 708 CG2 THR 81 2604 1185 1447 -350 -527 276

ATOM 709 C THR 81 28.770 31.016 8 ,855 1 .000 10 .27

ANISOU 709 C THR 81 1359 1307 1237 -525 237 72

ATOM 710 O THR 81 29.747 31.494 9 .437 1 .000 13 10

ANISOU 710 O THR 81 2007 1736 1232 -873 -19 300

ATOM 711 N THR 82 27.869 30.291 9 .480 1 .000 9 27

ANISOU 711 N THR 82 1233 1095 1195 -158 78 133

ATOM 712 CA THR 82 27.817 30.018 10 .895 1 .000 8 35

ANISOU 712 CA THR 82 1236 793 1144 -505 47 77

ATOM 713 CB THR 82 26.441 30.442 11 ,444 1 .000 9

ANISOU 713 CB THR 82 1332 955 1202 -510 305 -59

ATOM 714 OGl THR 82 26.197 31.824 11 ,160 1 .000 12 49

ANISOU 714 OGl THR 82 2175 1133 1437 -158 -71 -129

ATOM 715 CG2 THR 82 26.360 30.301 12 945 1 .000 9 87

ANISOU 715 CG2 THR 82 1531 1051 1170 -390 -12 35

ATOM 716 C THR 82 28.020 28.545 11 ,196 1 .000 7 93

ANISOU 716 C THR 82 732 1125 1158 -280 258 86

ATOM 717 O THR 82 27.340 27.664 10 674 1 .000 8 74

ANISOU 717 O THR 82 1399 1091 833 -267 -54 ^■41

ATOM 718 N VAL 83 28.968 28.279 12 110 1 .000 8.51

ANISOU 718 N VAL 83 845 1092 1295 -615 37 322

ATOM 719 CA VAL 83 29.166 26.900 12 516 1 .000 10 97

ANISOU 719 CA VAL 83 1418 1462 1289 -332 -237 335

ATOM 720 CB VAL 83 30.551 26.659 13 129 1 .000 11 94

ANISOU 720 CB VAL 83 1293 1814 1430 -484 -196 566

ATOM 721 CGI VAL 83 30.657 25.223 13 627 1 .000 12 67

ANISOU 721 CGI VAL 83 1041 1776 1996 -105 -222 701

ATOM 722 CG2 VAL 83 31.651 26.966 12 125 1 .000 14 19

ANISOU 722 CG2 VAL 83 1269 1923 2199 -463 40 914

ATOM 723 C VAL 83 28.080 26.528 13 534 1 .000 9 64

ANISOU 723 C VAL 83 1273 1140 1251 -151 94 338

ATOM 724 O VAL 83 27.894 27.284 14 505 1 .000 13

ANISOU 724 O VAL 83 2328 1262 1644 -602 268 -98

ATOM 725 N ILE 84 27.398 25.419 13 284 1 .000 7 79

ANISOU 725 N ILE 84 1373 756 831 233 -52 45

ATOM 726 CA ILE 84 26.332 24.972 14 169 1 .000 7 77

ANISOU 726 CA ILE 84 1291 757 906 -42 135

ATOM 727 CB ILE 84 .24.952 24.978 13 475 1 .000 9 90

ANISOU 727 CB ILE 84 1329 1330 1103 -321 207 288

ATOM 728 CG2 ILE 84 24.622 26.417 13 124 1 .000 11 89

ANISOU 728 CG2 ILE 84 1706 1581 1231 810 234 464

ATOM 729 CGI ILE 84 24.861 24.032 12 278 1 .000 11 40

ANISOU 729 CGI ILE 84 1163 1446 1723 -290 -330 341

ATOM 730 CDl ILE 84 23.477 23.849 11 710 1 .000 15 63

ANISOU 730 CDl ILE 84 1945 1805 2187 -864 -1014 536

ATOM 731 C ILE 84 26.624 23.545 14 632 1 .000 7 06

ANISOU 731 C ILE 84 1163 750 770 -180 206 115

ATOM 732 O ILE 84 27.433 22.876 13 990 1 .000 7 74

ANISOU 732 O ILE 84 948 1125 869 68 145 33

ATOM 733 N GLU 85 25.978 23.115 15 679 1 .000 7 24

ANISOU 733 N GLU 85 1160 676 913 -360 122 217 ATOM 734 CA GLU 85 25.945 21.746 16.138 1.000 6.94

ANISOU 734 CA GLU 85 1143 818 677 -423 154 252

ATOM 735 CB GLU 85 26.677 21.593 17. 469 1. 000 11 40

ANISOU 735 CB GLU 85 1584 1620 1126 -777 -293 414

ATOM 736 CG GLU 85 28.139 21.959 17. 391 1. 000 16 .04

ANISOU 736 CG GLU 85 2240 2298 1557 -496 -630 310

ATOM 737 CD GLU 85 28.920 21.633 18. 643 1. 000 19 25

ANISOU 737 CD GLU 85 2360 2897 2058 -836 -1240 546

ATOM 738 OEl GLU 85 28.334 21.219 19. 656 1. 000 19 .59

ANISOU 738 OEl GLU 85 2377 3079 1988 -680 -1385 583

ATOM 739 OE2 GLU 85 30.155 21.827 18. 567 1. 000 24 .58

ANISOU 739 OE2 GLU 85 2625 4128 2589 -356 -1313 1499

ATOM 740 C GLU 85 24.487 21.322 16. 246 1. 000 8 89

ANISOU 740 C GLU 85 1573 791 1014 -100 -70 400

ATOM 741 O GLU 85 23.646 22.102 16.681 1. 000 8 .81

ANISOU 741 O GLU 85 1287 798 1264 -43 -149 34

ATOM 742 N ARG 86 24.256 20.086 15.841 1. 000 7 73

ANISOU 742 N ARG 86 1173 752 1010 -204 101 336

ATOM 743 CA ARG 86 22.926 19.495 15. 997 1. 000 8 25

ANISOU 743 CA ARG 86 1299 747 1088 -116 -165 218

ATOM 744 CB ARG 86 22.158 19.480 14. 683 1. 000 7 91

ANISOU 744 CB ARG 86 1416 784 805 83 52 127

ATOM 745 CG ARG 86 21.725 20.836 14. 162 1. 000 8.59

ANISOU 745 CG ARG 86 1450 1058 756 24 -52 227

ATOM 746 CD ARG 86 20.708 21.494 15.048 1. 000 8 40

ANISOU 746 CD ARG 86 871 998 1325 -155 -169 200

ATOM 747 NE ARG 86 20.201 22.791 14.606 1. 000 7 93

ANISOU 747 NE ARG 86 1078 936 997 -152 -70 69

ATOM 748 CZ ARG 86 20.705 23 ,983 14.887 1. 000 7 48

ANISOU 748 CZ ARG 86 1260 837 745 2 17 488

ATOM 749 NHl ARG 86 21.813 24 ,087 15.631 1. 000 10 01

ANISOU 749 NHl ARG 86 1570 1097 1136 331 -311 -27

ATOM 750 NH2 ARG 86 20.142 25 ,087 14.445 1. 000 8 12

ANISOU 750 NH2 ARG 86 709 1329 1048 274 174 347

ATOM 751 C ARG 86 23.098 18 ,100 16. 590 1. 000 6 69

ANISOU 751 C ARG 86 568 952 1022 -173 74 179

ATOM 752 O ARG 86 24.039 17 ,413 16. 197 1. 000 7 84

ANISOU 752 O ARG 86 957 868 1154 66 207 292

ATOM 753 N THR 87 22.198 17 ,733 17. 491 1. 000 6 10

ANISOU 753 N THR 87 668 812 838 -138 225 205

ATOM 754 CA THR 87 22.261 16 ,536 18.285 1. 000 6 91

ANISOU 754 CA THR 87 860 1019 745 -58 260 207

ATOM 755 CB THR 87 22.198 16 ,933 19.780 1. 000 8 08

ANISOU 755 CB THR 87 1240 1012 818 -19 263 -50

ATOM 756 OGl THR 87 23.369 17 697 20.109 1. 000 9 07

ANISOU 756 OGl THR 87 1240 1024 1182 -448 -177 -139

ATOM 757 CG2 THR 87 22.197 15 725 20.695 1. 000 10 25

ANISOU 757 CG2 THR 87 1818 1386 690 207 234 232

ATOM 758 C THR 87 21.153 15 561 17.968 1. 000 5 56

ANISOU 758 C THR 87 716 800 594 20 196 17

ATOM 759 O THR 87 19.978 15 948 17.912 1. 000 6 27

ANISOU 759 O THR 87 659 880 845 22 188 216

ATOM 760 N PHE 88 21.551 14 301 17.747 1. 000 6 12

ANISOU 760 N PHE 88 754 597 975 -13 -11 71

ATOM 761 CA PHE 88 20.691 13 236 17.307 1. 000 6 86

ANISOU 761 CA PHE 88 948 708 949 -274 175 171

ATOM 762 CB PHE 88 21.047 12 817 15.854 1. 000 6 27

ANISOU 762 CB PHE 88 510 933 940 173 295 158

ATOM 763 CG PHE 88 20.979 13 998 14.899 1. 000 7 48 ANISOU 763 CG PHE 88 834 1117 890 428 164

ATOM 764 CDl PHE 88 22 . 072 14 817 14.662 1 000 8. 52

ANISOU 764 CDl PHE 88 939 1187 1112 208 117 118

ATOM 765 CD2 PHE 88 19 . 836 14 314 14.239 1 000 9.99

ANISOU 765 CD2 PHE 88 1252 1250 1296 495 -194 -152

ATOM 766 CEl PHE 88 21 . 959 15 862 13. 787 1 000 9.15

ANISOU 766 CEl PHE 88 1114 1318 1043 452 345 -54

ATOM 767 CE2 PHE 88 19 . 705 15 338 13. 315 1 000 11.22

ANISOU 767 CE2 PHE 88 1638 1473 1151 773 -287 -121

ATOM 768 CZ PHE 88 20 . 819 16 123 13. 092 1.000 10.06

ANISOU 768 CZ PHE 88 1678 1145 999 447 -40 173

ATOM 769 C PHE 88 20 . 838 11 991 18. 169 1 000 6.98

ANISOU 769 C PHE 88 1187 532 931 47 -76 -113

ATOM 770 O PHE 88 21 . 875 11 , 787 18. 788 1, 000 8.47

ANISOU 770 O PHE 88 756 1115 1348 -22 -188 302

ATOM 771 N HIS 89 19 . 825 11 .123 18. 132 1.000 6.54

ANISOU 771 N HIS 89 950 768 766 -174 -148 205

ATOM 772 CA HIS 89 19 . 833 9 .883 18.880 1.000 7.16

ANISOU 772 CA HIS 89 1195 675 850 122 -145 260

ATOM 773 CB HIS 89 19 . 134 10 .041 20.239 1.000 6.87

ANISOU 773 CB HIS 89 925 807 878 -12 131 148

ATOM 774 CG HIS 89 19 . 105 8 .780 21.029 1.000 7.49

ANISOU 774 CG HIS 89 892 1037 917 -164 103 38

ATOM 775 CD2 HIS 89 19 . 990 8 .260 21.909 1.000 7.07

ANISOU 775 CD2 HIS 89 665 1066 956 48 285 232

ATOM 776 ND1 HIS 89 18 . 067 7 .869 20.974 1.000 8.97

ANISOU 776 ND1 HIS 89 1290 989 1131 -65 29

ATOM 777 CEl HIS 89 18.327 6.858 21.772 1.000 8.12

ANISOU 777 CEl HIS 89 1028 1044 1015 -119 249 46

ATOM 778 NE2 HIS 89 19.505 7.068 22.360 1.000 8.44

ANISOU 778 NE2 HIS 89 1005 1218 985 -195 153 45

ATOM 779 C HIS 89 19.151 8.770 18.079 1.000 6.41

ANISOU 779 C HIS 89 924 856 657 150 176 354

ATOM 780 O HIS 89 18.104 9.012 17. 461 1.000 7.35

ANISOU 780 O HIS 89 931 698 1164 257 -31 206

ATOM 781 N VAL 90 19.764 7.607 18. 135 1.000 6.44

ANISOU 781 N VAL 90 795 714 939 Ill 72 86

ATOM 782 CA VAL 90 19.184 6.368 17.617 1.000 7.

ANISOU 782 CA VAL 90 915 824 1105 198 191 5

ATOM 783 CB VAL 90 19.793 5.949 16.273 1.000 8. 60

ANISOU 783 CB VAL 90 1050 866 1350 92 -20 -81

ATOM 784 CGI VAL 90 19.429 6.970 15.203 1.000 9. 45

ANISOU 784 CGI VAL 90 1150 1226 1214 407 223 156

ATOM 785 CG2 VAL 90 21.290 5.780 16.464 1.000 9.69

ANISOU 785 CG2 VAL 90 1464 806 1412 -171 274 212

ATOM 786 C VAL 90 19.320 5.294 18.689 1.000 7. 38

ANISOU 786 C VAL 90 713 1057 1035 369 163 138

ATOM 787 O VAL 90 19.937 5.513 19.723 1.000 8. 82

ANISOU 787 O VAL 90 974 1162 1217 180 -23 -58

ATOM 788 N GLU 91 18.725 4.129 18.497 1.000 8. 39

ANISOU 788 N GLU 91 1288 1028 874 289 -11 -12

ATOM 789 CA GLU 91 18.487 3.255 19.639 1.000 9. 40

ANISOU 789 CA GLU 91 1281 1260 1029 230 19 211

ATOM 790 CB GLU 91 17.173 2.484 19. 462 1.000 8. 90

ANISOU 790 CB GLU 91 636 1411 1334 -64 425 170

ATOM 791 CG GLU 91 15.917 3.328 19. 416 1.000 9. 63

ANISOU 791 CG GLU 91 877 1301 1480 238 199 -177

ATOM 792 CD GLU 91 15.572 4. 162 20.603 1.000 10. 32

ANISOU 792 CD GLU 91 1178 1415 1328 308 130 75 ATOM 793 OEl GLU 91 16.100 3 969 21.731 1 000 11. 77

ANISOU 793 OEl GLU 91 1445 1553 1475 58 129 -23

ATOM 794 OE2 GLU 91 14.727 5 086 20 .453 1 000 9 , 82

ANISOU 794 OE2 GLU 91 1107 1187 1439 99 155 ^■124

ATOM 795 C GLU 91 19.608 2 258 19 .919 1 000 8 . 38

ANISOU 795 C GLU 91 1204 1162 818 82 48 196

ATOM 796 O GLU 91 19.572 1 596 20 .964 1 000 10 02

ANISOU 796 O GLU 91 1442 1528 839 360 48 495

ATOM 797 N THR 92 20.584 2 115 19 032 1 000 7 48

ANISOU 797 N THR 92 891 1048 903 -96 187 201

ATOM 798 CA THR 92 21.680 1 201 19 250 1 000 9 01

ANISOU 798 CA THR 92 1218 1077 1129 -116 122 105

ATOM 799 CB THR 92 21.503 -0 160 18 563 1 000 9 62

ANISOU 799 CB THR 92 1472 1379 804 -124 49 -52

ATOM 800 OGl THR 92 21.389 0 004 17 .172 1 000 9 73

ANISOU 800 OGl THR 92 1418 966 1314 -37 107 -277

ATOM 801 CG2 THR 92 20.182 -0 827 18 .921 1 000 11 . 86

ANISOU 801 CG2 THR 92 2232 888 1388 -310 67 -99

ATOM 802 C THR 92 22.968 1 829 18 747 1 000 7 14

ANISOU 802 C THR 92 1001 730 981 30 359 62

ATOM 803 O THR 92 22.930 2 683 17 852 1 000 6 93

ANISOU 803 O THR 92 978 804 852 -22 327 76

ATOM 804 N PRO 93 24.123 1 426 19 292 1 000 8 41

ANISOU 804 N PRO 93 1222 885 1088 -123 123 197

ATOM 805 CD PRO 93 24.313 0 500 20 416 1 000 9 97

ANISOU 805 CD PRO 93 1387 1006 1395 93 -268 180

ATOM 806 CA PRO 93 25.395 1 951 18 800 1 000 8 82

ANISOU 806 CA PRO 93 1247 999 1105 142 87 167

ATOM 807 CB PRO 93 26.431 1 364 19 735 1 000 10 43

ANISOU 807 CB PRO 93 1692 1363 909 41 54

ATOM 808 CG PRO 93 25.785 0 230 20 425 1 000 10 28

ANISOU 808 CG PRO 93 1627 1035 1242 215 -142 423

ATOM 809 C PRO 93 25.657 1 548 17 340 1 000 7 83

ANISOU 809 C PRO 93 916 980 1079 278 185 91

ATOM 810 O PRO 93 26.339 2 292 16 631 1 000 8 30

ANISOU 810 O PRO 93 877 1025 1252 119 175 310

ATOM 811 N GLU 94 25.138 0 402 16 909 1. 000 7 64

ANISOU 811 N GLU 94 1000 945 957 146 221 95

ATOM 812 CA GLU 94 25.358 -0 050 15 542 1. 000 7 66

ANISOU 812 CA GLU 94 969 701 1242 1 255 -28

ATOM 813 CB GLU 94 24.833 -1. 475 15 324 1. 000 11 38

ANISOU 813 CB GLU 94 1747 895 1680 76 -206 298

ATOM 814 CG GLU 94 25.555 -2. 552 16 139 1. 000 11 75

ANISOU 814 CG GLU 94 1837 1121 1507 180 236 449

ATOM 815 CD GLU 94 25.229 -2. 549 17 604 1. 000 13 50

ANISOU 815 CD GLU 94 2212 1151 1765 193 -41 786

ATOM 816 OEl GLU 94 24.189 -2. 104 18 068 1. 000 11 77

ANISOU 816 OEl GLU 94 1585 1168 1718 -28 149 38

ATOM 817 OE2 GLU 94 26.055 -3. 074 18 393 1. 000 23 30

ANISOU 817 OE2 GLU 94 2846 3628 2381 311 80 843

ATOM 818 C GLU 94 24.715 0. 896 14 543 1. 000 7 69

ANISOU 818 C GLU 94 690 697 1533 259 127 -195

ATOM 819 O GLU 94 25.179 1. 267 13 474 1. 000 9 36

ANISOU 819 O GLU 94 1097 1227 1231 23 112 66

ATOM 820 N GLU 95 23.544 1. 418 14 794 1. 000 8 36

ANISOU 820 N GLU 95 1061 964 1152 -167 6 -189

ATOM 821 CA GLU 95 22.713 2. 313 14 047 1. 000 7 18

ANISOU 821 CA GLU 95 820 962 947 -60 205 -48

ATOM 822 CB GLU 95 21.299 2. 428 14 575 1. 000 7 48 ANISOU 822 CB GLU 95 819 979 1046 -114 -10 -19

ATOM 823 CG GLU 95 20. 421 1 .228 14.213 1.000 8. 47

ANISOU 823 CG GLU 95 757 1320 1142 -49 68 -44

ATOM 824 CD GLU 95 19. 091 1 .303 14 ,944 1.000 10. 65

ANISOU 824 CD GLU 95 1326 1447 1275 -385 66 147

ATOM 825 OEl GLU 95 18 . 074 1 , 730 14.378 1.000 14. 38

ANISOU 825 OEl GLU 95 1367 1937 2159 420 -148 179

ATOM 826 OE2 GLU 95 19.073 0.928 16 ,118 1, 000 11. 40

ANISOU 826 OE2 GLU 95 1251 1837 1243 -34 362 300

ATOM 827 C GLU 95 23.424 3.668 14 043 1.000 6. 39

ANISOU 827 C GLU 95 795 682 953 -332 120 -34

ATOM 828 O GLU 95 23.500 4.319 13.017 1.000 7. 28

ANISOU 828 O GLU 95 1094 839 833 51 221 218

ATOM 829 N ARG 96 23.930 4.066 15.221 1.000 6. 62

ANISOU 829 N ARG 96 1107 576 832 -76 67 -94

ATOM 830 CA ARG 96 24.713 5.296 15 ,263 1.000 6. 50

ANISOU 830 CA ARG 96 954 753 761 -66 120 -114

ATOM 831 CB ARG 96 25.181 5.582 16 692 1.000 7. 00

ANISOU 831 CB ARG 96 945 784 930 1 -43 -161

ATOM 832 CG ARG 96 25.992 6.868 16 773 1.000 6. 19

ANISOU 832 CG ARG 96 600 800 952 -221 85 -20

ATOM 833 CD ARG 96 26.328 7.245 18 188 1.000 8. 93

ANISOU 833 CD ARG 96 1195 981 1217 189 -12 -105

ATOM 834 NE ARG 96 27.112 6.232 18 906 1.000 7. 60

ANISOU 834 NE ARG 96 954 853 1082 256 4 -248

ATOM 835 CZ ARG 96 27.456 6.371 20 204 1.000 6. 40

ANISOU 835 CZ ARG 96 579 833 1019 -9 228 66

ATOM 836 NHl ARG 96 27.074 7.436 20 907 1.000 6. 50

ANISOU 836 NHl ARG 96 888 571 1009 239 -19 -5.

ATOM 837 NH2 ARG 96 28.168 5.407 20 745 1.000 8. 99

ANISOU 837 NH2 ARG 96 1133 1019 1263 361 -120 79

ATOM 838 C ARG 96 25.912 5.231 14 329 1.000 6. 79

ANISOU 838 C ARG 96 1016 776 788 -172 -132 19

ATOM 839 O ARG 96 26.174 6.191 13 605 1.000 6. 85

ANISOU 839 O ARG 96 1144 452 1006 -165 199 -39

ATOM 840 N GLU 97 26.605 4.100 14 350 1.000 6. 99

ANISOU 840 N GLU 97 780 956 918 -59 100 72

ATOM 841 CA GLU 97 27.756 3.960 13 475 1.000 6. 89

ANISOU 841 CA GLU 97 736 813 1071 -11 265 16

ATOM 842 CB GLU 97 28.527 2.658 13 749 1.000 12. 89

ANISOU 842 CB GLU 97 1577 1407 1914 190 -174 50

ATOM 843 CG GLU 97 30.008 2.762 13 347 1.000 15. 61

ANISOU 843 CG GLU 97 1551 2023 2356 190 262 599

ATOM 844 CD GLU 97 30.786 3.718 14 250 1.000 19. 47

ANISOU 844 CD GLU 97 1559 2687 3153 -454 562 779

ATOM 845 OEl GLU 97 30.417 3.931 15 453 1.000 25. 41

ANISOU 845 OEl GLU 97 2244 2821 4589 -345 68 -396

ATOM 846 OE2 GLU 97 31.792 4.303 13 795 1.000 32. 32

ANISOU 846 OE2 GLU 97 2690 4527 5061 945 362 1329

ATOM 847 C GLU 97 27.337 4.001 12 016 1.000 8. 34

ANISOU 847 C GLU 97 1054 878 1237 368 139 -105

ATOM 848 O GLU 97 28.048 4.546 11 160 1.000 8. 82

ANISOU 848 O GLU 97 1120 918 1315 210 137 -66

ATOM 849 N GLU 98 26.191 3.397 11 700 1.000 8. 78

ANISOU 849 N GLU 98 944 1143 1250 79 109 113

ATOM 850 CA GLU 98 25.728 3.467 10 314 1.000 8. 38

ANISOU 850 CA GLU 98 996 1077 1110 44 245 176

ATOM 851 CB GLU 98 24.440 2.667 10 114 1.000 8. 77

ANISOU 851 CB GLU 98 1049 1135 1147 -355 211 91 ATOM 852 CG GLU 98 24 . 648 1 , 159 10.206 1 000 12 30

ANISOU 852 CG GLU 98 154 9 1432 1693 -522 204 -244

ATOM 853 CD GLU 98 23.349 0.421 9.958 1 000 15 58

ANISOU 853 CD GLU 98 2060 1566 2296 -623 99 -315

ATOM 854 OEl GLU 98 22.342 0.698 10.642 1, 000 20 37

ANISOU 854 OEl GLU 98 2233 2226 3283 -637 434 -844

ATOM 855 OE2 GLU 98 23.276 -0.438 9.058 1, 000 19 02

ANISOU 855 OE2 GLU 98 1821 2206 3198 -145 -407 -1058

ATOM 856 C GLU 98 25.494 4.912 9.855 1, 000 8 .03

ANISOU 856 C GLU 98 880 1098 1072 130 345 101

ATOM 857 O GLU 98 25.865 5.284 8.740 1, 000 9 19

ANISOU 857 O GLU 98 1218 1231 1043 86 332 -70

ATOM 858 N TRP 99 24.868 5, 727 10.713 1.000 6 86

ANISOU 858 N TRP 99 734 937 935 70 384 79

ATOM 859 CA TRP 99 24.628 7.100 10.360 1.000 7 13

ANISOU 859 CA TRP 99 986 819 904 185 130 -290

ATOM 860 CB TRP 99 23.681 7.734 11.373 1.000 8 24

ANISOU 860 CB TRP 99 1161 992 979 45 284 -117

ATOM 861 CG TRP 99 22.236 7.608 11.048 1.000 9 72

ANISOU 861 CG TRP 99 1241 1418 1033 260 162 -163

ATOM 862 CD2 TRP 99 21.569 8.229 9.926 1.000 8 92

ANISOU 862 CD2 TRP 99 996 1377 1015 348 175 -159

ATOM 863 CE2 TRP 99 20.216 7.867 9.971 1.000 10 15

ANISOU 863 CE2 TRP 99 1383 1488 986 256 -68 -297

ATOM 864 CE3 TRP 99 22.032 9.054 8.924 1. 000 11 47

ANISOU 864 CE3 TRP 99 1707 1426 1224 135 -122 72

ATOM 865 CDl TRP 99 21.279 6.910 11.696 1. 000 9.61

ANISOU 865 CDl TRP 99 1103 1584 965 240 199 208

ATOM 866 NE1 TRP 99 20.045 7.056 11.063 1.000 9. 16

ANISOU 866 NE1 TRP 99 864 1706 908 24 177 -171

ATOM 867 CZ2 TRP 99 19.288 8.308 9.023 1.000 11.87

ANISOU 867 CZ2 TRP 99 1663 1650 1198 -36 -112 -76

ATOM 868 CZ3 TRP 99 21.114 9.492 7.979 1.000 12.24

ANISOU 868 CZ3 TRP 99 1880 1488 1283 -75 -101 294

ATOM 869 CH2 TRP 99 19.771 9.122 8.033 1.000 14.01

ANISOU 869 CH2 TRP 99 2237 1606 1480 349 -698 -98

ATOM 870 C TRP 99 25.907 7.917 10.286 1.000 6.69

ANISOU 870 C TRP 99 1042 695 805 131 131 -79

ATOM 871 O TRP 99 26.087 8.616 9.307 1.000 7.95

ANISOU 871 O TRP 99 1135 903 982 -17 -17

ATOM 872 N THR 100 26.791 7.852 11.289 1.000 8.06

ANISOU 872 N THR 100 973 1054 1035 103 149 -160

ATOM 873 CA THR 100 27.987 8.670 11.253 1.000 8.16

ANISOU 873 CA THR 100 1350 996 755 -210 128 -211

ATOM 874 CB THR 100 28.738 8.619 12.619 1.000 9.64

ANISOU 874 CB THR 100 1523 1100 1040 -128 -85

ATOM 875 OGl THR 100 28.944 7.265 13.014 1.000 10.49

ANISOU 875 OGl THR 100 2052 1020 915 -60 130 170

ATOM 876 CG2 THR 100 27.891 9.302 13.662 1.000 8.83

ANISOU 876 CG2 THR 100 1531 1258 566 379 37 -231

ATOM 877 C THR 100 28.892 8.247 10.110 1.000 8.74

ANISOU 877 C THR 100 981 1223 1116 -159 110

ATOM 878 O THR 100 29.533 9.056 9.437 1.000 9.91

ANISOU 878 O THR 100 1345 1221 1200 -309 222 124

ATOM 879 N THR 101 28.980 6.945 9.837 1.000 7.81

ANISOU 879 N THR 101 839 1118 1009 -176 24 72

ATOM 880 CA THR 101 29.811 6.505 8.720 1.000 8.69

ANISOU 880 CA THR 101 1161 1124 1015 55 -29 -55

ATOM 881 CB THR 101 30.006 4.985 8.744 1.000 9.61 ANISOU 881 CB THR 101 1043 1436 1172 357 376 - 142

ATOM 882 OGl THR 101 30.815 4 .703 9 .903 1 .000 12

ANISOU 882 OGl THR 101 1669 1576 1535 501 -164 290

ATOM 883 CG2 THR 101 30.734 4 .496 7 .527 1 .000 11 . 63

ANISOU 883 CG2 THR 101 1542 1154 1723 -175 515 121

ATOM 884 C THR 101 29.232 6. .970 7 .393 1, .000 8

ANISOU 884 C THR 101 1092 1255 1001 5 139 -100

ATOM 885 O THR 101 29.987 7 .432 6 .528 1, .000 9 06

ANISOU 885 O THR 101 1087 1219 1136 -158 297 164

ATOM 886 N ALA 102 27.918 6, .877 7 .215 1, .000 9 35

ANISOU 886 N ALA 102 1478 1025 1049 115 -40 -40

ATOM 887 CA ALA 102 27.342 7, .350 5 .966 1. .000 8

ANISOU 887 CA ALA 102 1310 1158 868 88 59 -75

ATOM 888 CB ALA 102 25.853 7, .106 5 .971 1, .000 8 26

ANISOU 888 CB ALA 102 1204 1284 650 -8 249 ^■ 112

ATOM 889 C ALA 102 27.601 8, .840 5 .760 1, .000 7

ANISOU 889 C ALA 102 957 949 824 -49 308 -167

ATOM 890 O ALA 102 27.924 9, .305 4 .668 1. .000 7 58

ANISOU 890 O ALA 102 1107 1095 679 -6 279 -142

ATOM 891 N ILE 103 27.430 9, .634 6 .821 1. .000 7 23

ANISOU 891 N ILE 103 1233 806 710 131 147 -87

ATOM 892 CA ILE 103 27.635 11. .074 6 .704 1. .000 7 54

ANISOU 892 CA ILE 103 1026 940 899 336 67 -344

ATOM 893 CB ILE 103 27.194 11, .821 7, .976 1. .000 6 73

ANISOU 893 CB ILE 103 735 919 903 270 91 -274

ATOM 894 CG2 ILE 103 27.658 13. ,265 7, .909 1. .000 7 08

ANISOU 894 CG2 ILE 103 930 1103 658 -1 34 -206

ATOM 895 CGI ILE 103 25.692 11. ,724 8. .206 1. .000 7 68

ANISOU 895 CGI ILE 103 723 1097 1097 144 44 -214

ATOM 896 CDl ILE 103 25.234 12. ,067 9. .608 1. ,000 7 74

ANISOU 896 CDl ILE 103 275 1611 1054 -2 153

ATOM 897 C ILE 103 29.104 11. 344 6. .355 1. ,000 7 66

ANISOU 897 C ILE 103 1049 852 1009 160 251 -33

ATOM 898 O ILE 103 29.404 12. 167 5. ,490 1. 000 9 41

ANISOU 898 O ILE 103 1254 1276 1046 93 -37 176

ATOM 899 N GLN 104 30.018 10. 642 7. ,027 1. 000 7 59

ANISOU 899 N GLN 104 1252 972 659 100 236 232

ATOM 900 CA GLN 104 31.432 10. 828 6. ,760 1. 000 7 34

ANISOU 900 CA GLN 104 1114 853 820 176 91 91

ATOM 901 CB GLN 104 32.314 10. 016 7. ,731 1. 000 8 84

ANISOU 901 CB GLN 104 1232 1277 850 567 180 -35

ATOM 902 CG GLN 104 33.793 10. 400 7. ,605 1. 000 10 06

ANISOU 902 CG GLN 104 1247 1535 1041 648 19

ATOM 903 CD GLN 104 34.059 11. 819 8. 019 1. 000 8 66

ANISOU 903 CD GLN 104 1144 1346 800 105 322 165

ATOM 904 OEl GLN 104 34.080 12. 143 9. 201 1. 000 10. .06

ANISOU 904 OEl GLN 104 1548 1392 882 -67 157 42

ATOM 905 NE2 GLN 104 34.267 12. 690 7. 052 1. 000 9, 84

ANISOU 905 NE2 GLN 104 945 1819 973 -281 374 14

ATOM 906 C GLN 104 31.770 10. 422 5. 327 1. 000 8, 07

ANISOU 906 C GLN 104 1254 961 850 267 164 136

ATOM 907 O GLN 104 32.580 11. 079 4. 691 1. 000 9, 19

ANISOU 907 O GLN 104 1252 1324 914 -3 338 90

ATOM 908 N THR 105 31.184 9. 353 4. 823 1. 000 9, 34

ANISOU 908 N THR 105 1387 1232 931 273 172 116

ATOM 909 CA THR 105 31.437 8. 908 3. 450 1. 000 10, 37

ANISOU 909 CA THR 105 1488 1351 1100 69 -25 240

ATOM 910 CB THR 105 30.715 7. 583 3. 150 1. 000 11, 96

ANISOU 910 CB THR 105 2041 1308 1196 -31 -37 176 ATOM 911 OGl THR 105 31 . 245 6 543 3.992 1.000 16 52

ANISOU 911 OGl THR 105 2931 1678 1669 443 683 112

ATOM 912 CG2 THR 105 30 . 965 7 147 1. 725 1.000 16 .14

ANISOU 912 CG2 THR 105 2487 1956 1691 -293 270 -382

ATOM 913 C THR 105 31 . 004 9 986 2.472 1.000 8 09

ANISOU 913 C THR 105 824 1529 722 -49 208 43

ATOM 914 O THR 105 31 . 728 10 .279 1.516 1.000 10 15

ANISOU 914 O THR 105 1096 1619 1143 15 191 85

ATOM 915 N VAL 106 29 . 836 10 , 572 2.695 1.000 8 28

ANISOU 915 N VAL 106 1055 1485 607 59 110 48

ATOM 916 CA VAL 106 29 . 414 11 , 656 1.796 1. 000 8 50

ANISOU 916 CA VAL 106 124 6 1445 537 -125 86 281

ATOM 917 CB VAL 106 27.981 12, 092 2.158 1. 000 9 .64

ANISOU 917 CB VAL 106 1217 1606 841 -92 85 -117

ATOM 918 CGI VAL 106 27.584 13, 382 1.460 1. 000 9 .22

ANISOU 918 CGI VAL 106 961 1572 971 -31 241 100

ATOM 919 CG2 VAL 106 27.019 10, 982 1.804 1.000 9 52

ANISOU 919 CG2 VAL 106 1114 1652 852 103 182 -268

ATOM 920 C VAL 106 30.356 12.832 1.866 1.000 8 41

ANISOU 920 C VAL 106 930 1656 609 254 167 292

ATOM 921 O VAL 106 30.750 13.396 0.855 1.000 10 05

ANISOU 921 O VAL 106 1231 1846 743 -93 278 -40

ATOM 922 N ALA 107 30.759 13.205 3.066 1.000 7 65

ANISOU 922 N ALA 107 702 1612 592 9 163 277

ATOM 923 CA ALA 107 31.669 14.325 3.252 1.000 9 84

ANISOU 923 CA ALA 107 1072 1845 820 36 -34 70

ATOM 924 CB ALA 107 31.888 14.643 4.720 1.000 8 54

ANISOU 924 CB ALA 107 1019 1595 632 -276 144 -47

ATOM 925 C ALA 107 32.982 14.038 2.545 1.000 9 32

ANISOU 925 C ALA 107 912 1888 742 17 196 120

ATOM 926 O ALA 107 33.532 14.920 1.890 1.000 10 36

ANISOU 926 O ALA 107 899 1822 1216 -259 108 283

ATOM 927 N ASP 108 33.464 12.811 2.651 1.000 9 99

ANISOU 927 N ASP 108 1143 1788 863 33 275 175

ATOM 928 CA ASP 108 34.714 12.461 1. 993 1.000 9

ANISOU 928 CA ASP 108 1221 1730 797 136 340 ^•109

ATOM 929 CB ASP 108 35.131 11.041 2. 377 1.000 10 10

ANISOU 929 CB ASP 108 1364 1710 762 138 265 •117

ATOM 930 CG ASP 108 35.614 10.902 3.806 1. 000 12 .23

ANISOU 930 CG ASP 108 1587 2014 1044 298 79 •125

ATOM 931 OD1 ASP 108 35.781 11.897 4.530 1. 000 12. 09

ANISOU 931 OD1 ASP 108 1494 2046 1053 447 -130 -234

ATOM 932 OD2 ASP 108 35.852 9.746 4.256 1. 000 16. 32

ANISOU 932 OD2 ASP 108 2621 2293 1288 626 -374 156

ATOM 933 C ASP 108 34.630 12.577 0. 475 1.000 10. 04

ANISOU 933 C ASP 108 1186 1709 922 64 334 24

ATOM 934 O ASP 108 35.573 12.995 -0. 200 1.000 12. 29

ANISOU 934 O ASP 108 1385 2279 1008 -33 314

ATOM 935 N GLY 109 33.479 12.183 -0.059 1.000 10. 49

ANISOU 935 N GLY 109 1199 2146 642 -121 417 129

ATOM 936 CA GLY 109 33.206 12.225 -1. 476 1.000 11. 09

ANISOU 936 CA GLY 109 1393 2197 624 -69 237 -215

ATOM 937 C GLY 109 33.241 13.656 -1. 983 1.000 11. 97

ANISOU 937 C GLY 109 1237 2540 773 -196 206

ATOM 938 O GLY 109 33.807 13.946 -3. 040 1.000 15. 96

ANISOU 938 O GLY 109 1958 2994 1114 85 399 215

ATOM 939 N LEU 110 32.609 14.547 -1.223 1.000 11. 28

ANISOU 939 N LEU 110 1035 2332 919 38 234 -35

ATOM 940 CA LEU 110 32.638 15.950 -1.603 1.000 13. 60 ANISOU 940 CA LEU 110 1860 2245 1062 -70 134 -29

ATOM 941 CB LEU 110 31.754 16.765 -0 656 1 000 13 39

ANISOU 941 CB LEU 110 1802 2204 1081 -295 166 -222

ATOM 942 CG LEU 110 30.263 16.453 -0 748 1, 000 15 30

ANISOU 942 CG LEU 110 1883 2465 1466 -245 117 277

ATOM 943 CDl LEU 110 29.545 17.044 0 445 1.000 15 .25

ANISOU 943 CDl LEU 110 1749 2137 1908 2 444 202

ATOM 944 CD2 LEU 110 29.721 16.973 -2.083 1, 000 15 89

ANISOU 944 CD2 LEU 110 1940 2619 1480 -393 -56 202

ATOM 945 C LEU 110 34.058 16.502 -1 580 1, 000 14 31

ANISOU 945 C LEU 110 1960 2320 1157 -346 312 120

ATOM 946 O LEU 110 34.450 17.298 -2 430 1, 000 16 04

ANISOU 946 O LEU 110 2241 2460 1394 -449 588 364

ATOM 947 N LYS 111 34.853 16.051 -0, 614 1.000 14 55

ANISOU 947 N LYS 111 1719 2244 1565 -195 279 -79

ATOM 948 CA LYS 111 36.232 16.518 -0.525 1.000 15 83

ANISOU 948 CA LYS 111 1698 2461 1855 -398 331 197

ATOM 949 CB LYS 111 36.878 16.036 0, 757 1.000 18 16

ANISOU 949 CB LYS 111 1689 2965 2247 -575 124 194

ATOM 950 CG LYS 111 38.269 16.513 1, 087 1, 000 21 84

ANISOU 950 CG LYS 111 1952 3668 2676 -491 75 147

ATOM 951 CD LYS 111 38.515 17.986 0, 919 1. 000 27 09

ANISOU 951 CD LYS 111 3153 4214 2928 -66 -305 157

ATOM 952 CE LYS 111 38.038 18.825 2. 088 1. 000 29 91

ANISOU 952 CE LYS 111 3328 4746 3291 88 -233 -46

ATOM 953 NZ LYS 111 39.077 19.759 2. 612 1. 000 40 .37

ANISOU 953 NZ LYS 111 4923 5190 5227 1126 -1001 -698

ATOM 954 C LYS 111 37.026 16.012 -1.720 1. 000 16 75

ANISOU 954 C LYS 111 1765 2689 1911 -507 402 344

ATOM 955 O LYS 111 37.857 16.714 -2.276 1.000 21 57

ANISOU 955 O LYS 111 2145 4065 1986 -330 776 488

ATOM 956 N LYS 112 36.771 14.754 -2.097 1.000 17 86

ANISOU 956 N LYS 112 1561 3238 1989 -514 611 396

ATOM 957 CA LYS 112 37.506 14.243 -3.265 1.000 20 99

ANISOU 957 CA LYS 112 1918 3870 2186 -523 853 674

ATOM 958 CB LYS 112 37.305 12.744 -3. 433 1.000 24 55

ANISOU 958 CB LYS 112 2596 4242 2489 -10 659

ATOM 959 CG LYS 112 38.022 12.079 -4. 595 1. 000 24 97

ANISOU 959 CG LYS 112 2486 4658 2344 520 1208 432

ATOM 960 CD LYS 112 39.530 12.180 -4. 463 1. 000 29 60

ANISOU 960 CD LYS 112 3368 4970 2911 1145 1129 308

ATOM 961 CE LYS 112 40.261 11.403 -5.562 1. 000 37 33

ANISOU 961 CE LYS 112 4995 5259 3929 1373 27 297

ATOM 962 NZ LYS 112 41.518 10.803 -4.990 1. 000 46 50

ANISOU 962 NZ LYS 112 6634 5920 5114 1544 -1045 446

ATOM 963 C LYS 112 37.106 15.038 -4.511 1. 000 20 02

ANISOU 963 C LYS 112 1806 3859 1942 -764 1109 1207

ATOM 964 O LYS 112 37.985 15.355 -5.312 1. 000 21 .37

ANISOU 964 O LYS 112 1849 4226 2045 308 1015 721

ATOM 965 N GLN 113 35.815 15.372 -4.634 1. 000 21 91

ANISOU 965 N GLN 113 2369 4012 1943 -336 928 1226

ATOM 966 CA GLN 113 35.352 16.200 -5.746 1.000 26 13

ANISOU 966 CA GLN 113 3197 4385 2346 -416 651 1321

ATOM 967 CB GLN 113 33.845 16.458 -5.649 1.000 26 90

ANISOU 967 CB GLN 113 3208 4452 2560 -511 423 1371

ATOM 968 CG GLN 113 32.961 15.304 -6.072 1.000 28 70

ANISOU 968 CG GLN 113 3503 4477 2924 -601 203 1324

ATOM 969 CD GLN 113 31.491 15.695 -6.056 1. 000 31 58

ANISOU 969 CD GLN 113 3804 4800 3392 -557 -192 1233 ATOM 970 OEl GLN 113 31 . 126 16 .774 -6.530 1.000 37.75

ANISOU 970 OEl GLN 113 4321 5368 4653 -1175 -1030 1985

ATOM 971 NE2 GLN 113 30 . 67 1 14 .813 -5.501 1. 000 34 69

ANISOU 971 NE2 GLN 113 4321 5150 3708 -196 -623 459

ATOM 972 C GLN 113 36 . 056 17 .552 -5.834 1. 000 28 .32

ANISOU 972 C GLN 113 3278 4781 2702 -660 729 1169

ATOM 973 O GLN 113 36 . 406 18 .029 -6.914 1. 000 28. 56

ANISOU 973 O GLN 113 3886 4785 2181 -337 1030 1449

ATOM 974 N GLU 114 36 . 24 9 18 . 181 -4.680 1. 000 32. 10

ANISOU 974 N GLU 114 3957 5020 3220 -1269 471 1372

ATOM 975 CA GLU 114 36 . 980 19 . 449 -4.612 1.000 36. 38

ANISOU 975 CA GLU 114 4818 5318 3685 -1841 74 1726

ATOM 976 CB GLU 114 36 . 978 19 .943 -3.176 1. 000 40. 61

ANISOU 976 CB GLU 114 5786 54 69 4173 -1959 -486 1623

ATOM 977 CG GLU 114 37 . 140 21 .423 -2.910 1. 000 45. 97

ANISOU 977 CG GLU 114 7123 5700 4644 -1812 -1192 1501

ATOM 978 CD GLU 114 37 . 201 21 .752 -1.428 1. 000 50. 27

ANISOU 978 CD GLU 114 8185 5730 5186 -1803 -1787 1318

ATOM 979 OEl GLU 114 36 . 940 20 .868 -0.582 1.000 57. 33

ANISOU 979 OEl GLU 114 9664 6347 5772 -746 -2892 1269

ATOM 980 OE2 GLU 114 37 . 519 22 .914 -1.099 1.000 54. 93

ANISOU 980 OE2 GLU 114 9677 5045 6148 -2472 -2537 779

ATOM 981 C GLU 114 38 . 389 19 .237 -5.138 1.000 38. 10

ANISOU 981 C GLU 114 4 94 9 5755 3774 -2156 91 2096

ATOM 982 O GLU 114 38.842 19.933 -6.053 1.000 42. 35

ANISOU 982 O GLU 114 5990 6293 3808 -1822 -215 2799

ATOM 983 N GLU 115 39.055 18.256 -4.530 1.000 38. 29

ANISOU 983 N GLU 115 4487 6312 3752 -2371 603 2036

ATOM 984 CA GLU 115 40.459 17.968 -4.822 1.000 39. 73

ANISOU 984 CA GLU 115 4207 6972 3918 -2346 784 1904

ATOM 985 CB GLU 115 41.012 16.778 -4.042 1.000 39. 95

ANISOU 985 CB GLU 115 3820 7240 4120 -2597 904 2147

ATOM 986 CG GLU 115 41.090 16.967 -2.538 1.000 41. 24

ANISOU 986 CG GLU 115 3380 7641 4648 -2061 1067 1857

ATOM 987 CD GLU 115 40.907 15.675 -1.768 1.000 42. 44

ANISOU 987 CD GLU 115 3287 8087 4752 -1643 1400 1633

ATOM 988 OEl GLU 115 41.180 14.586 -2.313 1.000 43. 76

ANISOU 988 OEl GLU 115 2579 8323 5724 -1255 1282 1854

ATOM 989 OE2 GLU 115 40.464 15.743 -0.611 1.000 49. 59

ANISOU 989 OE2 GLU 115 5687 9252 3904 -738 1321 850

ATOM 990 C GLU 115 40.564 17.747 -6.330 1.000 37. 77

ANISOU 990 C GLU 115 3562 7279 3509 -2154 1406 1588

ATOM 991 O GLU 115 41 . 505 18 .193 -6.981 1.000 42. 16

ANISOU 991 O GLU 115 4 182 7 94 9 3886 -1592 1256 1239

ATOM 992 N GLU 116 39.527 17.063 -6.852 1.000 37. 65

ANISOU 992 N GLU 116 3470 7463 3372 -1920 1179 1407

ATOM 993 CA GLU 116 39.455 17.140 -8.307 1.000 41. 97

ANISOU 993 CA GLU 116 4236 7692 4019 -1637 686 1163

ATOM 994 CB GLU 116 38.370 16.322 -8.960 1.000 43. 51

ANISOU 994 CB GLU 116 4697 7743 4092 -1301 653 964

ATOM 995 CG GLU 116 37.679 15. 182 -8.265 1.000 46. 80

ANISOU 995 CG GLU 116 5457 7787 4538 -1043 56 905

ATOM 996 CD GLU 116 38.417 13. 860 -8.319 1.000 47. 39

ANISOU 996 CD GLU 116 5504 7881 4620 -919 46 845

ATOM 997 OEl GLU 116 39.653 13.883 -8.131 1.000 47. 22

ANISOU 997 OEl GLU 116 4984 8042 4917 -1798 -28 1947

ATOM 998 OE2 GLU 116 37.747 12.820 -8.540 1.000 47. 76

ANISOU 998 OE2 GLU 116 5850 7691 4605 -1090 -149 424

ATOM 999 C GLU 116 39.281 18.643 -8.600 1.000 43. 21 ANISOU 999 C GLU 116 4530 7734 4155 -1853 524 1275

ATOM 1000 O GLU 116 38.370 19 125 -9.249 1. 000 50 13

ANISOU 1000 O GLU 116 6373 8375 4298 -1905 -217 1105

ATOM 1001 OP6 DRG 1001 16.185 23 283 11.404 1, 000 8 .08

ANISOU 1001 OP6 DRG 1001 1134 1036 901 12 172 124

ATOM 1002 P4 DRG 1001 16.923 23 686 12.725 1, 000 7 54

ANISOU 1002 P4 DRG 1001 1040 928 896 67 172 64

ATOM 1003 OP4 DRG 1001 17.862 24 865 12.522 1. 000 6 .76

ANISOU 1003 OP4 DRG 1001 568 1086 913 -140 98 -154

ATOM 1004 OP5 DRG 1001 17.610 22 556 13.413 1. 000 7 64

ANISOU 1004 OP5 DRG 1001 858 982 1064 206 78 -210

ATOM 1005 04 DRG 1001 15.699 24 179 13.661 1. 000 7 .58

ANISOU 1005 04 DRG 1001 978 1130 771 104 144 112

ATOM 1006 C4 DRG 1001 15.829 24 310 15.087 1.000 6 53

ANISOU 1006 C4 DRG 1001 923 855 704 -33 215 50

ATOM 1007 C3 DRG 1001 14.692 23 548 15.755 1.000 6 92

ANISOU 1007 C3 DRG 1001 1017 776 835 -33 121

ATOM 1008 03 DRG 1001 14.776 22 165 15.413 1.000 7 37

ANISOU 1008 03 DRG 1001 947 1011 841 -151 225 ^■98

ATOM 1009 P3 DRG 1001 13.467 21 325 15.007 1.000 8 72

ANISOU 1009 P3 DRG 1001 911 1319 1084 -260 214 -86

ATOM 1010 012 DRG 1001 12.944 22 013 13.670 1. 000 13 55

ANISOU 1010 012 DRG 1001 1583 2185 1379 -389 -405 168

ATOM 1011 Oil DRG 1001 12.436 21 432 16.046 1. 000 10 59

ANISOU 1011 Oil DRG 1001 1156 1566 1300 -462 445

ATOM 1012 O10 DRG 1001 13.964 19 965 14.578 1.000 10 40

ANISOU 1012 O10 DRG 1001 1204 1116 1631 -75 170 -647

ATOM 1013 C2 DRG 1001 14.780 23 707 17.276 1.000 6 64

ANISOU 1013 C2 DRG 1001 1024 707 793 -91 140 124

ATOM 1014 02 DRG 1001 16.004 23.153 17.771 1.000 7 68

ANISOU 1014 02 DRG 1001 1184 913 819 -11 -39 70

ATOM 1015 CI DRG 1001 14.725 25.182 17.689 1.000 6 .55

ANISOU 1015 CI DRG 1001 1020 724 746 -272 301 95

ATOM 1016 01 DRG 1001 14.964 25.294 19.108 1.000 6 72

ANISOU 1016 01 DRG 1001 952 980 620 -92 254 ^■13

ATOM 1017 PI DRG 1001 13.715 25.109 20.158 1.000 7 35

ANISOU 1017 PI DRG 1001 990 924 879 -45 117 -15

ATOM 1018 OP3 DRG 1001 13.370 26.587 20.580 1.000 7 75

ANISOU 1018 OP3 DRG 1001 886 1067 992 -66 392 -94

ATOM 1019 OP2 DRG 1001 12.551 24 496 19.423 1.000 7 40

ANISOU 1019 OP2 DRG 1001 517 1274 1020 -99 313 -34

ATOM 1020 OP1 DRG 1001 14.261 24 324 21.283 1.000 7 50

ANISOU 1020 OP1 DRG 1001 1024 990 835 -72 138 258

ATOM 1021 C6 DRG 1001 15.876 25.937 16 .997 1.000 6 15

ANISOU 1021 C6 DRG 1001 975 559 801 -138 332 80

ATOM 1022 06 DRG 1001 15.813 27.309 17 .355 1.000 8 43

ANISOU 1022 06 DRG 1001 1412 766 1025 -469 487 -134

ATOM 1023 C5 DRG 1001 15.759 25.788 15 .481 1.000 5 75

ANISOU 1023 C5 DRG 1001 587 887 712 -57 431 159

ATOM 1024 05 DRG 1001 16.850 26.489 14.892 1.000 7 19

ANISOU 1024 05 DRG 1001 1000 1053 679 135 305 82

ATOM 1025 P5 DRG 1001 16.583 27.689 13.851 1.000 8 99

ANISOU 1025 P5 DRG 1001 1301 1077 1037 137 243 232

ATOM 1026 OP9 DRG 1001 17.745 28.705 14.175 1.000 10 27

ANISOU 1026 OP9 DRG 1001 1627 1243 1031 263 572 100

ATOM 1027 OP8 DRG 1001 15.229 28.208 14.032 1.000 12 65

ANISOU 1027 OP8 DRG 1001 1465 1366 1977 743 275 453

ATOM 1028 OP7 DRG 1001 16.816 27.084 12.467 1.000 9 06

ANISOU 1028 OP7 DRG 1001 1591 968 884 -76 351 261 ATOM 1029 O HOH 3001 24.730 22.904 7.579 1.000 9.71

ANISOU 1029 O HOH 3001 1284 1102 1302 -110 137 -26

ATOM 1030 O HOH 3002 15.873 7 .375 19 .414 1 .000 9. 31

ANISOU 1030 O HOH 3002 1029 1190 1320 215 119 ^■107

ATOM 1031 O HOH 3003 28.163 4 .047 17 .595 1 .000 10. 97

ANISOU 1031 O HOH 3003 1317 1398 1454 273 -69 -484

ATOM 1032 O HOH 3004 14.052 28, .566 19 .005 1 .000 9. 21

ANISOU 1032 O HOH 3004 1475 880 1145 -156 181 155

ATOM 1033 O HOH 3005 9.318 19, .985 23 .213 1, .000 9. 46

ANISOU 1033 O HOH 3005 693 1232 1669 -133 64 -141

ATOM 1034 O HOH 3006 34.779 14, .086 12 .931 1, .000 12. 19

ANISOU 1034 O HOH 3006 1241 1655 1735 125 318 143

ATOM 1035 O HOH 3007 17.089 3, .577 16, .265 1, .000 10. 64

ANISOU 1035 O HOH 3007 1126 1309 1608 -114 -60 210

ATOM 1036 O HOH 3008 17.421 23, .726 9, .001 1. .000 10. . 68

ANISOU 1036 O HOH 3008 1962 840 1257 -160 203 -79

ATOM 1037 O HOH 3009 34.146 10, .165 11, .089 1. .000 11. 72

ANISOU 1037 O HOH 3009 1377 1595 1482 45 -107 357

ATOM 1038 O HOH 3010 13.201 5. .246 18, .262 1. .000 9. 26

ANISOU 1038 0 HOH 3010 1149 1107 1264 -29 284 -37

ATOM 1039 0 HOH 3011 27.181 33. .888 12. .403 1. .000 15. 52

ANISOU 1039 0 HOH 3011 2945 1456 1496 -411 342 -410

ATOM 1040 0 HOH 3012 7.546 13. ,980 13, .952 1. .000 14. 49

ANISOU 1040 0 HOH 3012 1874 2033 1600 -88 -7 232

ATOM 1041 0 HOH 3013 12.324 14. ,429 25. .301 1. ,000 14. 65

ANISOU 1041 0 HOH 3013 2439 1536 1592 -191 462 536

ATOM 1042 0 HOH 3014 25.376 -1. .998 8. .576 1. ,000 12. 71

ANISOU 1042 0 HOH 3014 1890 1367 1573 -4 -223 -276

ATOM 1043 0 HOH 3015 13.772 6. 189 22. ,744 1. ,000 12. 03

ANISOU 1043 0 HOH 3015 1589 1626 1356 -249 20 -102

ATOM 1044 0 HOH 3016 13.878 4. 419 10. ,097 1. 000 12. 77

ANISOU 1044 0 HOH 3016 1877 1098 1878 -439 481 -133

ATOM 1045 0 HOH 3017 23.195 24. 553 4. .414 1. 000 14. 69

ANISOU 1045 0 HOH 3017 2381 1620 1581 1035 -447 -21

ATOM 1046 0 HOH 3018 10.728 11. 923 22. ,455 1. 000 12. 26

ANISOU 1046 0 HOH 3018 1751 1277 1631 -163 -36

ATOM 1047 0 HOH 3019 34.831 14. 472 10. ,239 1. 000 11. 73

ANISOU 1047 0 HOH 3019 1648 1274 1535 -119 107 -66

ATOM 1048 0 HOH 3020 29.461 11. 450 26. ,449 1. 000 9. 99

ANISOU 1048 0 HOH 3020 731 1701 1362 -97 -19 -293

ATOM 1049 0 HOH 3021 17.922 2. 546 22. 914 1. 000 10. 94

ANISOU 1049 0 HOH 3021 1464 1445 1247 -322 393 ^■122

ATOM 1050 0 HOH 3022 19.862 4. 561 23. 655 1. 000 10. 99

ANISOU 1050 0 HOH 3022 986 1492 1696 -90 -48 75

ATOM 1051 0 HOH 3023 9.218 15. 487 21. 976 1. 000 12. 96

ANISOU 1051 0 HOH 3023 1035 1111 2778 3 166 -175

ATOM 1052 0 HOH 3024 26.963 3. 493 6. 822 1. 000 20. 79

ANISOU 1052 0 HOH 3024 3598 2854 1449 547 156 -394

ATOM 1053 0 HOH 3025 7.655 20. 530 14. 081 1. 000 14. 38

ANISOU 1053 0 HOH 3025 1270 1892 2302 -54 233 201

ATOM 1054 0 HOH 3026 15.175 22. 805 27. 731 1. 000 12. 92

ANISOU 1054 0 HOH 3026 1849 1893 1166 485 64 -244

ATOM 1055 0 HOH 3027 18.535 3. 997 4. 113 1. 000 16. 29

ANISOU 1055 0 HOH 3027 2549 1316 2323 -71 83 -533

ATOM 1056 0 HOH 3028 7.366 16. 038 15. 781 1. 000 14. 17

ANISOU 1056 0 HOH 3028 1385 1969 2030 -432 102 392

ATOM 1057 0 HOH 3029 15.613 5. 365 14. 706 1. 000 10. 89

ANISOU 1057 0 HOH 3029 1289 1358 1491 -101 1 272

ATOM 1058 0 HOH 3030 32.328 9. 783 15. 095 1. 000 17. 17 ANISOU 1058 O HOH 3030 1788 2406 2330 455 209 593

ATOM 1059 O HOH 3031 17.047 31, .424 17 .670 1 .000 16 13

ANISOU 1059 O HOH 3031 2103 1878 2148 -97 874 132

ATOM 1060 O HOH 3032 14.714 19, .240 17 .567 1 .000 15 . 45

ANISOU 1060 O HOH 3032 2221 1312 2337 760 141 471

ATOM 1061 O HOH 3033 21.460 31. .490 21 .842 1 .000 19 92

ANISOU 1061 O HOH 3033 2464 2494 2610 -190 -519 247

ATOM 1062 O HOH 3034 15.730 10. .036 22 .066 1 .000 15 46

ANISOU 1062 O HOH 3034 1926 1577 2369 185 -79 269

ATOM 1063 O HOH 3035 24.491 25, .417 16 .945 1. .000 21 70

ANISOU 1063 O HOH 3035 3491 2297 2458 -406 958 73

ATOM 1064 O HOH 3036 8.249 19, .203 17 .135 1, .000 11 03

ANISOU 1064 O HOH 3036 1021 1715 1455 4 141 -53

ATOM 1065 O HOH 3037 20.158 19. .647 18 .187 1, .000 17 02

ANISOU 1065 O HOH 3037 1695 1688 3084 497 1005 481

ATOM 1066 O HOH 3038 36.497 15. .518 14 .503 1, .000 16 57

ANISOU 1066 O HOH 3038 2100 2243 1955 84 -269 33

ATOM 1067 O HOH 3039 16.811 -0. .320 16. .984 1. .000 14 83

ANISOU 1067 O HOH 3039 1435 1724 2475 -335 255 60

ATOM 1068 O HOH 3040 29.587 12. .674 -1, .664 1. .000 18 11

ANISOU 1068 O HOH 3040 1721 2560 2599 -167 8 -715

ATOM 1069 0 HOH 3041 17.553 5. ,739 11, .332 1, .000 12 07

ANISOU 1069 0 HOH 3041 1570 1497 1519 330 147 247

ATOM 1070 0 HOH 3042 13.685 24. ,251 11, .099 1. .000 16 12

ANISOU 1070 0 HOH 3042 1265 3006 1854 -59 -41 -676

ATOM 1071 0 HOH 3043 12.724 28. ,441 15. .066 1. ,000 17 99

ANISOU 1071 0 HOH 3043 2387 2192 2256 -380 224 -224

ATOM 1072 0 HOH 3044 17.348 20. 855 17. .141 1. ,000 17 80

ANISOU 1072 0 HOH 3044 3585 1844 1334 1665 330 -275

ATOM 1073 0 HOH 3045 33.758 17. 544 2. ,755 1. ,000 15 40

ANISOU 1073 0 HOH 3045 1921 2153 1777 54 665 -156

ATOM 1074 0 HOH 3046 22.629 0. 947 24. .151 1. 000 19 89

ANISOU 1074 0 HOH 3046 2819 1929 2809 -478 -546 915

ATOM 1075 0 HOH 3047 7.273 17. 721 4. .001 1. 000 19 34

ANISOU 1075 0 HOH 3047 2310 2872 2167 -139 243 -439

ATOM 1076 0 HOH 3048 25.908 25. 484 4. ,541 1. 000 14 47

ANISOU 1076 0 HOH 3048 2652 1641 1206 32 39 -123

ATOM 1077 0 HOH 3049 29.156 21. 765 6. ,561 1. 000 19 29

ANISOU 1077 0 HOH 3049 1646 2443 3240 -59 428 -1234

ATOM 1078 0 HOH 3050 25.414 27. 948 16. ,236 1. 000 20 84

ANISOU 1078 0 HOH 3050 2978 2720 2220 567 356 -275

ATOM 1079 0 HOH 3051 33.230 8. 619 -0. ,290 1. 000 18 28

ANISOU 1079 0 HOH 3051 1998 2495 2450 197 501 -695

ATOM 1080 0 HOH 3052 25.206 7. 632 29. 691 1. 000 20 60

ANISOU 1080 0 HOH 3052 3182 2787 1858 -24 -532 493

ATOM 1081 0 HOH 3053 25.643 15. 003 23. 574 1. 000 16

ANISOU 1081 0 HOH 3053 2097 2109 2202 289 -312 523

ATOM 1082 0 HOH 3054 21.892 22. 372 2. 924 1. 000 20 30

ANISOU 1082 0 HOH 3054 3414 2252 2048 717 663 224

ATOM 1083 0 HOH 3055 12.029 24. 038 13. 095 1. 000 20 02

ANISOU 1083 0 HOH 3055 2888 3078 1641 2 8 -338

ATOM 1084 0 HOH 3056 21.010 3. 181 11. 164 1. 000 24 21

ANISOU 1084 0 HOH 3056 3620 3634 1946 774 862 1838

ATOM 1085 0 HOH 3057 34.480 15. 681 7. 227 1. 000 15 29

ANISOU 1085 0 HOH 3057 2053 1554 2203 100 -65 96

ATOM 1086 0 HOH 3058 26.363 3. 466 23. 325 1. 000 15 02

ANISOU 1086 0 HOH 3058 1986 1959 1763 -197 108 206

ATOM 1087 0 HOH 3059 30.349 30. 473 13. 485 1. 000 20 54

ANISOU 1087 0 HOH 3059 3117 2525 2163 -1600 -979 -128 ATOM 1088 O HOH 3060 38.242 12.061 0.426 1.000 25 50

ANISOU 1088 O HOH 3060 2160 5067 2461 -168 885 173

ATOM 1089 O HOH 3061 16.733 5.194 -0.151 1. 000 20 99

ANISOU 1089 O HOH 3061 3228 2735 2012 546 -280 -458

ATOM 1090 O HOH 3062 19.212 25.164 10.088 1. 000 18 .30

ANISOU 1090 O HOH 3062 2692 1987 2275 -336 282 -168

ATOM 1091 O HOH 3063 18.221 28.662 16.689 1. 000 19 .19

ANISOU 1091 O HOH 3063 2518 2869 1906 -1462 91 510

ATOM 1092 O HOH 3064 9.876 22.153 15.203 1. 000 12. 95

ANISOU 1092 O HOH 3064 1488 1677 1754 -90 147 112

ATOM 1093 O HOH 3065 8.288 18.592 7.800 1. 000 23. 60

ANISOU 1093 O HOH 3065 1881 2689 4396 -78 -1547 724

ATOM 1094 0 HOH 3066 15.656 30.893 15 ,247 1.000 24. 17

ANISOU 1094 0 HOH 3066 4147 3087 1947 1400 285 -670

ATOM 1095 0 HOH 3067 18.167 3.731 7 ,749 1.000 19. 26

ANISOU 1095 0 HOH 3067 1729 2059 3532 266 -467 363

ATOM 1096 0 HOH 3068 17.600 26.365 26 ,787 1.000 18. 64

ANISOU 1096 0 HOH 3068 2145 2956 1980 -146 -146 -263

ATOM 1097 0 HOH 3069 27.957 9.711 -11 ,964 1.000 16. 27

ANISOU 1097 o HOH 3069 2278 2096 1808 229 73 -206

ATOM 1098 0 HOH 3070 24.250 17.563 22 ,723 1.000 17.

ANISOU 1098 0 HOH 3070 2796 2254 1744 -646 -907 48

ATOM 1099 0 HOH 3071 18.973 4.063 12 ,827 1.000 16. 73

ANISOU 1099 0 HOH 3071 2292 1982 2084 316 431 306

ATOM 1100 0 HOH 3072 28.676 1.312 10 907 1.000 21. 85

ANISOU 1100 0 HOH 3072 2394 2921 2988 438 542 628

ATOM 1101 0 HOH 3073 31.324 6.252 12 148 1.000 19. 49

ANISOU 1101 0 HOH 3073 2250 2077 3077 -41 222 133

ATOM 1102 0 HOH 3074 15.459 0.884 13 939 1.000 27. 43

ANISOU 1102 0 HOH 3074 2061 3297 5066 1550 -271 -1352

ATOM 1103 0 HOH 3075 25.837 20.916 20 855 1.000 25. 91

ANISOU 1103 0 HOH 3075 4305 3067 2471 -979 -271 413

ATOM 1104 0 HOH 3076 29.642 2.990 20 064 1.000 19. 64

ANISOU 1104 o HOH 3076 1589 1981 3891 271 -555 -725

ATOM 1105 0 HOH 3077 25.664 7.502 -6 806 1.000 19. 59

ANISOU 1105 0 HOH 3077 3179 1931 2335 -348 -188 79

ATOM 1106 0 HOH 3078 28.068 17.500 -5 178 1.000 24. 32

ANISOU 1106 0 HOH 3078 3967 3228 2047 168 579 107

ATOM 1107 o HOH 3079 32.612 19.155 -3 486 1.000 27. 97

ANISOU 1107 0 HOH 3079 5061 2752 2816 36 106 646

ATOM 1108 0 HOH 3080 20.461 20.302 21 727 1.000 17. 48

ANISOU 1108 0 HOH 3080 1561 2722 2359 325 260 124

ATOM 1109 0 HOH 3081 9.378 18.031 -8 529 1.000 25. 04

ANISOU 1109 0 HOH 3081 3366 3726 2424 1219 852 -74

ATOM 1110 o HOH 3082 3.651 14.175 14 325 1.000 19. 69

ANISOU 1110 0 HOH 3082 2209 2576 2695 -417 54 -468

ATOM 1111 0 HOH 3083 35.516 16.863 4 670 1.000 26. 51

ANISOU 1111 0 HOH 3083 3800 3209 3063 -597 211 -585

ATOM 1112 0 HOH 3084 9.512 8.673 2 306 1.000 29. 06

ANISOU 1112 0 HOH 3084 2531 6064 2446 735 759 47

ATOM 1113 0 HOH 3085 5.522 12.048 13 426 1.000 22. 58

ANISOU 1113 0 HOH 3085 2924 3282 2374 -214 687 13

ATOM 1114 0 HOH 3086 6.673 15.106 4 977 1.000 22. 95

ANISOU 1114 o HOH 3086 3247 2900 2573 -243 -793 815

ATOM 1115 0 HOH 3087 19.145 5.015 1 434 1.000 23. 24

ANISOU 1115 o HOH 3087 2800 3639 2392 -852 441 -988

ATOM 1116 o HOH 3088 13.057 6.731 -0 837 1.000 28. 12

ANISOU 1116 0 HOH 3088 3228 4156 3301 144 -1091 966

ATOM 1117 0 HOH 3089 5.129 10.323 9 333 1.000 22. 16 ANISOU 1117 O HOH 3089 2188 3090 3140 -719 381 1283

ATOM 1118 O HOH 3090 4 . 137 10 533 6. 703 1.000 27, 13

ANISOU 1118 O HOH 3090 2434 4852 3024 -822 245 660

ATOM 1119 O HOH 3091 23.620 20 218 19. 374 1.000 22. 26

ANISOU 1119 O HOH 3091 4479 2165 1816 -1468 -201 169

ATOM 1120 O HOH 3092 6.340 16, 951 7. 547 1.000 17, 42

ANISOU 1120 O HOH 3092 2532 2132 1956 -535 -777 -11

ATOM 1121 O HOH 3093 20.833 -0, 163 22. 523 1.000 19. 46

ANISOU 1121 O HOH 3093 2778 2407 2209 -250 523 406

ATOM 1122 O HOH 3094 16.679 9, 403 29. 315 1.000 41. 48

ANISOU 1122 O HOH 3094 4520 5477 5764 -1612 -316 1152

ATOM 1123 O HOH 3095 4.935 12, 213 -5. 854 1.000 32. 00

ANISOU 1123 O HOH 3095 3702 5778 2677 -911 -1051 -1131

ATOM 1124 O HOH 3096 25.830 18, 265 -6. 979 1.000 26. 27

ANISOU 1124 O HOH 3096 3909 2682 3390 -542 -627 -508

ATOM 1125 O HOH 3097 21.898 26.359 18. 552 1.000 23. 10

ANISOU 1125 O HOH 3097 3466 3444 1868 -986 -364 -275

ATOM 1126 O HOH 3098 28.220 14. 908 -4. 762 1.000 24.99

ANISOU 1126 O HOH 3098 2651 3562 3283 -363 -585 188

ATOM 1127 O HOH 3099 7.040 21. 404 -1. 995 1.000 23.62

ANISOU 1127 O HOH 3099 3980 2273 2723 280 -698 571

ATOM 1128 0 HOH 3100 11.645 12. 503 1. 227 1.000 20.50

ANISOU 1128 0 HOH 3100 2269 2905 2615 -100 96 -423

ATOM 1129 0 HOH 3101 36.887 14.471 4. 657 1.000 30.51

ANISOU 1129 0 HOH 3101 4441 3413 3740 682 -520 -132

ATOM 1130 0 HOH 3102 9.640 3.275 0. 834 1.000 27.14

ANISOU 1130 0 HOH 3102 3912 3159 3242 258 -291 -1577

ATOM 1131 0 HOH 3103 21.750 26. 909 16. 173 1.000 26.28

ANISOU 1131 0 HOH 3103 5336 2181 2467 -503 -70 367

ATOM 1132 0 HOH 3104 10.922 25. 017 17. 485 1.000 9.29

ANISOU 1132 0 HOH 3104 1173 1328 1027 83 169 -147

ATOM 1133 0 HOH 3105 14.012 3.179 14. 219 1.000 12.03

ANISOU 1133 0 HOH 3105 1132 1650 1789 14 241 -52

ATOM 1134 0 HOH 3106 15.096 31.064 19. 511 1.000 10.44

ANISOU 1134 0 HOH 3106 1268 1303 1397 -96 671 -254

ATOM 1135 0 HOH 3107 12.276 3.292 12. 101 1.000 11.67

ANISOU 1135 0 HOH 3107 1715 1164 1553 -330 352 38

ATOM 1136 0 HOH 3108 15.245 6.688 16. 887 1.000 13.25

ANISOU 1136 0 HOH 3108 1519 1883 1633 2 100 553

ATOM 1137 0 HOH 3109 12.981 10.183 22. 666 1.000 11.76

ANISOU 1137 0 HOH 3109 1478 1417 1571 -355 -119 79

ATOM 1138 0 HOH 3110 8.079 17.855 21. 977 1.000 13.11

ANISOU 1138 0 HOH 3110 2134 1136 1711 66 24 -49

ATOM 1139 0 HOH 3111 12.189 25.763 15. 153 1.000 12.09

ANISOU 1139 0 HOH 3111 1381 1793 1421 409 97 103

ATOM 1140 0 HOH 3112 8.124 17.444 19. 097 1 000 13 38

ANISOU 1140 0 HOH 3112 1303 2182 1600 207 457 -1

ATOM 1141 0 HOH 3113 6.529 15.321 18. 298 1 000 13 99

ANISOU 1141 0 HOH 3113 2019 1481 1816 79 407 279

ATOM 1142 0 HOH 3114 12.970 20.956 28. 155 1 000 14 79

ANISOU 1142 0 HOH 3114 1741 1942 1939 368 278 233

ATOM 1143 0 HOH 3115 28.078 24.883 3. 177 1 000 21.88

ANISOU 1143 0 HOH 3115 3036 2475 2802 -202 69 •553

ATOM 1144 0 HOH 3116 9.389 24.417 13. 437 1 000 18.02

ANISOU 1144 0 HOH 3116 3063 2252 1531 32 710 78

ATOM 1145 0 HOH 3117 16.554 3.671 9. 869 1 000 21 11

ANISOU 1145 0 HOH 3117 2580 2371 3071 719 -602 -15

ATOM 1146 0 HOH 3118 31.966 4.574 20. 021 0 500 22 15

ANISOU 1146 0 HOH 3118 1682 2200 4534 0 -1174 ATOM 1147 O HOH 3119 26 . 836 4 .489 26.753 1, 000 20.72

ANISOU 1147 O HOH 3119 2158 2543 3171 -250 -32 732

ATOM 1148 O HOH 3120 6. 631 21 .812 11.978 1, 000 19. 70

ANISOU 1148 O HOH 3120 2539 2484 2462 -102 465 -419

ATOM 1149 O HOH 3121 26 . 120 19 .514 23..156 1, 000 18. 74

ANISOU 1149 O HOH 3121 2114 2810 2198 -544 -371 86

ATOM 1150 O HOH 3122 21.206 -2.417 15..527 1, 000 22. 36

ANISOU 1150 O HOH 3122 2268 2534 3695 -321 34 -972

ATOM 1151 O HOH 3123 29.207 33. 033 14..102 1. 000 27. 51

ANISOU 1151 O HOH 3123 3099 2207 5148 -1018 -1669 413

ATOM 1152 O HOH 3124 34.198 19. 431 0..941 1. 000 18.

ANISOU 1152 O HOH 3124 3218 1988 2006 -692 29 387

ATOM 1153 O HOH 3125 23.573 31.285 20..633 1. 000 21. 98

ANISOU 1153 O HOH 3125 2805 2320 3226 -696 298 1176

ATOM 1154 O HOH 3126 19.435 4.290 26..732 1, 000 25. 32>

ANISOU 1154 O HOH 3126 4776 2813 2032 -2248 -1668 1327

ATOM 1155 O HOH 3127 26.162 20.056 0..619 1.000 27. 29

ANISOU 1155 O HOH 3127 6031 2016 2323 112 -357 -343

ATOM 1156 O HOH 3128 14.902 7.139 28..392 1.000 23. 47

ANISOU 1156 O HOH 3128 3163 1728 4026 -379 -52 196

ATOM 1157 0 HOH 3129 34.193 3.793 14..250 1.000 27. 47

ANISOU 1157 0 HOH 3129 3475 2153 4808 -918 -1008 776

ATOM 1158 0 HOH 3130 23.242 29.366 15..441 1.000 23. 33

ANISOU 1158 0 HOH 3130 3793 2996 2075 -262 -670 -518

ATOM 1159 0 HOH 3131 11.840 9.727 1..726 1.000 24. 82

ANISOU 1159 0 HOH 3131 3091 3813 2527 -134 -717 542

ATOM 1160 0 HOH 3132 22.454 1.881 6..765 1.000 21. 61

ANISOU 1160 0 HOH 3132 2424 2569 3217 119 433 -1380

ATOM 1161 0 HOH 3133 6.549 20.632 9..527 1.000 22. 74

ANISOU 1161 0 HOH 3133 4100 2460 2082 478 452 ^■252

ATOM 1162 0 HOH 3134 20.997 17.466 29..004 1.000 33. 14

ANISOU 1162 0 HOH 3134 3729 3650 5215 -96 -1147 1639

ATOM 1163 0 HOH 3135 28.406 15.021 -15..227 1.000 21. 72

ANISOU 1163 0 HOH 3135 2602 2856 2797 -346 95 192

ATOM 1164 0 HOH 3136 12.172 3.708 8..020 1. 000 34. 07

ANISOU 1164 0 HOH 3136 6716 3068 3160 -1286 -313 -464

ATOM 1165 0 HOH 3137 7.430 5.614 8..860 1. 000 37. 19

ANISOU 1165 0 HOH 3137 4218 4636 5275 -2096 -1420 661

ATOM 1166 0 HOH 3138 33.359 24. 034 9..879 1. 000 35. 82

ANISOU 1166 0 HOH 3138 4170 4668 4771 2760 -427 -809

ATOM 1167 0 HOH 3139 1.121 16. 658 -0..388 1.000 32. 24

ANISOU 1167 0 HOH 3139 5385 3844 3022 734 -31 -691

ATOM 1168 0 HOH 3140 23.593 3.799 0.412 1.000 22. 71

ANISOU 1168 0 HOH 3140 2765 3348 2516 842 859 -139

ATOM 1169 0 HOH 3141 32.066 8.776 12.744 1.000 28. 54

ANISOU 1169 0 HOH 3141 2723 3713 4410 -583 -184 -210

ATOM 1170 0 HOH 3142 35.249 7.976 10.171 1.000 29. 70

ANISOU 1170 0 HOH 3142 5662 3603 2020 1811 -639 154

ATOM 1171 0 HOH 3143 29.326 17.803 -11.258 1.000 23. 12

ANISOU 1171 0 HOH 3143 3864 1899 3021 537 -333 572

ATOM 1172 0 HOH 3144 29.447 9.948 -1.549 1.000 31. 90

ANISOU 1172 0 HOH 3144 4371 2526 5222 -216 -610 -966

ATOM 1173 0 HOH 3145 40.315 12.912 -0.784 1.000 34. 99

ANISOU 1173 0 HOH 3145 4867 5274 3153 200 975 -221

ATOM 1174 0 HOH 3146 11.599 23.446 2.906 1.000 25. 96

ANISOU 1174 0 HOH 3146 3843 2847 3173 -392 -446 892

ATOM 1175 0 HOH 3147 5.602 7.635 -1.118 1.000 43. 07

ANISOU 1175 0 HOH 3147 6340 5368 4655 -142 -1078 -636

ATOM 1176 0 HOH 3148 38.198 16.722 12.071 1.000 27. 85 ANISOU 1176 O HOH 3148 3375 3641 3567 -613 -398 1077

ATOM 1177 O HOH 3149 30.936 1 357 17, 456 1. 000 43.

ANISOU 1177 O HOH 3149 6035 4680 5843 -1196 -1700 -193

ATOM 1178 O HOH 3150 27.800 19 735 -3.153 1. 000 39. 26

ANISOU 1178 O HOH 3150 5661 4001 5256 734 -622 ^■19

ATOM 1179 O HOH 3151 3.978 15 266 -5.394 1. 000 29. 06

ANISOU 1179 O HOH 3151 4382 3479 3181 -699 -1971 1097

ATOM 1180 O HOH 3152 26.635 14 403 31.968 1. 000 28. 71

ANISOU 1180 O HOH 3152 5194 2446 3267 -121 -1314 ^■991

ATOM 1181 0 HOH 3153 18.320 -1 229 23.324 1.000 29. 29

ANISOU 1181 0 HOH 3153 3363 2952 4813 951 -544 -1065

ATOM 1182 0 HOH 3154 28.360 36 045 8.063 1.000 29. 27

ANISOU 1182 0 HOH 3154 3745 2778 4600 -765 -422 -286

ATOM 1183 0 HOH 3155 8.518 20.831 6. 397 1.000 25. 45

ANISOU 1183 0 HOH 3155 2964 3554 3151 -578 -252 224

ATOM 1184 0 HOH 3156 13.589 9.894 25. 413 1.000 21. 53

ANISOU 1184 0 HOH 3156 3348 2545 2285 -172 -463 ^■959

ATOM 1185 0 HOH 3157 21.694 24.602 22. 189 1.000 26. 49

ANISOU 1185 0 HOH 3157 2594 4299 3173 -144 -40 -222

ATOM 1186 0 HOH 3158 13.180 4.436 5.768 1.000 31. 26

ANISOU 1186 0 HOH 3158 6504 2610 2763 285 82 -335

ATOM 1187 0 HOH 3159 31.415 8.047 -2.152 1.000 31. 96

ANISOU 1187 0 HOH 3159 4289 4692 3163 49 -519 515

ATOM 1188 0 HOH 3160 1.065 18.844 13.245 1.000 25. 10

ANISOU 1188 0 HOH 3160 3213 2780 3543 -3 -586 349

ATOM 1189 0 HOH 3161 12.170 3.609 0.796 1.000 32. 48

ANISOU 1189 0 HOH 3161 4870 3318 4152 330 21 -1852

ATOM 1190 0 HOH 3162 11.791 26.077 5.141 1.000 34. 62

ANISOU 1190 0 HOH 3162 3500 4347 5306 203 1087 -753

ATOM 1191 0 HOH 3163 25.853 6.695 -2.865 1.000 27. 90

ANISOU 1191 0 HOH 3163 4142 3379 3078 -258 229 -908

ATOM 1192 0 HOH 3164 12.548 11.920 25. 733 1.000 64. 39

ANISOU 1192 0 HOH 3164 8171 7484 8812 -783 -256 122

ATOM 1193 0 HOH 3165 23.909 14.740 30. 935 1.000 35.

ANISOU 1193 0 HOH 3165 5004 4728 3628 1382 1024 -1210

ATOM 1194 0 HOH 3166 14.475 18.647 28. 191 1.000 36.04

ANISOU 1194 0 HOH 3166 4511 4511 4672 2079 823 -1587

ATOM 1195 0 HOH 3167 17.196 1.479 11. 415 1.000 33.39

ANISOU 1195 0 HOH 3167 5448 4559 2679 -81 1086 1594

ATOM 1196 0 HOH 3168 29.448 29.087 15.802 1.000 28.37

ANISOU 1196 0 HOH 3168 3534 4400 2845 436 256 -201

ATOM 1197 0 HOH 3169 35.484 9.421 -1.373 1.000 29.39

ANISOU 1197 0 HOH 3169 3817 3545 3807 531 285 -354

ATOM 1198 0 HOH 3170 33.836 6.012 8.920 1.000 38.33

ANISOU 1198 0 HOH 3170 3450 6230 4885 631 365 -1373

ATOM 1199 0 HOH 3171 26.038 4.362 -0. 398 1.000 29.21

ANISOU 1199 0 HOH 3171 3149 4567 3382 575 1645 118

ATOM 1200 0 HOH 3172 25.670 2.436 27. 437 1.000 36.51

ANISOU 1200 0 HOH 3172 4778 3856 5240 -1058 193 972

ATOM 1201 0 HOH 3173 17.570 12.393 27.361 1.000 25.07

ANISOU 1201 0 HOH 3173 2961 4369 2194 -594 -681 379

ATOM 1202 0 HOH 3174 20.126 21.311 30.641 1.000 51.15

ANISOU 1202 0 HOH 3174 7578 5826 6032 2540 387 -670

ATOM 1203 0 HOH 3175 22.022 18.830 23.842 1.000 31.62

ANISOU 1203 0 HOH 3175 2024 4298 5692 -451 -600 152

ATOM 1204 0 HOH 3176 19.886 26.441 24.854 1.000 27.63

ANISOU 1204 0 HOH 3176 2882 3801 3814 206 478 -31

ATOM 1205 0 HOH 3177 29.020 4.575 4.596 1.000 35.41

ANISOU 1205 0 HOH 3177 4426 4011 5018 -116 -931 41 ATOM 1206 O HOH 3178 6.535 23.925 -0.965 1.000 23.96

ANISOU 1206 O HOH 3178 2680 4081 2341 -340 163 95

ATOM 1207 O HOH 3179 22.211 4.476 31.379 1.000 52.07

ANISOU 1207 O HOH 3179 6317 6398 7071 -2027 -331 1310

ATOM 1208 O HOH 3180 29.168 2.679 23.267 1.000 36.13

ANISOU 1208 O HOH 3180 6058 3855 3816 768 -182 -700

ATOM 1209 O HOH 3181 38.803 13.451 3.204 1.000 44.18

ANISOU 1209 O HOH 3181 3905 6413 6468 181 -312 -500

ATOM 1210 O HOH 3182 36.731 7.680 2.353 1.000 35.43

ANISOU 1210 O HOH 3182 5269 3975 4220 337 -707 -47

ATOM 1211 O HOH 3183 4.549 19.751 0.725 1.000 48.08

ANISOU 1211 O HOH 3183 5609 5718 6942 2032 428 -1220

ATOM 1212 O HOH 3184 19.312 0.264 9.183 1.000 68.23

ANISOU 1212 O HOH 3184 9442 8601 7882 1300 849 -1735

ATOM 1213 O HOH 3185 11.393 6.128 1.726 1.000 32.22

ANISOU 1213 O HOH 3185 3502 4710 4029 -687 521 -29

ATOM 1214 O HOH 3186 37.864 9.742 -0.601 1.000 36.98

ANISOU 1214 O HOH 3186 2457 5577 6017 437 582 477

ATOM 1215 O HOH 3187 25.433 31.666 22.740 1.000 41.89

ANISOU 1215 O HOH 3187 6099 4078 5739 382 -1044 123

ATOM 1216 O HOH 3188 2.447 16.858 11.718 1.000 34.76

ANISOU 1216 O HOH 3188 2356 4665 6188 563 -98 -906

ATOM 1217 O HOH 3189 8.945 23.538 7.069 1.000 34.94

ANISOU 1217 O HOH 3189 5338 3933 4005 959 -991 -134

ATOM 1218 0 HOH 3190 24.773 2.545 5.330 1.000 33.79

ANISOU 1218 0 HOH 3190 3499 4192 5147 -459 858 231

ATOM 1219 0 HOH 3191 2.410 19.117 0.181 1.000 34.07

ANISOU 1219 0 HOH 3191 5366 3174 4406 714 -1245 -192

ATOM 1220 0 HOH 3192 13.598 21.973 -2.525 1.000 38.16

ANISOU 1220 0 HOH 3192 5656 3457 5384 656 -1799 -1169

ATOM 1221 0 HOH 3193 24.060 28.389 19.602 1.000 33.60

ANISOU 1221 0 HOH 3193 4277 3396 5093 186 820 -188

ATOM 1222 0 HOH 3194 8.232 10.607 -0.917 1.000 31.96

ANISOU 1222 0 HOH 3194 4140 4483 3521 -68 584 -603

ATOM 1223 0 HOH 3195 34.968 9.533 -4.185 1.000 35.87

ANISOU 1223 0 HOH 3195 5012 4709 3909 -1224 834 -24

ATOM 1224 0 HOH 3196 39.032 19.195 12.706 1.000 40.82

ANISOU 1224 0 HOH 3196 5490 5467 4554 -1229 -249 284

ATOM 1225 0 HOH 3197 26.506 6.179 32.904 1.000 33.37

ANISOU 1225 0 HOH 3197 4550 3825 4304 -1202 277 -476

ATOM 1226 0 HOH 3198 14.352 7.527 31.054 1.000 49.65

ANISOU 1226 0 HOH 3198 7869 4866 6130 -1042 -984 -222

ATOM 1227 0 HOH 3199 6.803 9.448 -2.291 1.000 32.18

ANISOU 1227 0 HOH 3199 5402 3618 3205 437 -818 -790

ATOM 1228 0 HOH 3200 15.273 11.179 27.235 1.000 33.93

ANISOU 1228 0 HOH 3200 4372 5044 3475 -894 135 190

ATOM 1229 0 HOH 3201 23.406 22.750 23.249 1.000 44.58

ANISOU 1229 0 HOH 3201 7088 4470 5379 1126 62 218

ATOM 1230 0 HOH 3202 22.851 20.376 26.629 1.000 39.94

ANISOU 1230 0 HOH 3202 3573 5360 6243 1170 58 -849

ATOM 1231 0 HOH 3203 10.654 6.824 -1.186 1.000 43.09

ANISOU 1231 0 HOH 3203 4687 5647 6040 176 284 -445

ATOM 1232 0 HOH 3204 23.464 17.206 29.752 1.000 54.53

ANISOU 1232 0 HOH 3204 5340 7844 7534 616 964 453

ATOM 1233 0 HOH 3205 32.008 23.423 4.630 1.000 41.32

ANISOU 1233 0 HOH 3205 5633 4751 5316 626 -409 -1136

ATOM 1234 0 HOH 3206 31.941 32.893 9.775 1.000 31.26

ANISOU 1234 0 HOH 3206 3680 3977 4221 -1290 -835 964

ATOM 1235 0 HOH 3207 30.927 24.675 17.614 1.000 33.75 ANISOU 1235 O HOH 3207 4890 3751 4184 391 -403 767

ATOM 1236 O HOH 3208 9.485 4 .600 8 .987 1 .000 44. 32

ANISOU 1236 O HOH 3208 5304 6779 4757 -61 1144 -232

ATOM 1237 O HOH 3209 37.442 18 .437 5 .763 1 .000 36. 95

ANISOU 1237 O HOH 3209 4823 4435 4782 -861 -539 1432

ATOM 1238 O HOH 3210 6.226 20 .407 5 .250 1, .000 50. 17

ANISOU 1238 O HOH 3210 8105 5474 5485 -1991 -346 1374

ATOM 1239 O HOH 3211 8.283 7 .036 -2 .347 1. .000 47. 23

ANISOU 1239 O HOH 3211 7076 5824 5044 -973 -1169 223

ATOM 1240 O HOH 3212 13.676 -0, .922 13 .265 1, .000 32. 42

ANISOU 1240 O HOH 3212 3977 2994 5348 736 -576 -521

ATOM 1241 O HOH 3213 29.118 23, .161 4 .289 1, .000 28. 13

ANISOU 1241 O HOH 3213 3278 3906 3505 555 -210 -571

ATOM 1242 O HOH 3214 28.625 33, .719 16, .890 1. .000 31. 41

ANISOU 1242 O HOH 3214 3783 3175 4974 -362 -1510

ATOM 1243 O HOH 3215 22.868 18. .506 -6, .047 1. .000 33. 38

ANISOU 1243 O HOH 3215 6072 2866 3746 -651 -1947 1377

ATOM 1244 O HOH 3216 25.067 20, ,263 -3, .872 1. .000 32. 42

ANISOU 1244 O HOH 3216 2685 3642 5989 -1000 -873 449

ATOM 1245 O HOH 3217 23.927 23. ,517 19, .039 1. ,000 26. 36

ANISOU 1245 O HOH 3217 3682 4164 2170 326 -680 -358

ATOM 1246 O HOH 3218 28.647 25. ,582 17. .077 1. ,000 26. 78

ANISOU 1246 O HOH 3218 3302 4096 2778 -271 -565 263

ATOM 1247 O HOH 3219 24.040 1. ,638 1. .039 1. ,000 32. 65

ANISOU 1247 0 HOH 3219 6088 2999 3318 -117 -849 336

ATOM 1248 0 HOH 3220 19.876 30. ,026 17, .898 1. ,000 25. 38

ANISOU 1248 0 HOH 3220 3045 4797 1801 -1321 126 - 447

ATOM 1249 0 HOH 3221 30.284 10. 612 -12. .023 1. 000 33. 56

ANISOU 1249 0 HOH 3221 3773 5312 3668 -1509 -605 -126

ATOM 1250 0 HOH 3222 17.019 22. 671 29. ,574 1. 000 31. 57

ANISOU 1250 0 HOH 3222 4339 4944 2710 328 -1520 469

ATOM 1251 0 HOH 3223 40.075 21. 034 9. ,780 1. 000 30. 43

ANISOU 1251 0 HOH 3223 3282 5625 2655 713 -470 38

ATOM 1252 0 HOH 3224 27.822 11. 841 -7. ,466 1. 000 30. 33

ANISOU 1252 0 HOH 3224 2906 5050 3570 -12 -118

ATOM 1253 0 HOH 3225 33.999 7. 354 5. ,288 1. 000 31. 75

ANISOU 1253 0 HOH 3225 4255 3553 4256 1396 -1247 -821

ATOM 1254 0 HOH 3226 16.555 20. 006 30. ,349 1. 000 34. 94

ANISOU 1254 0 HOH 3226 5845 3412 4018 -513 -1815 537

ATOM 1255 0 HOH 3227 32.081 30. 474 10. ,342 1. 000 30. 82

ANISOU 1255 0 HOH 3227 4475 4253 2982 -1241 -1585 457

ATOM 1256 0 HOH 3228 7.638 21. 676 -4. ,634 1. 000 27. 91

ANISOU 1256 0 HOH 3228 3369 4447 2787 999 -342 745

ATOM 1257 0 HOH 3229 35.187 5. 334 11. ,425 1. 000 30. 73

ANISOU 1257 0 HOH 3229 4670 3745 3260 496 -1054 -1148

ATOM 1258 0 HOH 3230 21.901 11. 061 31. ,530 1. 000 27. 84

ANISOU 1258 0 HOH 3230 2911 4908 2757 -427 -425 198

ATOM 1259 0 HOH 3231 18.688 7. 868 29. ,503 1. 000 31. 08

ANISOU 1259 0 HOH 3231 4212 4647 2949 1190 -153 -17

ATOM 1260 0 HOH 3232 26.242 6. 061 -5. .070 1. 000 32. 10

ANISOU 1260 0 HOH 3232 5673 3490 3034 468 -1470 -819

ATOM 1261 0 HOH 3233 4.027 18. 596 8. ,931 1. 000 32.

ANISOU 1261 0 HOH 3233 3714 4492 4262 1611 -1348 -510

ATOM 1262 0 HOH 3234 -0.704 19. 421 11. ,575 1. 000 74. 26

ANISOU 1262 0 HOH 3234 8488 9515 10213 -229 -106 -165

ATOM 1263 0 HOH 3235 41.909 13. 185 -7. 145 1. 000 45. 73

ANISOU 1263 0 HOH 3235 4053 6812 6509 815 272 -168

ATOM 1264 0 HOH 3236 27.827 6. 716 -1. 011 1. 000 43. 85

ANISOU 1264 0 HOH 3236 4405 6032 6225 730 100 -1194 ATOM 1265 0 HOH 3237 25.361 21.438 24.646 1.000 39.82

ANISOU 1265 O HOH 3237 4110 5524 5495 -1169 621 67

ATOM 1266 0 HOH 3238 32.462 27.336 16.638 1.000 40.98

ANISOU 1266 O HOH 3238 4199 6745 4627 56 330 -272

Overall structure ofPKB_aPH, and its interaction with Ins(l,3,4,5)P₄

All figures were made with PyMOL (http://www.pymol.org).

The structure of the pleckstrin homology domain of protein kinase B (PKB_αPH) complexed to Ins(l,3,4,5)P was solved by selenomethionine- MAD, yielding experimental phases to 1.4 A resolution (Fig. IA). Refinement of the structure resulted in a complete model for residues 1-113 (Fig. IB). Well-defined density for Ins(l,3,4,5)P allowed the construction of a model for this ligand in the binding pocket (Figs. 1A-C). The PKB PH structure reveals a standard PH domain fold [5], with seven β-strands forming two orthogonal anti-parallel β-sheets, closed at one end by the C- terminal α-helix. At the other end of the β-barrel lie three loops (VL1-3) that are variable, both in sequence and length, in presently known PH domain structures [5]. These loops form a bowl lined with basic residues into which the Ins(l,3,4,5)P head group binds (Figs. 1C,2). The head group forms specific interactions with these basic residues and other side chains, and also with the protein backbone. The DI -phosphate forms relatively few interactions, with Arg23 and the backbone nitrogen of He 19 (Fig. 1C). In contrast, the D3 -phosphate interacts with four side chains, Lysl4, Arg23, Arg25, and Asn53. This relatively large number of residues that interact with this phosphate group is likely to account for inability of PKB_αPH to interact with PtdIns(4,5)P₂, which lacks a D3-phosphate [9, 10]. Similarly, the D4-phosphate makes tight interactions with Lys 14, Asn53 and Arg86, explaining why PKB_αPH does not bind to PtdIns3P or PtdIns(3,5)P₂ [9, 10] (Fig 1C). Interestingly, the D5-phosphate does not interact with any protein atoms in the binding pocket. It is oriented towards the solvent and interacts only with five ordered water molecules. This explains the observation that PKB can interact with both PtdIns(3,4)P₂ or PtdIns(3,4,5)P₃ with similar affinity [9, 10].

Structure ofapo-PKBJΗ

The apo-PKB_αPH structure was solved by molecular replacement with AMoRe [36], using the selenomethionine PKB PH as a search model against 8-4 A data. A clear solution with an R-factor of 0.36 and a correlation coefficient of 0.61 was found. The resulting model phases were used as input for warpNtrace [33] which was able to build 94 out of the 123 possible residues, against 1.65 A resolution data. Iterative model building in O [34] together with refinement in CNS resulted in a final model with R=0.203 (R _ree=0.239), which included residues 4-121.

All figures were made with PyMOL (http://www.pymol.org).

Table 3 lists the data set of structural co-ordinates collected on native apo PKB_αPH crystals.

Table 3

REMARK Created by MOLEMAN V. 010306/7.3.2 at Wed Mar 13 09:17:57 2002 for christi REMARK MoleMan PDB file

REMARK coordinates from restrained individual B-factor refinement

REMARK refinement resolution: 20 - 1.65 A

REMARK starting r= 0.2033 free_r= 0.2341

REMARK final r= 0.2024 free_r= 0.2346 REMARK B rmsd for bonded mainchain atoms= 1.583 target= 1.5

REMARK B rmsd for bonded sidechain atoms= 2.104 target= 2.0

REMARK B rmsd for angle mainchain atoms= 2.561 target= 2.0

REMARK B rmsd for angle sidechain atoms= 3.173 target= 2.5

REMARK rweight= 0.1000 (with wa= 0.964835) REMARK target= mlf steps= 30

REMARK sg= C2 a= 84.0640 b= 33.8030 c= 42.0710 alpha= 90 beta=

119.4770 gamma= 90

REMARK parameter file 1 : CNS_TOPPAR:protein_rep.param

REMARK parameter file 2 : CNS TOPPAR: water_rep .param REMARK molecular structure file: .. /generate/alternate .mtf REMARK input coordinates: ../mi.nimize/minimize .]pdb

REMARK refl€ :ction file= ../../1/hkl/cns. hkl

REMARK ncs= none

REMARK B-correction resolution: 6.0 - 1. 65

REMARK initial B -factor correction applied to fobs :

REMARK Bl] 2.414 B22= -6. 464 B33= 4.050

REMARK B12 >₌ 0.000 B13= 1. 553 B23= 0.000

REMARK B-factor correction appl .ied to coordinate array B: O.i 067

REMARK bulk solvent: density level= 0.53241 e/A' "3 , B-factor= 70 .72

A^Λ2

REMARK reflections with I Fobs I / 'sigma F < 0.0 re;jected

REMARK reflections with I Fobs | > 10000 * rms(Fobs) rejected

REMARK theoretical total number : of refl. in resol. range: 12574 (

100.0 i * )

REMARK numbe :r of unobserved reflections (no entry or |F|=0): 180 ( 1.4 % ) REMARK numbe :r of reflections reijected: 0 ( 0.0 % )

REMARK total . number of reflections used: 12394 ( 98.6 ^! * )

REMARK numbe :r of reflections int working set: 11793 ( 93.8 ' * )

REMARK numbeιr of reflections ini test set 601 ( 4.8 ■ * )

REMARK FILENAME= "bindivi .dual.pdb"

REMARK DATE: 25-Feb-2002 09:05: 14 created by user : chr:ist: L

REMARK VERSION :1 .0

CRYST1 84. 064 33.803i 42.071 90.00 119.48 90.00 i Z 2 1

ORIGX1 1.000000 0. 000000 0.000000 0.00000

ORIGX2 0.000000 1. 000000 0.000000 0.00000

ORIGX3 0.000000 0. 000000 1.000000 0.00000

SCALE1 0.011896 0. 000000 0.006725 0.00000

SCALE2 0.000000 0. 029583 0.000000 0.00000

SCALE3 0.000000 0. 000000 0.027305 0.00000

ATOM 1 CB ASP A 3 30.760 3.152 -7.540 1.00 37 .33 A

ATOM 2 CG ASP A 3 29.822 2.341 -8.413 1.00 38 .80 A

ATOM 3 OD1 ASP A 3 29.509 2.798 -9.536 1.00 40 .84 A

ATOM 4 OD2 ASP A 3 29.398 1.245 -7.982 1.00 39 .63 A

ATOM 5 C ASP A 3 29.715 2.649 -5.324 1.00 32 .82 A

ATOM 6 O ASP A 3 28.975 3.625 -5.455 1.00 32 .55 A

ATOM 7 N ASP A 3 31.413 1.098 -6.319 1.00 36 .86 A

ATOM 8 CA ASP A 3 30.984 2.515 -6.164 1.00 34 .85 A

ATOM 9 N VAL A 4 29.473 1.672 -4.455 1.00 29. .70 A

ATOM 10 CA VAL A 4 28.288 1.683 -3.602 1.00 26 .19 A

ATOM 11 CB VAL 4 28.025 0.289 -2.996 0.50 26 .45

ACI

ATOM 12 CGI VAL 4 27.821 -0.727 -4.106 0.50 27 .36

ACI

ATOM 13 CG2 VAL 4 29.190 ^■ -0.124 -2.107 0.50 26, .09

ACI

ATOM 14 C VAL A 4 28.439 2.688 -2.460 1.00 23, .64 A

ATOM 15 O VAL A 4 29.462 2.713 -1.777 1.00 25. .00 A

ATOM 16 N ALA A 5 27.417 3.513 -2.256 1.00 17, .34 A

ATOM 17 CA ALA A 5 27.442 4.515 -1.196 1.00 14, .86 A

ATOM 18 CB ALA A 5 27.716 5.910 -1.795 1.00 14, .42 A

ATOM 19 C ALA A 5 26.115 4.527 -0.447 1.00 11, .32 A

ATOM 20 0 ALA A 5 25.089 4.108 -0.984 1.00 11, .60 A

ATOM 21 N ILE A 6 26.137 5.000 0.798 1.00 10, .83 A

ATOM 22 CA ILE A 6 24.917 5.096 1.590 1.00 8, .53 A

ATOM 23 CB ILE A 6 25.225 5.362 3.083 1.00 10, .78 A

ATOM 24 CG2 ILE A 6 23.947 5.713 3.831 1.00 10. .40 A

ATOM 25 CGI ILE A 6 25.911 4.135 3.689 1.00 12. .28 A

ATOM 26 CDl ILE A 6 26.468 4.361 5.079 1.00 12. .09 A

ATOM 27 C ILE A 6 24.118 6.275 1.042 1.00 11. .04 A

ATOM 28 0 ILE A 6 24.655 7.370 0.882 1.00 11. .45 A

ATOM 29 N VAL A 7 22.842 6.036 0.754 1.00 9. .69 A ATOM 30 CA VAL A 7 21 . 938 7 . 057 0 .223 1 . 00 12 . 75 A

ATOM 31 CB VAL A 7 20 .889 6 .403 -0 .724 1 .00 13 .62 A

ATOM 32 CGI VAL A 7 19 .758 7 .384 -1 .057 1 .00 14 .24 A

ATOM 33 CG2 VAL A 7 21 .583 5 .943 -1 .994 1 .00 13 .79 A

ATOM 34 C VAL A 7 21 .213 7 .782 1 .353 1 .00 13 .83 A

ATOM 35 O VAL A 7 21 .055 9 .008 1 .333 1 .00 13 .70 A

ATOM 36 N LYS A 8 20 .779 7 .010 2 .339 1 .00 12 .79 A

ATOM 37 CA LYS A 8 20 .058 7 .545 3 .480 1 .00 12 .18 A

ATOM 38 CB LYS A 8 18 .595 7 .797 3. .102 1 .00 13 .47 A

ATOM 39 CG LYS A 8 17 .732 8 .339 4 .235 1 .00 15 .48 A

ATOM 40 CD LYS A 8 16 .300 8 .539 3 .755 1 .00 19 .67 A

ATOM 41 CE LYS A 8 15 .380 9 .011 4. .869 1 .00 22 .89 A

ATOM 42 NZ LYS A 8 15 .837 10 .303 5, .428 1, .00 25 .22 A

ATOM 43 C LYS A 8 20 .126 6 .544 4 .626 1 .00 12 .22 A

ATOM 44 O LYS A 8 20 .136 5 .334 .408 1 .00 11 .49 A

ATOM 45 N GLU A 9 20 .196 7. .057 5, .846 1, .00 12 .08 A

ATOM 46 CA GLU A 9 20. .230 6, .203 7, .021 1, .00 12 .21 A

ATOM 47 CB GLU A 9 21, .672 5, .886 7, .436 1, .00 14 .00 A

ATOM 48 CG GLU A 9 22, .584 7, .094 7. .600 1, .00 16 .92 A

ATOM 49 CD GLU A 9 23 .959 6. .707 8. .111 1 .00 18 .70 A

ATOM 50 OEl GLU A 9 24, .081 6, .370 9, .310 1, .00 18 .98 A

ATOM 51 OE2 GLU A 9 24 .916 6, .727 7. .312 1, .00 21, .30 A

ATOM 52 C GLU A 9 19, .494 6, .893 8. .152 1, .00 13. .33 A

ATOM 53 O GLU A 9 19, .439 8, .121 8. .205 1, .00 15, .39 A

ATOM 54 N GLY A 10 18. .919 6, .100 9. .047 1. .00 13, .33 A

ATOM 55 CA GLY A 10 18. .189 6. .665 10. .165 1. .00 13. .37 A

ATOM 56 C GLY A 10 17, .329 5, .637 10. .872 1, .00 12, .40 A

ATOM 57 O GLY A 10 17. .290 4. .469 10. .479 1. .00 13, .13 A

ATOM 58 N TRP A 11 16. .638 6. .062 11. .923 1. .00 12, .75 A

ATOM 59 CA TRP A 11 15. .786 5. .145 12. .667 1. .00 12. .98 A

ATOM 60 CB TRP A 11 15. .595 5. .623 14. .109 1. ,00 14. .45 A

ATOM 61 CG TRP A 11 16. .815 5. .523 14. .938 1. ,00 14. .72 A

ATOM 62 CD2 TRP A 11 17. .280 4. .359 15. .626 1. .00 15, .71 A

ATOM 63 CE2 TRP A 11 18. .481 4. .711 16. .277 1. .00 16. .70 A

ATOM 64 CE3 TRP A 11 16. .796 3. .050 15. ,754 1. .00 16. .24 A

ATOM 65 CDl TRP A 11 17. .726 6. .509 15. ,187 1. .00 15. .62 A

ATOM 66 NE1 TRP A 11 18. .731 6. .028 15. .994 1. .00 14. .52 A

ATOM 67 CZ2 TRP A 11 19. .210 3. .799 17. ,048 1. ,00 16. ,45 A

ATOM 68 CZ3 TRP A 11 17. ,521 2. .139 16. .521 1. ,00 16, ,20 A

ATOM 69 CH2 TRP A 11 18. .717 2. .521 17. ,158 1. .00 17. .63 A

ATOM 70 C TRP A 11 14. .416 4. .968 12. ,034 1. .00 12. .84 A

ATOM 71 O TRP A 11 13. .832 5. .914 11. ,504 1. .00 14. .14 A

ATOM 72 N LEU A 12 13. .914 3. .742 12. ,100 1. .00 13. ,22 A

ATOM 73 CA LEU A 12 12. ,599 3. ,401 11. ,574 1. ,00 13. ,64 A

ATOM 74 CB LEU A 12 12. ,715 2. ,678 10. ,226 1. ,00 14. ,51 A

ATOM 75 CG LEU A 12 13. .245 3. .416 8. ,999 1. .00 14. .70 A

ATOM 76 CDl LEU A 12 13. .434 2. .420 7. ,860 1. .00 16. .11 A

ATOM 77 CD2 LEU A 12 12. .274 4. .512 8. ,587 1. ,00 14. .03 A

ATOM 78 C LEU A 12 11. ,952 2. ,449 12. ,559 1. ,00 15. ,22 A

ATOM 79 O LEU A 12 12. ,636 1. ,647 13. ,195 1. .00 15. ,02 A

ATOM 80 N HIS A 13 10. ,637 2. ,543 12. 706 1. 00 13. ,94 A

ATOM 81 CA HIS A 13 9. ,935 1. .619 13. ,575 1. .00 13. .82 A

ATOM 82 CB HIS A 13 8. .698 2. .286 14. ,167 1. .00 16. ,12 A

ATOM 83 CG HIS A 13 9. ,023 3. .393 15. ,119 1. ,00 19. ,13 A

ATOM 84 CD2 HIS A 13 9. ,001 4. ,738 14. ,966 1. ,00 22. ,91 A

ATOM 85 ND1 HIS A 13 9. ,493 3. ,159 16. 394 1. 00 23. ,19 A

ATOM 86 CEl HIS A 13 9. ,746 4. ,313 16. 986 1. 00 22. ,52 A

ATOM 87 NE2 HIS A 13 9. ,457 5. ,287 16. 141 1. ,00 25. ,18 A

ATOM 88 C HIS A 13 9. ,549 0. ,486 12. ,637 1. ,00 15. ,17 A

ATOM 89 O HIS A 13 8. ,764 0. ,688 11. ,714 1. ,00 16. ,14 A

ATOM 90 N LYS A 14 10. ,126 -0. ,694 12. 844 1. ,00 12. ,77 A

ATOM 91 CA LYS A 14 9. ,821 -1. ,828 11. 975 1. 00 13. ,66 A ATOM 92 CB LYS A 14 11.100 -2.537 11.527 1.00 13.56 A

ATOM 93 CG LYS A 14 10 .820 -3 .711 10 .589 1 .00 15 .37 A

ATOM 94 CD LYS A 14 12 .086 -4 .464 10 .212 1 .00 17 .57 A

ATOM 95 CE LYS A 14 11 .769 -5 .602 9 .259 1 .00 18 .38 A

ATOM 96 NZ LYS A 14 10 .865 -6 .598 9 .885 1 .00 17 .77 A

ATOM 97 C LYS A 14 8 .900 -2 .852 12 .615 1 .00 14 .05 A

ATOM 98 o LYS A 14 9 .087 -3 .252 13 .768 1 .00 13 .33 A

ATOM 99 N ARG A 15 7 .901 -3 .284 11 .856 1 .00 12 .46 A

ATOM 100 CA ARG A 15 6 .970 -4 .275 12 .357 1 .00 14 .58 A

ATOM 101 CB ARG A 15 5 .624 -4 .147 11 .653 1 .00 14 .27 A

ATOM 102 CG ARG A 15 4 .493 -4 .823 12 .402 1 .00 14 .58 A

ATOM 103 CD ARG A 15 3 .214 -4 .783 11 .597 1. .00 16 .76 A

ATOM 104 NE ARG A 15 2 .042 -5 .002 12 .434 1. .00 16 .97 A

ATOM 105 CZ ARG A 15 0 .793 -4 .978 11 .985 1 .00 19 .31 A

ATOM 106 NHl ARG A 15 0 .552 -4 .750 10 .700 1. .00 21 .08 A

ATOM 107 NH2 ARG A 15 -0 .215 -5 .158 12 .826 1. .00 21 .55 A

ATOM 108 C ARG A 15 7 .560 -5 .653 12 .095 1. .00 15 .05 A

ATOM 109 0 ARG A 15 8 .115 -5. .904 11 .026 1. .00 16 .56 A

ATOM 110 N GLY A 16 7 .444 -6 .547 13. .072 1, .00 17 .30 A

ATOM 111 CA GLY A 16 7. .989 -7 .881 12, .900 1, .00 20, .82 A

ATOM 112 C GLY A 16 7 .266 -8. .722 11, .863 1, .00 23, .28 A

ATOM 113 0 GLY A 16 6 .104 -8 .474 11, .541 1. .00 23, .31 A

ATOM 114 N GLU A 17 7, .962 -9, .722 11. .331 1. .00 27, .23 A

ATOM 115 CA GLU A 17 7, .374 -10. .616 10. .341 1. .00 30, .34 A

ATOM 116 CB GLU A 17 8, .462 -11 .282 9. .493 1, .00 32. .00 A

ATOM 117 CG GLU A 17 8, .904 -10, .485 8, .270 1. .00 34, .44 A

ATOM 118 CD GLU A 17 9, .772 -9, .294 8, .612 1. .00 34, .87 A

ATOM 119 OEl GLU A 17 10, .853 -9, .496 9. .203 1. .00 37, .51 A

ATOM 120 OE2 GLU A 17 9, .379 -8. .156 8. .282 1. .00 36. .10 A

ATOM 121 C GLU A 17 6. .552 -11. .691 11. .047 1. .00 31. .92 A

ATOM 122 0 GLU A 17 5. .516 -12. .125 10. .542 1, ,00 32. .34 A

ATOM 123 N TYR A 18 7. .021 -12. .115 12. ,216 1. ,00 33. .96 A

ATOM 124 CA TYR A 18 6. .329 -13. .134 12. ,998 1. ,00 35. .71 A

ATOM 125 CB TYR A 18 7. .339 -14. .164 13. ,508 1. ,00 37. .96 A

ATOM 126 CG TYR A 18 8. ,044 -14. .859 12. ,366 1. ,00 40. .54 A

ATOM 127 CDl TYR A 18 7. ,324 -15. .615 11. ,439 1. ,00 41. .57 A

ATOM 128 CEl TYR A 18 7. ,949 -16. .198 10. ,342 1. ,00 43. .07 A

ATOM 129 CD2 TYR A 18 9. ,416 -14. ,710 12. ,168 1. ,00 41. .62 A

ATOM 130 CE2 TYR A 18 10. ,053 -15. .290 11. ,070 1. ,00 42. .61 A

ATOM 131 CZ TYR A 18 9. ,312 -16. .030 10. ,161 1. ,00 43. .07 A

ATOM 132 OH TYR A 18 9. ,923 -16. ,588 9. ,060 1. ,00 44. .30 A

ATOM 133 C TYR A 18 5. ,574 -12. ,472 14. ,143 1. ,00 35. 34 A

ATOM 134 0 TYR A 18 4. ,355 -12. ,610 14. 248 1. 00 36. 79 A

ATOM 135 N ILE A 19 6. 291 -11. ,760 15. 005 1. 00 34. 40 A

ATOM 136 CA ILE A 19 5. 639 -11. ,040 16. 093 1. 00 33. 05 A

ATOM 137 CB ILE A 19 6. 566 -10. ,843 17. 312 1. 00 33. 84 A

ATOM 138 CG2 ILE A 19 5. 878 -9. .967 18. 348 1. 00 34. 31 A

ATOM 139 CGI ILE A 19 6. ,922 -12. .196 17. ,930 1. ,00 34. ,10 A

ATOM 140 CDl ILE A 19 7. ,773 -12. ,087 19. ,184 1. ,00 34. ,19 A

ATOM 141 C ILE A 19 5. ,337 -9. ,679 15. ,477 1. ,00 31. 33 A

ATOM 142 0 ILE A 19 6. ,238 -8. ,857 15. ,305 1. ,00 31. 33 A

ATOM 143 N LYS A 20 4. 073 -9. ,453 15. 130 1. 00 28. 42 A

ATOM 144 CA LYS A 20 3. 661 -8. ,201 14. 503 1. 00 26. 61 A

ATOM 145 CB LYS A 20 2. 225 -8. .325 13. 994 1. 00 27. 51 A

ATOM 146 CG LYS A 20 2. 109 -8. 368 12. 479 1. 00 31. 24 A

ATOM 147 CD LYS A 20 2. 901 -9. 516 11. 874 1. 00 32. 16 A

ATOM 148 CE LYS A 20 2. 800 -9. 497 10. 354 1. 00 32. 79 A

ATOM 149 NZ LYS A 20 3. 562 -10. 603 9. 715 1. 00 33. 44 A

ATOM 150 C LYS A 20 3. 791 -6. 952 15. 370 1. 00 23. 91 A

ATOM 151 0 LYS A 20 3. 079 -5. 971 15. 161 1. 00 22. 22 A

ATOM 152 N THR A 21 4. 698 -6. 988 16. 340 1. 00 21. 76 A

ATOM 153 CA THR A 21 4. 926 -5. 835 17. 202 1. 00 21. 46 A ATOM 154 CB THR A 21 5.533 -6.248 18.557 1.00 22.18 A

ATOM 155 OGl THR A 21 6 .725 -7 .010 18 .333 1 .00 23 .59 A

ATOM 156 CG2 THR A 21 4 .541 -7 .080 19 .354 1 .00 23 .86 A

ATOM 157 C THR A 21 5 .901 -4 .911 16 .479 1 .00 20 .23 A

ATOM 158 O THR A 21 6 .485 -5 .291 15 .461 1 .00 20 .91 A

ATOM 159 N TRP A 22 6 .077 -3 .701 17 .002 1 .00 18 .22 A

ATOM 160 CA TRP A 22 6 .972 -2 .732 16 .387 1 .00 17 .94 A

ATOM 161 CB TRP A 22 6 .237 -1 .408 16 .177 1 .00 16 .92 A

ATOM 162 CG TRP A 22 5 .006 -1 .544 15 .330 1 .00 14 .97 A

ATOM 163 CD2 TRP A 22 4 .860 -1 .144 13 .961 1 .00 14 .46 A

ATOM 164 CE2 TRP A 22 3 .534 -1 .447 13 .575 1 .00 14 .69 A

ATOM 165 CE3 TRP A 22 5 .720 -0 .556 13 .025 1 .00 16 .05 A

ATOM 166 CDl TRP A 22 3 .798 -2 .064 15 .708 1 .00 14 .85 A

ATOM 167 NE1 TRP A 22 2 .908 -2 .007 14 .657 1 .00 15 .58 A

ATOM 168 CZ2 TRP A 22 3 .047 -1 .177 12 .289 1 .00 15 .29 A

ATOM 169 CZ3 TRP A 22 5 .237 -0 .289 11 .747 1 .00 15 .41 A

ATOM 170 CH2 TRP A 22 3 .911 -0 .600 11 .393 1 .00 12 .91 A

ATOM 171 C TRP A 22 8 .221 -2 .497 17 .223 1 .00 17 .89 A

ATOM 172 O TRP A 22 8 .141 -2 .331 18 .441 1. .00 20 .49 A

ATOM 173 N ARG A 23 9 .372 -2 .482 16 .558 1. .00 16 .67 A

ATOM 174 CA ARG A 23 10 .655 -2 .273 17 .223 1 .00 16 .97 A

ATOM 175 CB ARG A 23 11 .437 -3 .590 17, .301 1. .00 17, .51 A

ATOM 176 CG ARG A 23 10. .821 -4 .645 18, .187 1, .00 20, .00 A

ATOM 177 CD ARG A 23 11. .015 -4 .316 19, .653 1, .00 23, .01 A

ATOM 178 NE ARG A 23 10. .441 -5 .347 20, .508 1, .00 25, .80 A

ATOM 179 CZ ARG A 23 10. .521 -5 .347 21, .834 1, .00 27, .35 A

ATOM 180 NHl ARG A 23 11. .155 -4, .364 22. .458 1. .00 27, .10 A

ATOM 181 NH2 ARG A 23 9, .968 -6, .329 22. .533 1. .00 29, .68 A

ATOM 182 C ARG A 23 11, .503 -1, .265 16, .463 1, .00 17, .30 A

ATOM 183 O ARG A 23 11, .503 -1, .242 15. .229 1. .00 17. .22 A

ATOM 184 N PRO A 24 12. .242 -0, .417 17. .189 1. .00 15. .64 A

ATOM 185 CD PRO A 24 12. .262 -0, .248 18. .652 1. .00 18. .03 A

ATOM 186 CA PRO A 24 13. .094 0, .577 16. .536 1. .00 16. .55 A

ATOM 187 CB PRO A 24 13, .477 1, .505 17. .685 1. .00 17. .72 A

ATOM 188 CG PRO A 24 13. .501 0. .589 18. .860 1. .00 18. .48 A

ATOM 189 C PRO A 24 14. .304 -0. .108 15. .908 1. ,00 16. ,50 A

ATOM 190 O PRO A 24 14. .950 -0. .954 16. ,531 1. ,00 16. ,78 A

ATOM 191 N ARG A 25 14. .595 0. .247 14. ,663 1. ,00 14. ,35 A

ATOM 192 CA ARG A 25 15. ,728 -0. .325 13. ,958 1. ,00 14. ,93 A

ATOM 193 CB ARG A 25 15. ,253 -1. .390 12. ,966 1. ,00 15. ,06 A

ATOM 194 CG ARG A 25 14. ,603 -2. .610 13. ,606 1. ,00 16. ,19 A

ATOM 195 CD ARG A 25 15. ,641 -3, .576 14. ,165 1. ,00 18, ,26 A

ATOM 196 NE ARG A 25 15. ,024 -4. .772 14. ,737 1. ,00 18. ,64 A

ATOM 197 CZ ARG A 25 14. ,724 -4. .925 16. ,025 1. .00 18. ,22 A

ATOM 198 NHl ARG A 25 14. ,989 -3. .958 16. ,893 1. ,00 18. ,60 A

ATOM 199 NH2 ARG A 25 14. ,152 -6. ,048 16. ,444 1. ,00 19. ,77 A

ATOM 200 C ARG A 25 16. ,444 0. ,788 13. ,216 1. ,00 13. ,17 A

ATOM 201 O ARG A 25 15. ,808 1. ,690 12. ,664 1. ,00 12. ,94 A

ATOM 202 N TYR A 26 17. 771 0. ,735 13. ,213 1. ,00 11. ,30 A

ATOM 203 CA TYR A 26 18. ,546 1. ,746 12. ,518 1. ,00 12. ,99 A

ATOM 204 CB TYR A 26 19. ,847 2. ,044 13. ,262 1. 00 13. ,29 A

ATOM 205 CG TYR A 26 20. 533 3. ,270 12. 725 1. 00 13. 39 A

ATOM 206 CDl TYR A 26 20. 110 4. ,545 13. .101 1. 00 15. .13 A

ATOM 207 CEl TYR A 26 20. 680 5. ,681 12. 550 1. 00 15. 80 A

ATOM 208 CD2 TYR A 26 21. 552 3. ,163 11. 781 1. 00 15. 79 A

ATOM 209 CE2 TYR A 26 22. 132 4. ,296 11. 223 1. 00 16. 72 A

ATOM 210 CZ TYR A 26 21. 688 5. 553 11. 614 1. 00 17. 05 A

ATOM 211 OH TYR A 26 22. 247 6. 683 11. .071 1. 00 19. 83 A

ATOM 212 C TYR A 26 18. ,856 1. ,172 11. ,142 1. ,00 12. ,27 A

ATOM 213 O TYR A 26 19. ,588 0. ,189 11. ,031 1. ,00 11. ,87 A

ATOM 214 N PHE A 27 18. 288 1. ,780 10. ,105 1. ,00 10. ,77 A

ATOM 215 CA PHE A 27 18. .476 1. ,303 8. ,737 1. ,00 10. ,16 A ATOM 216 CB PHE A 27 17.126 1.196 8.018 1.00 12.33 A

ATOM 217 CG PHE A 27 16 .437 -0 .121 8 .209 1 .00 9 .11 A

ATOM 218 CDl PHE A 27 15 .705 -0 .382 9 .365 1 .00 9 .25 A

ATOM 219 CD2 PHE A 27 16 .528 -1 .109 7 .233 1 .00 10 .16 A

ATOM 220 CEl PHE A 27 15 .071 -1 .608 9 .546 1 .00 10 .54 A

ATOM 221 CE2 PHE A 27 15 .899 -2 .340 7 .406 1 .00 9 .82 A

ATOM 222 CZ PHE A 27 15 .167 -2 .590 8 .566 1 .00 9 .20 A

ATOM 223 C PHE A 27 19 .391 2 .145 7 .870 1 .00 12 .52 A

ATOM 224 O PHE A 27 19 .499 3 .358 8 .042 1 .00 11 .50 A

ATOM 225 N LEU A 28 20 .034 1 .477 6 .918 1 .00 10 .83 A

ATOM 226 CA LEU A 28 20 .909 2 .138 5, .968 1 .00 12 .08 A

ATOM 227 CB LEU A 28 22 .378 1 .799 6 .237 1 .00 14, .22 A

ATOM 228 CG LEU A 28 22 .909 2 .192 7, .615 1 .00 17. .52 A

ATOM 229 CDl LEU A 28 22 .772 1 .014 8 .560 1 .00 20 .31 A

ATOM 230 CD2 LEU A 28 24 .363 2 .615 7 .505 1 .00 19. .48 A

ATOM 231 C LEU A 28 20 .525 1. .660 4 .581 1 .00 11. .67 A

ATOM 232 O LEU A 28 20 .456 0 .456 4, .328 1 .00 11. .85 A

ATOM 233 N LEU A 29 20 .244 2. .610 3, .697 1 .00 10, .77 A

ATOM 234 CA LEU A 29 19 .884 2. .302 2, .318 1 .00 10, .20 A

ATOM 235 CB LEU A 29 18. .675 3. .134 1. .886 1, .00 10. .37 A

ATOM 236 CG LEU A 29 18 .335 3, .132 0, .392 1 .00 9, .68 A

ATOM 237 CDl LEU A 29 17 .800 1. .763 -0. .013 1 .00 12. .39 A

ATOM 238 CD2 LEU A 29 17. .292 4, .216 0. .108 1 .00 9. .96 A

ATOM 239 C LEU A 29 21, .084 2, .668 1. .458 1 .00 11. .47 A

ATOM 240 O LEU A 29 21, .567 3. .798 1. .521 1, .00 10. .47 A

ATOM 241 N LYS A 30 21, .573 1. .714 0. .670 1, .00 9. .64 A

ATOM 242 CA LYS A 30 22 .719 1, .961 -0. .204 1 .00 11. .91 A

ATOM 243 CB LYS A 30 23, .745 0. .834 -0. ,066 1. .00 13. .82 A

ATOM 244 CG LYS A 30 24, .291 0. .673 1. .342 1, .00 19. .66 A

ATOM 245 CD LYS A 30 25, .310 -0. .456 1. ,406 1, .00 22. .51 A

ATOM 246 CE LYS A 30 25. .966 -0. .515 2. ,776 1, .00 28. ,21 A

ATOM 247 NZ LYS A 30 24. .951 -0. ,650 3. ,856 1. .00 29. ,74 A

ATOM 248 C LYS A 30 22. .241 2. .072 -1. ,647 1, .00 13. ,51 A

ATOM 249 O LYS A 30 21. .168 1. .567 -1. ,991 1, .00 13. ,30 A

ATOM 250 N ASN A 31 23. .026 2. .725 -2. ,501 1. .00 14. ,38 A

ATOM 251 CA ASN A 31 22. .593 2. .899 -3. ,880 1, .00 15. ,18 A

ATOM 252 CB ASN 31 23. .430 4. .000 -4. ,536 0. .50 17. ,58

ACI

ATOM 253 CG ASN 31 22. .780 4. ,556 -5. 780 0, .50 19. ,98

ACI

ATOM 254 OD1 ASN 31 21. .607 4. ,928 -5. ,762 0. .50 21. ,01

ACI

ATOM 255 ND2 ASN 31 23. .537 4. ,624 -6. 869 0. .50 21. ,89

ACI

ATOM 256 C ASN A 31 22. .622 1. ,637 -4. 740 1. .00 14. .97 A

ATOM 257 o ASN A 31 22. .219 1. .672 -5. ,901 1, .00 16. ,56 A

ATOM 258 N ASP A 32 23. .089 0. ,522 -4. .183 1. .00 13. ,19 A

ATOM 259 CA ASP A 32 23. .101 -0. ,734 -4. 934 1, .00 14. ,24 A

ATOM 260 CB ASP A 32 24, .356 -1. ,563 -4. 609 1. .00 14. ,44 A

ATOM 261 CG ASP A 32 24, .368 -2. ,099 -3. 188 1. .00 16. ,95 A

ATOM 262 ODl ASP A 32 23. ,598 -1. ,609 -2. 340 1. .00 13. ,75 A

ATOM 263 OD2 ASP A 32 25. .170 -3. ,016 -2. 915 1. .00 21. ,64 A

ATOM 264 C ASP A 32 21. .827 -1. ,518 -4. 600 1. .00 13. ,77 A

ATOM 265 O ASP A 32 21. .618 -2. ,628 -5. 088 1. .00 13. ,00 A

ATOM 266 N GLY A 33 20. ,976 -0. ,925 -3. 767 1. ,00 10. ,97 A

ATOM 267 CA GLY A 33 19. ,729 -1. 571 -3. 390 1. .00 10. 81 A

ATOM 268 C GLY A 33 19. ,729 -2. 177 -2. 001 1. .00 9. 76 A

ATOM 269 O GLY A 33 18. ,677 -2. 544 -1. 470 1. .00 10. 50 A

ATOM 270 N THR A 34 20, .911 -2. ,275 -1. 403 1. .00 10. ,25 A

ATOM 271 CA THR A 34 21, ,039 -2. ,842 -0. 070 1. .00 10. ,58 A

ATOM 272 CB THR A 34 22. ,519 -2. 895 0. 371 1. .00 12. 03 A

ATOM 273 OGl THR A 34 23. ,259 -3. 717 -0. 536 1. .00 15. 74 A ATOM 274 CG2 THR A 34 22.642 -3.464 1.782 1.00 14.43 A

ATOM 275 C THR A 34 20 .262 -2 .047 0 .976 1 .00 9 .98 A

ATOM 276 O THR A 34 20 .406 -0 .831 1 .077 1 .00 12 .46 A

ATOM 277 N PHE A 35 19 .418 -2 .734 1 .736 1 .00 10 .82 A

ATOM 278 CA PHE A 35 18 .661 -2 .086 2 .804 1 .00 9 .78 A

ATOM 279 CB PHE A 35 17 .174 -2 .005 2 .448 1 .00 10 .52 A

ATOM 280 CG PHE A 35 16 .401 -0 .995 3 .267 1 .00 11 .75 A

ATOM 281 CDl PHE A 35 16 .954 0 .249 3 .564 1 .00 13 .74 A

ATOM 282 CD2 PHE A 35 15 .113 -1 .275 3 .707 1 .00 12 .52 A

ATOM 283 CEl PHE A 35 16 .225 1 .202 4 .287 1 .00 14 .09 A

ATOM 284 CE2 PHE A 35 14 .380 -0 .334 4 .427 1 .00 14 .43 A

ATOM 285 CZ PHE A 35 14 .938 0 .906 .715 1 .00 12 .70 A

ATOM 286 C PHE A 35 18 .909 -2 .977 4, .017 1 .00 11, .64 A

ATOM 287 O PHE A 35 18 .388 -4 .085 4 .111 1 .00 11 .27 A

ATOM 288 N ILE A 36 19 .722 -2 .476 4 .939 1 .00 9, .95 A

ATOM 289 CA ILE A 36 20 .113 -3 .239 6 .112 1 .00 11, .31 A

ATOM 290 CB ILE 36 21 .640 -3 .493 6, .044 0 .50 12, .00

ACI

ATOM 291 CG2 ILE 36 22 .394 -2 .172 6, .145 0 .50 12, .75

ACI

ATOM 292 CGI ILE 36 22, .075 -4 .454 7, .140 0. .50 11, .83

ACI

ATOM 293 CDl ILE 36 23, .506 -4, .911 6. .981 0, .50 15. .13

ACI

ATOM 294 C ILE A 36 19, .730 -2, .535 7. .417 1 .00 12, .09 A

ATOM 295 O ILE A 36 19, .940 -1, .332 7. .569 1, .00 10. .89 A

ATOM 296 N GLY A 37 19, .157 -3, .295 8. .347 1, .00 10. .87 A

ATOM 297 CA GLY A 37 18. .726 -2. .722 9. .612 1, .00 12. .52 A

ATOM 298 C GLY A 37 19, .350 -3. .377 10. .827 1, .00 12. .45 A

ATOM 299 0 GLY A 37 19. .480 -4. .600 10. .891 1, .00 12. .09 A

ATOM 300 N TYR A 38 19. .710 -2. .545 11. ,799 1. .00 13. .90 A

ATOM 301 CA TYR A 38 20. ,345 -2. .998 13. ,031 1. .00 14. .75 A

ATOM 302 CB TYR A 38 21. ,747 -2. .405 13. ,144 1. .00 14. .39 A

ATOM 303 CG TYR A 38 22. .682 -2. .738 12, ,009 1. .00 16. .33 A

ATOM 304 CDl TYR A 38 22. .619 -2. .049 10. ,797 1. .00 16. .73 A

ATOM 305 CEl TYR A 38 23. .508 -2. .334 9. ,763 1. .00 19. .46 A

ATOM 306 CD2 TYR A 38 23. .652 -3, .723 12. ,157 1. .00 17. ,24 A

ATOM 307 CE2 TYR A 38 24. ,540 -4. .017 11. ,136 1. .00 19. ,86 A

ATOM 308 CZ TYR A 38 24. .466 -3. .318 9. ,943 1. .00 20. .31 A

ATOM 309 OH TYR A 38 25. .361 -3. .600 8. ,943 1, .00 22. .67 A

ATOM 310 C TYR A 38 19. .570 -2. .601 14. ,284 1. .00 15. .44 A

ATOM 311 O TYR A 38 18. .801 -1. .637 14. ,284 1, .00 15. ,40 A

ATOM 312 N LYS A 39 19. .800 -3. .348 15. .358 1, .00 15. ,58 A

ATOM 313 CA LYS A 39 19. .161 -3. .083 16. .638 1. .00 17. .49 A

ATOM 314 CB LYS A 39 19. .466 -4. .225 17. .610 1, .00 19. .29 A

ATOM 315 CG LYS A 39 18, .796 -4. .106 18. .965 1, .00 21, .76 A

ATOM 316 CD LYS A 39 19. ,159 -5. .294 19. ,844 1. .00 26. ,52 A

ATOM 317 CE LYS A 39 18. ,477 -5. ,211 21. 198 1. .00 30. ,06 A

ATOM 318 NZ LYS A 39 18. .843 -3. .969 21. ,931 1, .00 32. .76 A

ATOM 319 C LYS A 39 19. .735 -1. .774 17. ,172 1. .00 18. .21 A

ATOM 320 O LYS A 39 19. .031 -0. .961 17. ,769 1. .00 18. .12 A

ATOM 321 N GLU A 40 21. .028 -1. ,580 16. ,942 1. .00 20. ,94 A

ATOM 322 CA GLU A 40 21. ,716 -0. ,376 17. 382 1. .00 24. ,43 A

ATOM 323 CB GLU A 40 22. .671 -0. .712 18. ,530 1. .00 26. .21 A

ATOM 324 CG GLU A 40 21. ,994 -1. .304 19. ,756 1. .00 29. .96 A

ATOM 325 CD GLU A 40 21. ,147 -0. ,291 20. 504 1. .00 33. ,10 A

ATOM 326 OEl GLU A 40 20. ,464 -0. ,685 21. 473 1. .00 34. ,92 A

ATOM 327 OE2 GLU A 40 21. ,170 0. ,900 20. 128 1. ,00 35. ,42 A

ATOM 328 C GLU A 40 22, ,503 0. ,227 16. ,224 1. .00 26. ,23 A

ATOM 329 0 GLU A 40 22. ,862 -0. ,469 15. 273 1. ,00 23. ,96 A

ATOM 330 N ARG A 41 22, ,765 1. ,526 16. 304 1. ,00 27. ,72 A

ATOM 331 CA ARG A 41 23. ,528 2. ,210 15. 269 1. ,00 32. ,25 A ATOM 332 CB ARG A 41 23.695 3.677 15.655 1.00 32.48 A

ATOM 333 CG ARG A 41 24 .088 4 .597 14 .522 1 .00 34 .71 A

ATOM 334 CD ARG A 41 23 .639 6 .013 14 .842 1 .00 34 .79 A

ATOM 335 NE ARG A 41 23 .994 6 .967 13 .799 1 .00 34 .58 A

ATOM 336 CZ ARG A 41 23 .545 8 .217 13 .758 1 .00 34 .58 A

ATOM 337 NHl ARG A 41 22 .723 8 .653 14 .703 1 .00 33 .47 A

ATOM 338 NH2 ARG A 41 23 .919 9 .030 12 .779 1 .00 34 .95 A

ATOM 339 C ARG A 41 24 .892 1 .516 15 .142 1 .00 34 .15 A

ATOM 340 O ARG A 41 25 .620 1 .380 16 .126 1 .00 34 .09 A

ATOM 341 N PRO A 42 25 .246 1 .063 13 .925 1 .00 36 .46 A

ATOM 342 CD PRO A 42 24 .434 1 .269 12 .712 1 .00 36 .86 A

ATOM 343 CA PRO A 42 26 .497 0, .366 13, .590 1 .00 38 .85 A

ATOM 344 CB PRO A 42 26 .501 0, .393 12, .064 1 .00 38, .38 A

ATOM 345 CG PRO A 42 25 .054 0 .295 11 .738 1 .00 37 .91 A

ATOM 346 C PRO A 42 27 .794 0. .928 14. .175 1 .00 41 .91 A

ATOM 347 O PRO A 42 27 .869 2, .096 14, .556 1 .00 42 .10 A

ATOM 348 N GLN A 43 28 .812 0, .071 14, .235 1 .00 45, .16 A

ATOM 349 CA GLN A 43 30. .129 0, .439 14, .753 1. .00 48, .46 A

ATOM 350 CB GLN A 43 30, .498 -0. .447 15, .945 1 .00 49, .32 A

ATOM 351 CG GLN A 43 29 .654 -0. .188 17. .180 1 .00 50 .59 A

ATOM 352 CD GLN A 43 29, .819 1. .224 17, .705 1 .00 51, .58 A

ATOM 353 OEl GLN A 43 30, .914 1, .627 18, .096 1. .00 52, .44 A

ATOM 354 NE2 GLN A 43 28, .731 1, .984 17, .715 1 .00 52, .12 A

ATOM 355 C GLN A 43 31. .188 0. .308 13. .661 1 .00 49, .94 A

ATOM 356 O GLN A 43 30, .915 -0. .226 12. .584 1, .00 50, .98 A

ATOM 357 N ASP A 44 32. .398 0. .783 13. .945 1, .00 51. .42 A

ATOM 358 CA ASP A 44 33, .483 0. .744 12, .966 1 .00 53, .08 A

ATOM 359 CB ASP A 44 34, .169 2. .113 12. .907 1, .00 52, .84 A

ATOM 360 CG ASP A 44 33. .249 3. .203 12. .387 1, .00 53. .74 A

ATOM 361 ODl ASP A 44 32. .785 3. .088 11. .232 1, .00 53. .84 A

ATOM 362 OD2 ASP A 44 32. .989 4, .172 13. .130 1, .00 53. .96 A

ATOM 363 C ASP A 44 34. .537 -0. ,342 13. ,170 1, .00 53. .79 A

ATOM 364 O ASP A 44 35. .727 -0, .046 13. .294 1, .00 54. .33 A

ATOM 365 N VAL A 45 34. .108 -1, .600 13. .190 1, .00 54. .43 A

ATOM 366 CA VAL A 45 35. .037 -2. .714 13. .359 1, .00 55. .18 A

ATOM 367 CB VAL A 45 35. .271 -3. ,052 14. .850 1, .00 55. .09 A

ATOM 368 CGI VAL A 45 36. .483 -3. ,961 14. ,981 1. .00 54. ,96 A

ATOM 369 CG2 VAL A 45 35. ,458 -1. ,787 15. ,666 1. .00 55. ,18 A

ATOM 370 C VAL A 45 34. ,487 -3. ,967 12. ,686 1, ,00 55. ,67 A

ATOM 371 O VAL A 45 33. .281 -4. .080 12. ,467 1, .00 56, ,61 A

ATOM 372 N ASP A 46 35. .368 -4. .909 12. ,360 1. .00 56, ,16 A

ATOM 373 CA ASP A 46 34. .942 -6. .157 11. ,732 1, .00 56. ,20 A

ATOM 374 CB ASP A 46 36. .157 -6. ,997 11. ,337 1. .00 57. ,06 A

ATOM 375 CG ASP A 46 37. ,109 -6. ,252 10. ,420 1, .00 58. ,07 A

ATOM 376 ODl ASP A 46 36. ,677 -5. 814 9. 331 1, .00 58. ,38 A

ATOM 377 OD2 ASP A 46 38. .294 -6. ,109 10. ,792 1, .00 57. ,97 A

ATOM 378 C ASP A 46 34. .096 -6. ,919 12. ,747 1. .00 55. ,71 A

ATOM 379 O ASP A 46 33. .522 -7. ,970 12. .451 1. .00 55. ,74 A

ATOM 380 N GLN A 47 34. .032 -6. ,362 13. .951 1. .00 54. .98 A

ATOM 381 CA GLN A 47 33. .275 -6. ,938 15. .051 1. .00 53. ,88 A

ATOM 382 CB GLN A 47 33. ,698 -6. 286 16. 367 1. .00 54. 61 A

ATOM 383 CG GLN A 47 35. .168 -6. ,411 16. ,716 1. .00 55. ,81 A

ATOM 384 CD GLN A 47 35. .620 -5. ,298 17. ,648 1. .00 56. ,61 A

ATOM 385 OEl GLN A 47 36. ,756 -5. ,288 18. ,121 1. .00 56. ,37 A

ATOM 386 NE2 GLN A 47 34. ,728 -4. ,346 17. ,906 1, .00 56. ,56 A

ATOM 387 C GLN A 47 31. ,772 -6. ,738 14. 881 1. ,00 52. 50 A

ATOM 388 O GLN A 47 31. ,011 -7. 704 14. 833 1. ,00 52. 81 A

ATOM 389 N ARG A 48 31. ,365 -5. 472 14. 798 1. ,00 50. 74 A

ATOM 390 CA ARG A 48 29. .961 -5. ,087 14. ,677 1. .00 48. ,01 A

ATOM 391 CB ARG A 48 29. ,779 -4. ,003 13. .607 1. .00 49. ,27 A

ATOM 392 CG ARG A 48 30. ,067 -4. .416 12. 175 1. ,00 50. 55 A

ATOM 393 CD ARG A 48 29. ,442 -3. 394 11. 233 1. ,00 51. 74 A ATOM 394 NE ARG A 48 29.760 -3.628 9.828 1.00 53.05 A

ATOM 395 CZ ARG A 48 30 .931 -3 .341 9 .269 1 .00 53 .73 A

ATOM 396 NHl ARG A 48 31 .903 -2 .804 9 .996 1 .00 53 .90 A

ATOM 397 NH2 ARG A 48 31 .129 -3 .589 7 .981 1 .00 53 .98 A

ATOM 398 C ARG A 48 28 .971 -6 .215 14 .425 1 .00 45 .29 A

ATOM 399 O ARG A 48 29 .077 -6 .962 13 .450 1 .00 44 .38 A

ATOM 400 N GLU A 49 28 .003 -6 .320 15 .328 1 .00 42 .28 A

ATOM 401 CA GLU A 49 26 .961 -7 .333 15 .261 1 .00 39 .30 A

ATOM 402 CB GLU A 49 25 .887 -7 .034 16 .308 1 .00 42 .13 A

ATOM 403 CG GLU A 49 25 .522 -8 .206 17 .199 1 .00 45 .09 A

ATOM 404 CD GLU A 49 24 .516 -7 .822 18 .266 1 .00 47 .52 A

ATOM 405 OEl GLU A 49 24 .812 -6 .909 19 .065 1 .00 48 .91 A

ATOM 406 OE2 GLU A 49 23 .427 -8 .432 18 .306 1 .00 49 .59 A

ATOM 407 C GLU A 49 26 .321 -7 .370 13 .881 1 .00 35 .69 A

ATOM 408 O GLU A 49 26 .307 -6 .372 13 .157 1 .00 34 .83 A

ATOM 409 N ALA A 50 25 .796 -8 .531 13 .517 1 .00 31 .38 A

ATOM 410 CA ALA A 50 25 .145 -8 .686 12 .232 1 .00 27 .38 A

ATOM 411 CB ALA A 50 24 .902 -10, .161 11, .947 1 .00 28 .11 A

ATOM 412 C ALA A 50 23, .822 -7, .931 12, .287 1 .00 24 .03 A

ATOM 413 O ALA A 50 23, .281 -7, .680 13, .363 1 .00 22, .60 A

ATOM 414 N PRO A 51 23, .291 -7. .536 11, .125 1 .00 22, .20 A

ATOM 415 CD PRO A 51 23, .813 -7. .671 9. .755 1, .00 21, .74 A

ATOM 416 CA PRO A 51 22, .021 -6. .814 11. .131 1, .00 20, .00 A

ATOM 417 CB PRO A 51 21. .961 -6. .231 9. .730 1, .00 19, .01 A

ATOM 418 CG PRO A 51 22. .599 -7. .326 8. .918 1 .00 21, .14 A

ATOM 419 C PRO A 51 20, .887 -7. .790 11, .384 1 .00 18, .93 A

ATOM 420 O PRO A 51 21, .047 -8. .999 11. .188 1, .00 20, .80 A

ATOM 421 N LEU A 52 19. .745 -7. .269 11. .821 1, .00 17, .81 A

ATOM 422 CA LEU A 52 18. .574 -8. .098 12. .078 1, .00 18, .34 A

ATOM 423 CB LEU A 52 17. ,746 -7. .495 13. .214 1, .00 19. .42 A

ATOM 424 CG LEU A 52 18. .501 -7. .289 14. .531 1, .00 22. .82 A

ATOM 425 CDl LEU A 52 17. .599 -6. .596 15. .542 1. .00 22. .31 A

ATOM 426 CD2 LEU A 52 18. .979 -8. ,631 15. .055 1, .00 23. .43 A

ATOM 427 C LEU A 52 17. .733 -8. ,187 10. ,808 1. .00 18. .39 A

ATOM 428 O LEU A 52 16. ,921 -9. ,100 10. ,650 1. .00 19. ,70 A

ATOM 429 N ASN A 53 17. ,941 -7. ,230 9. ,905 1. .00 16. ,89 A

ATOM 430 CA ASN A 53 17. ,222 -7. ,175 8. ,643 1. .00 15. ,85 A

ATOM 431 CB ASN A 53 16. ,164 -6. ,069 8. ,696 1. .00 20. ,09 A

ATOM 432 CG ASN A 53 15. ,590 -5. ,884 10. ,091 1. .00 24. ,54 A

ATOM 433 ODl ASN A 53 16. ,123 -5. ,120 10. 899 1. .00 28. ,78 A

ATOM 434 ND2 ASN A 53 14. ,514 -6. 598 10. 389 1. .00 25. ,27 A

ATOM 435 C ASN A 53 18. 235 -6. 893 7. 533 1. .00 13. .09 A

ATOM 436 O ASN A 53 19. 147 -6. 085 7. 698 1. ,00 10. 99 A

ATOM 437 N ASN A 54 18. 073 -7. 561 6. 399 1. ,00 13. 37 A

ATOM 438 CA ASN A 54 19. 007 -7. 393 5. 294 1. ,00 12. 57 A

ATOM 439 CB ASN A 54 20. 246 -8. 253 5. 571 1. ,00 13. 00 A

ATOM 440 CG ASN A 54 21. .351 -8. ,070 4. 540 1. ,00 11. ,75 A

ATOM 441 ODl ASN A 54 21. 296 -7. .189 3. 683 1. .00 11. ,78 A

ATOM 442 ND2 ASN A 54 22. 378 -8. 909 4. 637 1. ,00 14. 42 A

ATOM 443 C ASN A 54 18. 317 -7. 839 4. 018 1. ,00 13. 21 A

ATOM 444 O ASN A 54 18. 123 -9. 032 3. 798 1. ,00 13. 02 A

ATOM 445 N PHE A 55 17. 921 -6. 881 3. 186 1. ,00 11. 96 A

ATOM 446 CA PHE A 55 17. 241 -7. 229 1. 950 1. ,00 11. 70 A

ATOM 447 CB PHE A 55 15. 760 -7. 546 2. 227 1. ,00 13. 37 A

ATOM 448 CG PHE A 55 14. 957 -6. 372 2. 734 1. ,00 12. 93 A

ATOM 449 CDl PHE A 55 14. 214 -5. 585 1. 854 1. ,00 14. 55 A

ATOM 450 CD2 PHE A 55 14. 928 -6. 068 4. 093 1. ,00 15. 27 A

ATOM 451 CEl PHE A 55 13. 454 -4. 511 2. 322 1. 00 15. 01 A

ATOM 452 CE2 PHE A 55 14. 171 -4. 994 4. 574 1. 00 15. 09 A

ATOM 453 CZ PHE A 55 13. 431 -4. 215 3. 683 1. 00 15. 58 A

ATOM 454 C PHE A 55 17. 360 -6. 147 0. 893 1. 00 12. 59 A

ATOM 455 O PHE A 55 17. 440 -4. 954 1. 202 1. 00 14. 95 A ATOM 456 N SER A 56 17.378 -6.579 -0.360 1.00 11.55 A

ATOM 457 CA SER A 56 17 .487 -5.672 -1 .487 1 .00 11 .99 A

ATOM 458 CB SER A 56 18 .056 -6.404 -2 .698 1 .00 11 .54 A

ATOM 459 OG SER A 56 18 .012 -5.577 -3 .842 1 .00 13 .78 A

ATOM 460 C SER A 56 16 .126 -5.108 -1 .858 1 .00 12 .60 A

ATOM 461 O SER A 56 15 .135 -5.837 -1 .870 1 .00 11 .81 A

ATOM 462 N VAL A 57 16 .089 -3.812 -2 .156 1 .00 10 .78 A

ATOM 463 CA VAL A 57 14 .851 -3.152 -2 .563 1 .00 12 .24 A

ATOM 464 CB VAL A 57 14 .795 -1.682 -2 .083 1 .00 11 .22 A

ATOM 465 CGI VAL A 57 14 .818 -1.631 -0. .564 1 .00 12 .09 A

ATOM 466 CG2 VAL A 57 15 .956 -0.880 -2, .679 1 .00 13 .55 A

ATOM 467 C VAL A 57 14 .699 -3.170 -4, .083 1 .00 13 .22 A

ATOM 468 O VAL A 57 13 .726 -2.647 -4, .626 1 .00 13 .51 A

ATOM 469 N ALA A 58 15 .661 -3.772 -4 .773 1 .00 13 .74 A

ATOM 470 CA ALA A 58 15 .602 -3.842 -6 .227 1 .00 15 .17 A

ATOM 471 CB ALA A 58 16 .843 -4.553 -6. .769 1 .00 17 .19 A

ATOM 472 C ALA A 58 14 .337 -4.599 -6. .630 1 .00 15 .57 A

ATOM 473 O ALA A 58 14 .004 -5.621 -6. .037 1 .00 18 .17 A

ATOM 474 N GLN A 59 13 .624 -4.080 -7. .622 1. .00 18 .77 A

ATOM 475 CA GLN A 59 12 .403 -4.725 -8, .102 1, .00 20, .01 A

ATOM 476 CB GLN A 59 12 .701 -6.165 -8, .525 1, .00 25, .04 A

ATOM 477 CG GLN A 59 13 .752 -6.306 -9, .613 1, .00 28, .93 A

ATOM 478 CD GLN A 59 14 .080 -7.758 -9. .906 1, .00 31, .44 A

ATOM 479 OEl GLN A 59 13, .202 -8.545 -10. .263 1. .00 33. .64 A

ATOM 480 NE2 GLN A 59 15, .349 -8.121 -9. .752 1. .00 34. .46 A

ATOM 481 C GLN A 59 11, .249 -4.745 -7. .099 1. .00 20. .79 A

ATOM 482 O GLN A 59 10, .266 -5.455 -7. .304 1. .00 20. .58 A

ATOM 483 N CYS A 60 11, .353 -3.984 -6. ,015 1. .00 18. ,64 A

ATOM 484 CA CYS A 60 10, .270 -3.980 -5. .040 1. .00 17. .53 A

ATOM 485 C CYS A 60 9, .309 -2.815 -5. .271 1. .00 15. .76 A

ATOM 486 O CYS A 60 9, .624 -1.860 -5. ,989 1. .00 17, .53 A

ATOM 487 CB CYS A 60 10, .832 -3.944 -3. ,617 1. .05 20. .77 A

ATOM 488 SG CYS A 60 12, .045 -5.266 -3. ,268 1. .05 24. .17 A

ATOM 489 N GLN A 61 8. .133 -2.921 -4. ,665 1. ,00 13. ,16 A

ATOM 490 CA GLN A 61 7. .078 -1.920 -4. ,783 1. ,00 12. ,89 A

ATOM 491 CB GLN A 61 5. .785 -2.611 -5. 220 1. ,00 14. ,47 A

ATOM 492 CG GLN A 61 4. .529 -1.762 -5. ,160 1. ,00 15. ,33 A

ATOM 493 CD GLN A 61 3. .290 -2.568 -5. .520 1. ,00 16. ,17 A

ATOM 494 OEl GLN A 61 3. .132 -3.707 -5. 081 1. ,00 18. ,30 A

ATOM 495 NE2 GLN A 61 2. .405 -1.977 -6. 312 1. ,00 16. ,93 A

ATOM 496 C GLN A 61 6. .861 -1.219 -3. 449 1. .00 12. .69 A

ATOM 497 O GLN A 61 6. .935 -1.848 -2. 399 1. .00 13. .22 A

ATOM 498 N LEU A 62 6. .592 0.084 -3. 498 1. 00 11. .41 A

ATOM 499 CA LEU A 62 6. .350 0.859 -2. ,285 1. ,00 11. .95 A

ATOM 500 CB LEU A 62 7, .125 2.175 -2. ,320 1. ,00 12. .82 A

ATOM 501 CG LEU A 62 8. .627 2.111 -2. ,090 1. ,00 14. ,28 A

ATOM 502 CDl LEU A 62 9, .239 3.469 -2. 328 1. ,00 14. ,57 A

ATOM 503 CD2 LEU A 62 8. .886 1.660 -0. 658 1. ,00 18. ,43 A

ATOM 504 C LEU A 62 4, .879 1.184 -2. 127 1. ,00 11. ,65 A

ATOM 505 O LEU A 62 4. ,244 1.686 -3. 056 1. 00 13. .64 A

ATOM 506 N MET A 63 4. ,338 0.900 -0. 950 1. 00 11. 62 A

ATOM 507 CA MET A 63 2. ,942 1.208 -0. 681 1. 00 12. 35 A

ATOM 508 CB MET A 63 2. ,135 -0.077 -0. 512 1. 00 14. 82 A

ATOM 509 CG MET A 63 2. ,199 -1.009 -1. 713 1. 00 19. 65 A

ATOM 510 SD MET A 63 1. ,082 -2.405 -1. 511 1. 00 25. 36 A

ATOM 511 CE MET A 63 1. ,934 -3.320 -0. 254 1. 00 21. 42 A

ATOM 512 C MET A 63 2. ,877 2.036 0. 593 1. 00 12. 87 A

ATOM 513 O MET A 63 3. ,731 1.898 1. 474 1. 00 13. 39 A

ATOM 514 N LYS A 64 1, .888 2.921 0. ,671 1. 00 11. ,25 A

ATOM 515 CA LYS A 64 1. .699 3.755 1. 852 1. 00 10. 73 A

ATOM 516 CB LYS A 64 1. .703 5.241 1. 481 1. 00 10. 38 A

ATOM 517 CG LYS A 64 3. .036 5.765 0. 982 1. 00 14. 35 A ATOM 518 CD LYS A 64 2.895 7.203 0.510 1.00 16.37 A

ATOM 519 CE LYS A 64 4 .226 7 .773 0 .056 1 .00 21 .62 A

ATOM 520 NZ LYS A 64 4 .070 9 .190 -0 381 1 .00 24 .38 A

ATOM 521 C LYS A 64 0 .359 3 .403 2 .478 1 .00 9 .79 A

ATOM 522 O LYS A 64 0 .611 3 .128 1 769 1 .00 10 .92 A

ATOM 523 N THR A 65 0 .303 3 .394 3 806 1 .00 9 .52 A

ATOM 524 CA THR A 65 0 .940 3 .094 4 497 1 .00 10 .30 A

ATOM 525 CB THR A 65 1 .088 1 578 4 762 1 .00 10 85 A

ATOM 526 OGl THR A 65 2 .412 1 309 5 239 1 00 13 81 A

ATOM 527 CG2 THR A 65 0 .062 1 097 5 784 1 .00 10 51 A

ATOM 528 C THR A 65 0 977 3 876 5 806 1 00 9 99 A

ATOM 529 O THR A 65 0 053 4 383 6 251 1 00 9 34 A

ATOM 530 N GLU A 66 2 165 3 985 6 397 1 00 9 71 A

ATOM 531 CA GLU A 66 2 349 4 726 7 639 1 00 9 59 A

ATOM 532 CB GLU A 66 3 .333 5 885 7 428 1 00 10 68 A

ATOM 533 CG GLU A 66 3 .028 6 801 6 250 1 00 11 77 A

ATOM 534 CD GLU A 66 1 635 7 387 6 307 1 00 11 57 A

ATOM 535 OEl GLU A 66 1 242 7 890 7 386 1 00 15 29 A

ATOM 536 OE2 GLU A 66 0 942 7 352 5 269 1 00 14 44 A

ATOM 537 C GLU A 66 2 872 3 861 8 782 1 00 10 84 A

ATOM 538 O GLU A 66 3 094 4 363 9 885 1 00 12 25 A

ATOM 539 N ARG A 67 3 082 2 573 8 528 1 00 9 80 A

ATOM 540 CA ARG A 67 3 593 1 683 9 572 1 00 12 02 A

ATOM 541 CB ARG A 67 5 057 1 323 9 295 1 00 12 34 A

ATOM 542 CG ARG A 67 5 985 2 529 9 165 1 00 13 20 A

ATOM 543 CD ARG A 67 6 030 3 349 10 448 1 00 14 65 A

ATOM 544 NE ARG A 67 6 863 4 540 10 290 1 00 16 90 A

ATOM 545 CZ ARG A 67 8 191 4 532 10 265 1 00 16 21 A

ATOM 546 NHl ARG A 67 8 858 3 393 10 394 1 00 19 02 A

ATOM 547 NH2 ARG A 67 8 855 5 667 10 107 1 00 16 39 A

ATOM 548 C ARG A 67 2 773 0 403 9 673 1 00 12 87 A

ATOM 549 O ARG A 67 2 370 -0 159 8 658 1 00 12 43 A

ATOM 550 N PRO A 68 2 536 -0 083 10 908 1 00 14 81 A

ATOM 551 CD PRO A 68 1 873 -1 372 11 168 1 00 14 62 A

ATOM 552 CA PRO A 68 3 002 0 519 12 162 1 00 14 23 A

ATOM 553 CB PRO A 68 2 814 -0 612 13 172 1 00 16 22 A

ATOM 554 CG PRO A 68 1 604 -1 305 12 661 1 00 14 84 A

ATOM 555 C PRO A 68 2 266 1 796 12 576 1 00 14 75 A

ATOM 556 O PRO A 68 2 772 2 571 13 389 1 00 14 52 A

ATOM 557 N ARG A 69 1 081 2 020 12 019 1 00 12 35 A

ATOM 558 CA ARG A 69 0 311 3 214 12 367 1 00 12 41 A

ATOM 559 CB ARG A 69 1 106 2 836 12 805 1 00 11 02 A

ATOM 560 CG ARG A 69 1 167 1 762 13 869 1 00 10 76 A

ATOM 561 CD ARG A 69 2 575 1 610 14 416 1 00 10 45 A

ATOM 562 NE ARG A 69 2 929 2 732 15 279 1 00 15 03 A

ATOM 563 CZ ARG A 69 4 061 2 815 15 972 1 00 16 61 A

ATOM 564 NHl ARG A 69 4 959 1 838 15 903 1 00 16 34 A

ATOM 565 NH2 ARG A 69 4 285 3 870 16 746 1 00 15 68 A

ATOM 566 C ARG A 69 0 211 4 210 11 218 1 00 12 12 A

ATOM 567 O ARG A 69 0 046 3 834 10 073 1 00 12 64 A

ATOM 568 N PRO A 70 0 406 5 504 11 509 1 00 13 61 A

ATOM 569 CD PRO A 70 0 649 6 167 12 801 1 00 16 07 A

ATOM 570 CA PRO A 70 0 306 6 484 10 429 1 00 13 65 A

ATOM 571 CB PRO A 70 0 731 7 784 11 103 1 00 15 68 A

ATOM 572 CG PRO A 70 0 244 7 598 12 501 1 00 18 48 A

ATOM 573 C PRO A 70 1 140 6 543 9 944 1 00 12 21 A

ATOM 574 O PRO A 70 2 054 6 089 ^O 634 1 00 12 18 A

ATOM 575 N ASN A 71 1 341 7 082 8 751 1 00 10 74 A

ATOM 576 CA ASN A 71 2 685 7 228 8 210 1 00 10 53 A

ATOM 577 CB ASN A 71 3 475 8 217 9 064 1 00 12 35 A

ATOM 578 CG ASN A 71 2 745 9 521 9 241 1 00 13 72 A

ATOM 579 ODl ASN A 71 2 300 10 130 8 267 1 00 15 41 A ATOM 580 ND2 ASN A 71 2.616 9.964 10.487 1.00 16.26 A

ATOM 581 C ASN A 71 3 .445 5. .921 8 .103 1 .00 11 .94 A

ATOM 582 O ASN A 71 4 .636 5, .840 8 .414 1 .00 11 .12 A

ATOM 583 N THR A 72 2 .743 4 .896 7 .650 1 .00 10 .34 A

ATOM 584 CA THR A 72 3. .351 3 .595 7. .474 1 .00 10 .17 A

ATOM 585 CB THR A 72 2 .378 2 .481 7. .933 1 .00 10 .71 A

ATOM 586 OGl THR A 72 2 .185 2 .575 9, .349 1 .00 11 .47 A

ATOM 587 CG2 THR A 72 2 .920 1 .097 7, .580 1 .00 9 .71 A

ATOM 588 C THR A 72 3 .677 3, .408 5, .997 1 .00 10 .82 A

ATOM 589 O THR A 72 2 .941 3 .880 5, .122 1 .00 9 .57 A

ATOM 590 N PHE A 73 4 .811 2, .781 5, .716 1 .00 8 .12 A

ATOM 591 CA PHE A 73 5. .152 2, .487 4, .335 1 .00 9 .45 A

ATOM 592 CB PHE A 73 6. .190 3, .472 3, .764 1 .00 11 .83 A

ATOM 593 CG PHE A 73 7, .545 3. .414 4. .406 1 .00 12 .20 A

ATOM 594 CDl PHE A 73 8, .558 2, .630 3, .859 1 .00 12 .58 A

ATOM 595 CD2 PHE A 73 7, .838 4, .215 5. .508 1 .00 11 .47 A

ATOM 596 CEl PHE A 73 9. .847 2, .651 4. .396 1 .00 13 .52 A

ATOM 597 CE2 PHE A 73 9, .127 4, .241 6. .052 1 .00 13 .10 A

ATOM 598 CZ PHE A 73 10, .129 3. .461 5. .494 1, .00 12 .71 A

ATOM 599 C PHE A 73 5, .602 1. .033 4, .282 1. .00 10. .51 A

ATOM 600 O PHE A 73 6, .209 0. .511 5. .221 1, .00 9, .91 A

ATOM 601 N ILE A 74 5. .245 0. .371 3. .193 1. .00 9, .56 A

ATOM 602 CA ILE A 74 5. .540 -1, .038 3. .016 1. .00 9, .56 A

ATOM 603 CB ILE A 74 4. .223 -1. .842 2. .910 1. .00 10, .21 A

ATOM 604 CG2 ILE A 74 4. .518 -3. .296 2. .555 1, .00 9, .66 A

ATOM 605 CGI ILE A 74 3. .438 -1. .727 4. .220 1. .00 11. .83 A

ATOM 606 CDl ILE A 74 1. .974 -2. .113 4. .086 1. .00 14. .73 A

ATOM 607 C ILE A 74 6. .352 -1. .273 1. .759 1. .00 10. .35 A

ATOM 608 O ILE A 74 6. .077 -0. .685 0. ,710 1. .00 10. .22 A

ATOM 609 N ILE A 75 7. .369 -2. .118 1. ,882 1. .00 9. .61 A

ATOM 610 CA ILE A 75 8. .208 -2, .476 0. ,750 1. .00 10. .63 A

ATOM 611 CB ILE A 75 9. .705 -2. .408 1. ,099 1. .00 10. .23 A

ATOM 612 CG2 ILE A 75 10. ,541 -2. .699 -0. ,152 1. .00 11. .74 A

ATOM 613 CGI ILE A 75 10. ,041 -1. .027 1. ,669 1, ,00 11. .39 A

ATOM 614 CDl ILE A 75 11. ,502 -0. .859 2. ,073 1. ,00 11. .40 A

ATOM 615 C ILE A 75 7. ,821 -3. ,910 0. ,443 1, .00 11. .45 A

ATOM 616 O ILE A 75 7. ,980 -4. ,799 1. ,281 1, .00 11. .89 A

ATOM 617 N ARG A 76 7. ,286 -4. ,125 -0. 754 1. .00 11. .69 A

ATOM 618 CA ARG A 76 6. ,842 -5. ,448 -1. .167 1. .00 14. .45 A

ATOM 619 CB ARG A 76 5. ,351 -5. ,405 -1. 532 1, .00 17. .53 A

ATOM 620 CG ARG A 76 4. ,821 -6. ,684 -2. 161 1, .00 21. .84 A

ATOM 621 CD ARG A 76 3. ,412 -6. ,493 -2. ,718 1. .00 26. .90 A

ATOM 622 NE ARG A 76 2. ,388 -6. ,476 -1. 677 1. ,00 31. .13 A

ATOM 623 CZ ARG A 76 1. ,104 -6. ,206 -1. 901 1, ,00 32. .44 A

ATOM 624 NHl ARG A 76 0. ,688 -5. ,924 -3. 128 1, ,00 32. .50 A

ATOM 625 NH2 ARG A 76 0. ,235 -6. ,225 -0. 900 1. ,00 34. .28 A

ATOM 626 C ARG A 76 7. ,649 -5. ,942 -2. 356 1. ,00 15. ,47 A

ATOM 627 O ARG A 76 7. ,805 -5. ,236 -3. 351 1. ,00 13. ,35 A

ATOM 628 N CYS A 77 8. ,172 -7. ,157 -2. 248 1, ,00 16. ,61 A

ATOM 629 CA CYS A 77 8. ,950 -7. ,728 -3. 336 1. ,00 20. ,64 A

ATOM 630 C CYS A 77 8. ,399 -9. ,108 -3. 666 1, ,00 23. ,44 A

ATOM 631 O CYS A 77 8. ,105 -9. ,904 -2. 771 1. ,00 21. ,80 A

ATOM 632 CB CYS A 77 10. ,425 -7. ,857 -2. 947 1. ,00 19. ,86 A

ATOM 633 SG CYS A 77 11. ,134 -6. ,507 -1. 944 1. ,00 23. ,59 A

ATOM 634 N LEU A 78 8. ,246 -9. ,378 -4. 957 1. ,00 26. ,82 A

ATOM 635 CA LEU A 78 7. ,746 -10. ,666 -5. 416 1. ,00 30. ,24 A

ATOM 636 CB LEU A 78 6. ,755 -10. ,473 -6. 565 1. ,00 31. ,80 A

ATOM 637 CG LEU A 78 5. ,576 -9. ,538 -6. 282 1. ,00 33. ,92 A

ATOM 638 CDl LEU A 78 4. ,692 -9. ,446 -7. 518 1. ,00 34. ,22 A

ATOM 639 CD2 LEU A 78 4. ,784 -10. ,049 -5. 086 1. ,00 35. ,59 A

ATOM 640 C LEU A 78 8. ,948 -11. ,463 -5. 891 1. ,00 31. ,38 A

ATOM 641 0 LEU A 78 9. ,392 -11. ,321 -7. 031 1. .00 33. ,32 A ATOM 642 N GLN A 79 9.482 -12.293 -5.003 1.00 32.76 A

ATOM 643 CA GLN A 79 10 .650 -13 .103 -5 .315 1.00 33 .31 A

ATOM 644 CB GLN A 79 11 .666 -12 .973 -4 .179 1.00 32 .20 A

ATOM 645 CG GLN A 79 12 .351 -11 .613 -4 .161 1.00 30 .37 A

ATOM 646 CD GLN A 79 12 .960 -11 .265 -2 .819 1.00 29 .05 A

ATOM 647 OEl GLN A 79 13 .454 -12 .130 -2 .100 1.00 27 .19 A

ATOM 648 NE2 GLN A 79 12 .939 -9 .983 -2 .482 1.00 29 .45 A

ATOM 649 C GLN A 79 10 .284 -14 .563 -5 .553 1.00 34 .24 A

ATOM 650 O GLN A 79 10 .018 -15 .310 -4 .612 1.00 33 .93 A

ATOM 651 N ALA A 80 10 .280 -14 .961 -6 .822 1.00 35 .54 A

ATOM 652 CA ALA A 80 9 .930 -16 .325 -7 .200 1.00 36 .60 A

ATOM 653 CB ALA A 80 10 .872 -17 .320 -6 .523 1.00 36 .65 A

ATOM 654 C ALA A 80 8 .485 -16 .584 -6. .783 1.00 37 .25 A

ATOM 655 O ALA A 80 7 .563 -15 .963 -7 .309 1.00 37 .84 A

ATOM 656 N ALA A 81 8 .290 -17 .494 -5 .834 1.00 37 .54 A

ATOM 657 CA ALA A 81 6 .951 -17 .816 -5 .356 1.00 37 .86 A

ATOM 658 CB ALA A 81 6 .794 -19 .328 -5 .215 1.00 37 .88 A

ATOM 659 C ALA A 81 6 .700 -17 .137 -4 .014 1.00 37 .91 A

ATOM 660 O ALA A 81 5 .563 -17 .053 -3 .547 1.00 38 .61 A

ATOM 661 N THR A 82 7 .772 -16. .645 -3, .404 1.00 37 .16 A

ATOM 662 CA THR A 82 7 .683 -15 .985 -2, .109 1.00 35 .91 A

ATOM 663 CB THR A 82 8 .987 -16, .186 -1, .303 1.00 37 .22 A

ATOM 664 OGl THR A 82 9 .212 -17, .588 -1, .101 1.00 39 .15 A

ATOM 665 CG2 THR A 82 8. .896 -15, .493 0. .050 1.00 37 .58 A

ATOM 666 C THR A 82 7 .411 -14, .487 -2. .232 1.00 33, .93 A

ATOM 667 O THR A 82 8 .009 -13, .801 -3. .060 1.00 33, .96 A

ATOM 668 N VAL A 83 6, .493 -13, .995 -1. .406 1.00 31, .66 A

ATOM 669 CA VAL A 83 6, .151 -12. .578 -1. .389 1.00 29, .37 A

ATOM 670 CB VAL A 83 4, .626 -12. ,357 -1. .372 1.00 31. .42 A

ATOM 671 CGI VAL A 83 4, .316 -10. .864 -1. .355 1.00 32. .25 A

ATOM 672 CG2 VAL A 83 3, .994 -13. .011 -2. .590 1.00 33. .25 A

ATOM 673 C VAL A 83 6, .745 -11. ,970 -0. ,123 1.00 26. .95 A

ATOM 674 O VAL A 83 6, .342 -12. ,312 0. ,992 1.00 28. .10 A

ATOM 675 N ILE A 84 7. .712 -11. .079 -0. ,302 1.00 21. .09 A

ATOM 676 CA ILE A 84 8, .371 -10. ,423 0. ,818 1.00 20. .34 A

ATOM 677 CB ILE A 84 9. .871 -10. ,161 0. ,506 1.00 20. .03 A

ATOM 678 CG2 ILE A 84 10. .518 -9. ,368 1. .632 1.00 22. .50 A

ATOM 679 CGI ILE A 84 10. .599 -11. ,489 0. ,286 1.00 23. .05 A

ATOM 680 CDl ILE A 84 10. .452 -12. ,457 1. .439 1.00 23. ,10 A

ATOM 681 C ILE A 84 7. .688 -9. ,091 1. ,087 1.00 16. ,81 A

ATOM 682 O ILE A 84 7. .459 -8. .314 0. ,166 1.00 16. ,04 A

ATOM 683 N GLU A 85 7. .351 -8. ,838 2. ,346 1.00 16. ,32 A

ATOM 684 CA GLU A 85 6. .718 -7. ,578 2. ,713 1.00 16. ,13 A

ATOM 685 CB GLU A 85 5. .209 -7. ,779 2. ,911 1.00 19. ,58 A

ATOM 686 CG GLU A 85 4. .424 -6. ,496 3. ,135 1.00 22. ,28 A

ATOM 687 CD GLU A 85 2. .930 -6. .647 2. .849 1.00 24. ,29 A

ATOM 688 OEl GLU A 85 2. ,115 -6. .168 3. ,664 1.00 24. ,62 A

ATOM 689 OE2 GLU A 85 2. ,569 -7. 229 1. 802 1.00 26. .11 A

ATOM 690 C GLU A 85 7. ,381 -7. 076 3. 995 1.00 15. .20 A

ATOM 691 O GLU A 85 7. ,425 -7. 782 5. 002 1.00 16. 57 A

ATOM 692 N ARG A 86 7. ,920 -5. 864 3. 941 1.00 12. 68 A

ATOM 693 CA ARG A 86 8. ,590 -5. 262 5. 094 1.00 13. 03 A

ATOM 694 CB ARG A 86 10. ,051 -4. 986 4. 749 1.00 14. 49 A

ATOM 695 CG ARG A 86 10. ,840 -6. 252 4. 409 1.00 16. 45 A

ATOM 696 CD ARG A 86 11. ,217 -7. 009 5. 671 1.00 17. 82 A

ATOM 697 NE ARG A 86 11. ,944 -8. 246 5. 387 1.00 20. 25 A

ATOM 698 CZ ARG A 86 11. ,365 -9. 413 5. 124 1.00 19. 21 A

ATOM 699 NHl ARG A 86 10. ,042 -9. 513 5. 110 1.00 19. 27 A

ATOM 700 NH2 ARG A 86 12. .110 -10. 485 4. 880 1.00 18. ,54 A

ATOM 701 C ARG A 86 7. .832 -3. 976 5. 403 1.00 12. ,66 A

ATOM 702 O ARG A 86 7. .668 -3. 131 4. 535 1.00 12. ,73 A

ATOM 703 N THR A 87 7. ,396 -3. 837 6. 650 1.00 10. ,68 A ATOM 704 CA THR A 87 6.572 -2.709 7.070 1.00 8.97 A

ATOM 705 CB THR A 87 5 .273 -3 .255 7 .671 1 .00 11 .83 A

ATOM 706 OGl THR A 87 4 .674 -4 .157 6 .727 1 .00 14 .14 A

ATOM 707 CG2 THR A 87 4 .299 -2 .130 7 .997 1 .00 11 .51 A

ATOM 708 C THR A 87 7 .249 -1 .771 8 .056 1 .00 10 .56 A

ATOM 709 O THR A 87 7 .807 -2 .208 9 .065 1 .00 10 .84 A

ATOM 710 N PHE A 88 7 .176 -0 .476 7 .769 1 .00 8 .26 A

ATOM 711 CA PHE A 88 7 .820 0 .522 8 .610 1 .00 9 .27 A

ATOM 712 CB PHE A 88 9 .064 1. .061 7 .913 1 .00 10 .65 A

ATOM 713 CG PHE A 88 9 .995 -0 .007 7 .419 1 .00 11 .28 A

ATOM 714 CDl PHE A 88 9 .829 -0 .569 6. .156 1 .00 11 .07 A

ATOM 715 CD2 PHE A 88 11 .039 -0. .453 8 .217 1 .00 12 .76 A

ATOM 716 CEl PHE A 88 10 .694 -1. .559 5, .695 1 .00 14 .90 A

ATOM 717 CE2 PHE A 88 11. .908 -1, .441 7. .767 1 .00 14 .88 A

ATOM 718 CZ PHE A 88 11. .737 -1, .995 6. .504 1, .00 12 .78 A

ATOM 719 C PHE A 88 6 .922 1, .693 8, .954 1 .00 11, .60 A

ATOM 720 O PHE A 88 5. .989 2, .018 8, .219 1, .00 11. .54 A

ATOM 721 N HIS A 89 7, .230 2. .333 10. .077 1, .00 11, .13 A

ATOM 722 CA HIS A 89 6, .474 3. .484 10. .536 1, .00 12, .24 A

ATOM 723 CB HIS A 89 5. .569 3. .084 11. .709 1, .00 12, .47 A

ATOM 724 CG HIS A 89 5. .095 4. .240 12. ,539 1, .00 14, .06 A

ATOM 725 CD2 HIS A 89 5, .484 4. .673 13. .763 1, .00 13, .13 A

ATOM 726 ND1 HIS A 89 4, .111 5. .112 12. .121 1. .00 14, .24 A

ATOM 727 CEl HIS A 89 3, .915 6. .031 13. .051 1, .00 14, .31 A

ATOM 728 NE2 HIS A 89 4, .736 5. .787 14. .058 1. .00 14, .19 A

ATOM 729 C HIS A 89 7, .418 4. .590 10. .989 1, .00 12, .07 A

ATOM 730 O HIS A 89 8, .480 4. .325 11. .551 1, .00 12, .27 A

ATOM 731 N VAL A 90 7. .037 5. .827 10. .697 1. .00 11, .22 A

ATOM 732 CA VAL A 90 7. .792 6. .992 11. .134 1. .00 14, .02 A

ATOM 733 CB VAL A 90 8. .592 7. .661 9. .990 1. .00 14. .33 A

ATOM 734 CGI VAL A 90 9. .762 6. ,772 9. .610 1. .00 16. .10 A

ATOM 735 CG2 VAL A 90 7. .699 7. ,917 8. .786 1. .00 14, .04 A

ATOM 736 C VAL A 90 6. .753 7. ,944 11. .708 1. .00 14. .50 A

ATOM 737 O VAL A 90 5. .570 7. ,856 11. ,379 1. .00 13. .20 A

ATOM 738 N GLU A 91 7. .189 8. ,856 12. ,568 1. .00 15. .15 A

ATOM 739 CA GLU A 91 6, .263 9. ,758 13. ,231 1. .00 17. .54 A

ATOM 740 CB GLU A 91 6. .981 10. ,450 14. ,389 1. .00 19. .96 A

ATOM 741 CG GLU A 91 6, .048 11. ,155 15. ,348 1. .00 24. .38 A

ATOM 742 CD GLU A 91 6. .716 11. ,477 16. .664 1. .00 24, .10 A

ATOM 743 OEl GLU A 91 7. .211 10. ,538 17. .320 1. .00 27, .31 A

ATOM 744 OE2 GLU A 91 6. .746 12. ,666 17. .041 1. .00 28, .49 A

ATOM 745 C GLU A 91 5. .524 10. ,796 12. .392 1. .00 16, .51 A

ATOM 746 O GLU A 91 4. .411 11. .184 12. .742 1. .00 17, .79 A

ATOM 747 N THR A 92 6. .116 11. .239 11. .289 1. .00 15, .40 A

ATOM 748 CA THR A 92 5. .467 12. .251 10. .463 1. .00 14. .75 A

ATOM 749 CB THR A 92 6. .219 13. .594 10. ,554 1. .00 17. .00 A

ATOM 750 OGl THR A 92 7. .520 13. .453 9. .970 1. .00 16, .02 A

ATOM 751 CG2 THR A 92 6, .375 14. .018 12. .002 1. .00 18, .24 A

ATOM 752 C THR A 92 5, .368 11, .871 8. .988 1. .00 15, .14 A

ATOM 753 O THR A 92 6, .172 11. .083 8. .484 1. .00 13, .30 A

ATOM 754 N PRO A 93 4, .375 12. .431 8. .275 1. .00 15, .28 A

ATOM 755 CD PRO A 93 3, .297 13. .330 8. .729 1. .00 16, .62 A

ATOM 756 CA PRO A 93 4, .228 12. .116 6. .850 1. .00 15, .13 A

ATOM 757 CB PRO A 93 2. .918 12. .806 6. .471 1. .00 17, .18 A

ATOM 758 CG PRO A 93 2. .843 13, .957 7. .434 1. .00 16, .19 A

ATOM 759 C PRO A 93 5. .424 12. .637 6. .054 1, .00 15, .43 A

ATOM 760 O PRO A 93 5. .786 12. ,073 5. .027 1. .00 13, .87 A

ATOM 761 N GLU A 94 6. .041 13, ,711 6. .543 1. .00 14, .56 A

ATOM 762 CA GLU A 94 7. .205 14. ,276 5. ,874 1. .00 16. .01 A

ATOM 763 CB GLU A 94 7. .658 15. ,568 6. ,560 1. .00 18. .75 A

ATOM 764 CG GLU A 94 6. .640 16. ,696 6. ,532 1. .00 22. ,27 A

ATOM 765 CD GLU A 94 5. ,389 16. ,372 7. ,317 1. .00 22. .01 A ATOM 766 OEl GLU A 94 5.515 15.865 8.449 1.00 22.83 A

ATOM 767 OE2 GLU A 94 4 .280 16 .632 6 .806 1 .00 27 .66 A

ATOM 768 C GLU A 94 8 .346 13 .265 5 .903 1 .00 13 .55 A

ATOM 769 0 GLU A 94 9 .037 13 .071 4 .905 1 .00 15 .49 A

ATOM 770 N GLU A 95 8 .541 12 .619 7 .051 1 .00 12 .81 A

ATOM 771 CA GLU A 95 9 .604 11 .628 7 .188 1 .00 14 .32 A

ATOM 772 CB GLU A 95 9 .706 11 .136 8 .630 1 .00 17 .64 A

ATOM 773 CG GLU A 95 10 .211 12 .162 9 .615 1 .00 23 .75 A

ATOM 774 CD GLU A 95 10 .272 11 .603 11 .018 1 .00 25 .77 A

ATOM 775 OEl GLU A 95 11 .144 10 .745 11 .280 1 .00 27 .91 A

ATOM 776 OE2 GLU A 95 9. .435 12 .008 11 .851 1 .00 29 .69 A

ATOM 777 C GLU A 95 9 .349 10 .434 6 .276 1 .00 14 .49 A

ATOM 778 O GLU A 95 10 .281 9 .883 5 .687 1 .00 13 .63 A

ATOM 779 N ARG A 96 8. .087 10 .024 6 .167 1. .00 13 .10 A

ATOM 780 CA ARG A 96 7. .771 8 .894 5 .305 1 .00 10 .80 A

ATOM 781 CB ARG A 96 6. .299 8 .494 5 .427 1 .00 11 .22 A

ATOM 782 CG ARG A 96 5. .921 7 .370 4, .460 1 .00 10 .47 A

ATOM 783 CD ARG A 96 4. .502 6. .872 4, .697 1, .00 10 .66 A

ATOM 784 NE ARG A 96 3, .510 7 .926 4, .495 1, .00 10, .11 A

ATOM 785 CZ ARG A 96 2, .207 7, .756 4, .672 1, .00 11, .04 A

ATOM 786 NHl ARG A 96 1. .738 6, .571 5. .050 1, .00 10, .22 A

ATOM 787 NH2 ARG A 96 1, .370 8, .775 4, .483 1, .00 13, .07 A

ATOM 788 C ARG A 96 8, .088 9, .219 3, .855 1. .00 12, .21 A

ATOM 789 O ARG A 96 8, .604 8, .376 3. .126 1, .00 11, .54 A

ATOM 790 N GLU A 97 7, .779 10 .443 3, .435 1, .00 12 .71 A

ATOM 791 CA GLU A 97 8, .041 10 .858 2, .062 1, .00 14, .86 A

ATOM 792 CB GLU A 97 7, .490 12, .264 1, .820 1, .00 18, .50 A

ATOM 793 CG GLU A 97 7, .218 12, .565 0. .361 1, .00 25. .19 A

ATOM 794 CD GLU A 97 6. .171 11, .636 -0, ,219 1. .00 27. .67 A

ATOM 795 OEl GLU A 97 5, .117 11, .455 0. .428 1. .00 31, .19 A

ATOM 796 OE2 GLU A 97 6. .399 11, .089 -1. ,318 1. .00 33. .18 A

ATOM 797 C GLU A 97 9. .544 10, .851 1. .818 1. .00 14. .60 A

ATOM 798 O GLU A 97 10. .009 10. .524 0. .730 1. .00 16. .46 A

ATOM 799 N GLU A 98 10. .288 11. .234 2. .848 1. .00 14. .01 A

ATOM 800 CA GLU A 98 11. .744 11. .275 2. .807 1. ,00 16. .84 A

ATOM 801 CB GLU A 98 12. .260 11. .694 4. .186 1. .00 21. .02 A

ATOM 802 CG GLU A 98 13. .683 12. .192 4. .239 1. ,00 26. .55 A

ATOM 803 CD GLU A 98 14. ,024 12. .769 5. .604 1. .00 27. .90 A

ATOM 804 OEl GLU A 98 13. .198 13. .533 6. .150 1. ,00 30. .20 A

ATOM 805 OE2 GLU A 98 15. .114 12. .467 6. ,128 1. ,00 31. .70 A

ATOM 806 C GLU A 98 12. ,256 9. .875 2. ,456 1. .00 14, .69 A

ATOM 807 O GLU A 98 13. ,036 9. .690 1. ,516 1. .00 15. .97 A

ATOM 808 N TRP A 99 11. ,790 8. .887 3. .209 1. .00 12. ,08 A

ATOM 809 CA TRP A 99 12. ,205 7, ,511 2. .989 1. ,00 11. .00 A

ATOM 810 CB TRP A 99 11. ,781 6. .631 4. .165 1. ,00 11. .65 A

ATOM 811 CG TRP A 99 12. ,733 6. .691 5. .300 1. ,00 11. .20 A

ATOM 812 CD2 TRP A 99 13. ,988 6. ,011 5. .389 1. ,00 13. .96 A

ATOM 813 CE2 TRP A 99 14. ,556 6, .340 6. .641 1. ,00 13. .78 A

ATOM 814 CE3 TRP A 99 14, ,690 5, .154 4. .531 1. ,00 13. .32 A

ATOM 815 CDl TRP A 99 12. ,590 7. .392 6. .464 1. .00 14. .23 A

ATOM 816 NE1 TRP A 99 13. ,683 7, .184 7. .278 1. .00 14. ,01 A

ATOM 817 CZ2 TRP A 99 15. ,793 5. .840 7. .058 1, .00 16. .39 A

ATOM 818 CZ3 TRP A 99 15. ,925 4. .658 4. .946 1. .00 14. .63 A

ATOM 819 CH2 TRP A 99 16. ,462 5. .003 6. .200 1. .00 15. ,87 A

ATOM 820 C TRP A 99 11. ,693 6. .894 1. .700 1. .00 11. .99 A

ATOM 821 O TRP A 99 12. ,460 6. .275 0. .963 1. .00 12. .68 A

ATOM 822 N THR A 100 10. ,405 7. .055 1. ,415 1. ,00 11. .82 A

ATOM 823 CA THR A 100 9. ,850 6. .456 0. ,206 1. ,00 11. ,56 A

ATOM 824 CB THR A 100 8. ,304 6. .603 0. ,141 1. ,00 11. ,25 A

ATOM 825 OGl THR A 100 7. ,936 7. ,985 0. ,202 1. ,00 13. ,74 A

ATOM 826 CG2 THR A 100 7. ,656 5. ,855 1. ,304 1. ,00 15. ,38 A

ATOM 827 C THR A 100 10 . 483 7 . 018 - 1 . 060 1 . 00 11 . 42 A ATOM 828 O THR A 100 10.734 6.278 -2.007 1.00 11.46 A

ATOM 829 N THR A 101 10 .751 8 .319 -1 .079 1 .00 10 .00 A

ATOM 830 CA THR A 101 11 .384 8 .931 -2 .243 1 .00 13 .38 A

ATOM 831 CB THR A 101 11 .470 10 .461 -2 .086 1 .00 15 .31 A

ATOM 832 OGl THR A 101 10 .147 11 .009 -2 .115 1 .00 19 .25 A

ATOM 833 CG2 THR A 101 12 .299 11 .078 -3 .213 1 .00 19 .50 A

ATOM 834 C THR A 101 12 .788 8 .358 -2 .421 1 .00 11 .87 A

ATOM 835 O THR A 101 13 .188 8 .024 -3 .531 1. .00 13 .27 A

ATOM 836 N ALA A 102 13 .530 8 .235 -1 .325 1 .00 10 .91 A

ATOM 837 CA ALA A 102 14 .887 7 .703 -1 .391 1 .00 11 .26 A

ATOM 838 CB ALA A 102 15 .543 7 .761 -0 .019 1. .00 12 .57 A

ATOM 839 C ALA A 102 14 .889 6 .269 -1 .917 1. .00 10 .50 A

ATOM 840 O ALA A 102 15 .643 5 .937 -2 .827 1, .00 9, .28 A

ATOM 841 N ILE A 103 14 .041 5 .428 -1 .337 1, .00 11, .11 A

ATOM 842 CA ILE A 103 13. .947 4 .034 -1 .757 1, .00 9, .76 A

ATOM 843 CB ILE A 103 12 .952 3 .260 -0, .867 1, .00 10, .54 A

ATOM 844 CG2 ILE A 103 12. .763 1. .846 -1, .403 1, .00 9, .25 A

ATOM 845 CGI ILE A 103 13. .481 3, .211 0 .570 1, .00 9, .93 A

ATOM 846 CDl ILE A 103 12, .440 2, .780 1. .596 1. .00 11, .32 A

ATOM 847 C ILE A 103 13, .516 3, .916 -3, .221 1, .00 10. .12 A

ATOM 848 O ILE A 103 14, .090 3, .136 -3, .988 1. .00 11. .05 A

ATOM 849 N GLN A 104 12, .509 4, .692 -3. .610 1. .00 9. ,83 A

ATOM 850 CA GLN A 104 12, .019 4. .649 -4. .978 1. .00 9. .93 A

ATOM 851 CB GLN A 104 10. .784 5. .541 -5. .126 1. .00 10. .79 A

ATOM 852 CG GLN A 104 10. .061 5. .368 -6. .457 1. .00 12, .55 A

ATOM 853 CD GLN A 104 9, .511 3. .965 -6. .641 1, .00 11, .65 A

ATOM 854 OEl GLN A 104 10. .124 3. .111 -7. .293 1. .00 16, .00 A

ATOM 855 NE2 GLN A 104 8, .356 3, .715 -6. .051 1. .00 12, .93 A

ATOM 856 C GLN A 104 13, .099 5. .086 -5. .969 1. .00 11, .81 A

ATOM 857 O GLN A 104 13. .209 4. .530 -7. .064 1. .00 11. ,78 A

ATOM 858 N THR A 105 13. .903 6. .076 -5. .590 1. .00 10. .41 A

ATOM 859 CA THR A 105 14. .950 6. .559 -6. .479 1. .00 12. ,11 A

ATOM 860 CB THR A 105 15. .604 7. .834 -5. .920 1. ,00 13. ,87 A

ATOM 861 OGl THR A 105 14. .611 8. .867 -5. .836 1. ,00 15. ,72 A

ATOM 862 CG2 THR A 105 16. .744 8. .297 -6. ,824 1. ,00 15. ,30 A

ATOM 863 C THR A 105 15. ,999 5. .479 -6. ,697 1. ,00 10. ,95 A

ATOM 864 O THR A 105 16. .450 5. .259 -7. ,819 1. ,00 13. ,91 A

ATOM 865 N VAL A 106 16. .367 4, .786 -5. ,627 1. ,00 11. ,05 A

ATOM 866 CA VAL A 106 17, .351 3. .716 -5. ,725 1. ,00 10. ,74 A

ATOM 867 CB VAL A 106 17. .726 3. .185 -4. ,326 1. ,00 10. ,63 A

ATOM 868 CGI VAL A 106 18. .597 1. .945 -4. ,448 1. ,00 11. ,76 A

ATOM 869 CG2 VAL A 106 18. .476 4. ,279 -3. ,551 1. ,00 10. ,98 A

ATOM 870 C VAL A 106 16. .797 2. ,580 -6. ,582 1. ,00 11. ,23 A

ATOM 871 O VAL A 106 17. ,486 2. ,065 -7. ,467 1. ,00 11. .75 A

ATOM 872 N ALA A 107 15. ,548 2. ,203 -6. ,330 1. .00 11. .32 A

ATOM 873 CA ALA A 107 14. ,930 1. ,126 -7. ,088 1. .00 11. .51 A

ATOM 874 CB ALA A 107 13. ,538 0. ,821 -6. .530 1. .00 12. ,49 A

ATOM 875 C ALA A 107 14. .850 1, ,493 -8. .568 1. ,00 12. ,51 A

ATOM 876 O ALA A 107 15. ,157 0. ,676 -9. .434 1. ,00 13, .54 A

ATOM 877 N ASP A 108 14. .462 2. .731 -8. .856 1. ,00 12. .76 A

ATOM 878 CA ASP A 108 14. .349 3. ,171 -10. .243 1. ,00 13. ,62 A

ATOM 879 CB ASP A 108 13. .773 4. ,583 -10. .307 1. ,00 14. ,60 A

ATOM 880 CG ASP A 108 12. .303 4. ,623 -9. ,951 1. ,00 15. ,80 A

ATOM 881 ODl ASP A 108 11. .693 3. ,540 -9. ,827 1. ,00 15. ,40 A

ATOM 882 OD2 ASP A 108 11. ,760 5. ,736 -9. ,802 1. 00 15. ,39 A

ATOM 883 C ASP A 108 15. ,698 3. ,125 -10. ,945 1. ,00 14. ,52 A

ATOM 884 O ASP A 108 15. ,788 2. ,744 -12. ,115 1. ,00 16. ,11 A

ATOM 885 N GLY A 109 16. ,745 3. ,517 -10. ,226 1. 00 14. ,47 A

ATOM 886 CA GLY A 109 18. ,074 3. ,491 -10. ,802 1. 00 15. ,46 A

ATOM 887 C GLY A 109 18. .447 2. ,075 -11. ,192 1. 00 14. 48 A

ATOM 888 O GLY A 109 19. ,006 1. ,843 -12. ,264 1. 00 16. 34 A

ATOM 889 N LEU A 110 18. ,121 1. ,120 -10. ,325 1. 00 13. 65 A ATOM 890 CA LEU A 110 18.427 -0.284 -10.576 1.00 15.32 A

ATOM 891 CB LEU A 110 18 .222 -1 .103 -9 .295 1 .00 15 .50 A

ATOM 892 CG LEU A 110 19 .143 -0 .726 -8 .126 1 .00 16 .34 A

ATOM 893 CDl LEU A 110 18 .708 -1 .479 -6 .873 1 .00 15 .65 A

ATOM 894 CD2 LEU A 110 20 .589 -1 .038 -8 .471 1 .00 19 .70 A

ATOM 895 C LEU A 110 17 .568 -0 .848 -11 .706 1 .00 16 .52 A

ATOM 896 O LEU A 110 18 .024 -1 .695 -12 .483 1 .00 16 .03 A

ATOM 897 N LYS A 111 16 .331 -0 .373 -11 .802 1 .00 16 .02 A

ATOM 898 CA LYS A 111 15 .427 -0 .827 -12 .853 1 .00 18 .02 A

ATOM 899 CB LYS A 111 14 .033 -0 .235 -12 .660 1 .00 18 .95 A

ATOM 900 CG LYS A 111 12 .992 -0 .808 -13 .615 1 .00 22 .75 A

ATOM 901 CD LYS A 111 11 .647 -0 .114 -13 .464 1 .00 25 .18 A

ATOM 902 CE LYS A 111 11 .712 1 .325 -13 .946 1 .00 27 .57 A

ATOM 903 NZ LYS A 111 10 .393 2 .010 -13 .868 1 .00 29 .93 A

ATOM 904 C LYS A 111 15 .977 -0 .374 -14 .202 1 .00 18 .54 A

ATOM 905 O LYS A 111 15 .888 -1 .096 -15 .201 1 .00 19 .11 A

ATOM 906 N LYS A 112 16 .538 0 .830 -14. .221 1 .00 17 .66 A

ATOM 907 CA LYS A 112 17 .113 1 .390 -15 .435 1 .00 20 .12 A

ATOM 908 CB LYS A 112 17 .627 2 .808 -15 .175 1. .00 21, .54 A

ATOM 909 CG LYS A 112 18 .090 3 .545 -16 .423 1. .00 26, .39 A

ATOM 910 CD LYS A 112 16 .930 3 .782 -17 .372 1. .00 29, .80 A

ATOM 911 CE LYS A 112 17. .347 4 .624 -18 .568 1. .00 32, .74 A

ATOM 912 NZ LYS A 112 16. .188 4 .893 -19 .466 1, .00 33, .84 A

ATOM 913 C LYS A 112 18. .261 0 .501 -15 .891 1, .00 19, .33 A

ATOM 914 O LYS A 112 18. .381 0, .189 -17. .075 1. .00 18. .73 A

ATOM 915 N GLN A 113 19. .103 0, .090 -14. .947 1. .00 18. .16 A

ATOM 916 CA GLN A 113 20, .232 -0. .779 -15. .269 1. .00 18. ,60 A

ATOM 917 CB GLN A 113 21. .106 -1. .007 -14. .033 1. .00 19. ,47 A

ATOM 918 CG GLN A 113 22, .253 -1. .978 -14. .270 1, .00 26. ,96 A

ATOM 919 CD GLN A 113 23. .105 -2. .201 -13. .035 1. .00 30. ,47 A

ATOM 920 OEl GLN A 113 22. .594 -2. .545 -11. .966 1. .00 33. ,57 A

ATOM 921 NE2 GLN A 113 24. .413 -2. .014 -13. .177 1, ,00 32. ,81 A

ATOM 922 C GLN A 113 19. ,734 -2, .128 -15. .790 1. ,00 17. ,40 A

ATOM 923 O GLN A 113 20. ,301 -2, .692 -16. .727 1. ,00 18. ,15 A

ATOM 924 N GLU A 114 18. ,674 -2, ,641 -15. .176 1. ,00 15. ,33 A

ATOM 925 CA GLU A 114 18. ,107 -3, ,918 -15. .580 1. ,00 16. .85 A

ATOM 926 CB GLU A 114 16. ,948 -4. .296 -14. .654 1. ,00 17. ,76 A

ATOM 927 CG GLU A 114 16. ,206 -5. .554 -15. .058 1. ,00 22. ,42 A

ATOM 928 CD GLU A 114 15. .169 -5. .970 -14. .034 1. ,00 25. ,60 A

ATOM 929 OEl GLU A 114 14. .558 -5. .078 -13. .403 1. ,00 27. ,20 A

ATOM 930 OE2 GLU A 114 14. ,956 -7, .190 -13. .867 1. ,00 30. ,15 A

ATOM 931 C GLU A 114 17. ,626 -3, .853 -17. .024 1. .00 15. ,62 A

ATOM 932 O GLU A 114 17. ,937 -4. .729 -17. .828 1. ,00 17. ,27 A

ATOM 933 N GLU A 115 16. ,878 -2, .807 -17. .351 1. ,00 14. ,43 A

ATOM 934 CA GLU A 115 16. ,360 -2, .646 -18. .707 1. ,00 16. ,86 A

ATOM 935 CB GLU A 115 15. .507 -1. .379 -18. .799 1. ,00 18. 65 A

ATOM 936 CG GLU A 115 14. .393 -1. .310 -17. .772 1. ,00 24. ,13 A

ATOM 937 CD GLU A 115 13. 559 -0. ,050 -17. ,897 1. 00 27. 46 A

ATOM 938 OEl GLU A 115 14. 146 1. ,047 -18. ,019 1. 00 28. 86 A

ATOM 939 OE2 GLU A 115 12. .317 -0. 157 -17. ,864 1. 00 31. 74 A

ATOM 940 C GLU A 115 17. 495 -2. 576 -19. ,726 1. 00 16. 85 A

ATOM 941 O GLU A 115 17. 409 -3. 156 -20. ,810 1. 00 16. 74 A

ATOM 942 N GLU A 116 18. 564 -1. ,869 -19. ,372 1. 00 16. 72 A

ATOM 943 CA GLU A 116 19. 704 -1. 725 -20. ,267 1. 00 17. 07 A

ATOM 944 CB GLU A 116 20. 678 -0. 685 -19. ,701 1. 00 17. 93 A

ATOM 945 CG GLU A 116 20. 097 0. 724 -19. ,724 1. 00 21. 47 A

ATOM 946 CD GLU A 116 21. 025 1. 770 -19. ,141 1. 00 22. 69 A

ATOM 947 OEl GLU A 116 20. 691 2. 969 -19. ,239 1. 00 24. 54 A

ATOM 948 OE2 GLU A 116 22. 079 1. 397 -18. ,584 1. 00 26. 71 A

ATOM 949 C GLU A 116 20. 418 -3. 046 -20. ,526 1. 00 16. 90 A

ATOM 950 O GLU A 116 21. 114 -3. 201 -21. ,531 1. 00 16. 87 A

ATOM 951 N GLU A 117 20. 224 -4. 005 -19. 629 1. 00 19. 22 A ATOM 952 CA GLU A 117 20.852 -5.310 -19.772 1.00 21.09 A

ATOM 953 CB GLU A 117 21 .214 -5 .882 -18 .403 1 .00 21 .76 A

ATOM 954 CG GLU A 117 21 .948 -7 .212 -18 .483 1 .00 25 .90 A

ATOM 955 CD GLU A 117 21 .694 -8 .097 -17 .280 1 .00 25 .09 A

ATOM 956 OEl GLU A 117 21 .749 -7 .587 -16 .142 1 .00 27 .47 A

ATOM 957 OE2 GLU A 117 21 .445 -9 .306 -17 .476 1 .00 26 .85 A

ATOM 958 C GLU A 117 19 .943 -6 .310 -20 .477 1 .00 22 .38 A

ATOM 959 O GLU A 117 20 .406 -7 .120 -21 .280 1 .00 25 .10 A

ATOM 960 N MET A 118 18 .649 -6 .238 -20 .182 1 .00 22 .91 A

ATOM 961 CA MET A 118 17 .679 -7 .177 -20 .735 1 .00 24 .24 A

ATOM 962 CB MET A 118 16 .608 -7 .474 -19 .681 1 .00 25 .91 A

ATOM 963 CG MET A 118 17 .151 -8 .064 -18 .387 1 .00 29 .08 A

ATOM 964 SD MET A 118 18 .031 -9 .616 -18 .656 1 .00 34 .28 A

ATOM 965 CE MET A 118 16 .657 -10 .781 -18 .688 1 .00 32 .76 A

ATOM 966 C MET A 118 16 .986 -6 .824 -22 .049 1 .00 25 .07 A

ATOM 967 O MET A 118 16 .508 -7 .717 -22 .750 1 .00 26 .87 A

ATOM 968 N ASP A 119 16 .919 -5 .542 -22 .390 1 .00 23. .37 A

ATOM 969 CA ASP A 119 16. .236 -5 .142 -23 .619 1 .00 22, .68 A

ATOM 970 CB ASP A 119 15. .758 -3 .689 -23 .514 1 .00 23. .54 A

ATOM 971 CG ASP A 119 14. .634 -3 .508 -22 .510 1 .00 26. .85 A

ATOM 972 ODl ASP A 119 14, .140 -2 .367 -22 .385 1 .00 26. .56 A

ATOM 973 OD2 ASP A 119 14, .243 -4 .494 -21 .847 1 .00 27. .00 A

ATOM 974 C ASP A 119 17, .036 -5 .300 -24 .909 1 .00 20. .85 A

ATOM 975 O ASP A 119 18, .206 -4 .931 -24 .981 1. .00 17. .42 A

ATOM 976 N PHE A 120 16, .378 -5 .849 -25 .928 1. .00 22. .47 A

ATOM 977 CA PHE A 120 16, .970 -6, .039 -27 .249 1. .00 22. .92 A

ATOM 978 CB PHE A 120 16. .937 -4, .704 -27. .999 1. .00 22. .46 A

ATOM 979 CG PHE A 120 15. .583 -4, .049 -27. .996 1. .00 19. .89 A

ATOM 980 CDl PHE A 120 15. .431 -2, .727 -27. .584 1, .00 19. .89 A

ATOM 981 CD2 PHE A 120 14. .450 -4, .763 -28. .376 1, .00 19. .35 A

ATOM 982 CEl PHE A 120 14. .174 -2, .131 -27, .548 1. .00 20. .00 A

ATOM 983 CE2 PHE A 120 13. .189 -4. .175 -28, .344 1. .00 18. .49 A

ATOM 984 CZ PHE A 120 13. .050 -2. .856 -27. .927 1. .00 18. .46 A

ATOM 985 C PHE A 120 18. ,389 -6. .596 -27. .209 1. .00 26. .66 A

ATOM 986 O PHE A 120 19. ,309 -6. .034 -27. .809 1. .00 24. ,94 A

ATOM 987 N ARG A 121 18. ,548 -7. .716 -26. .508 1. .00 29. ,24 A

ATOM 988 CA ARG A 121 19. ,842 -8. .376 -26. .358 1. .00 34. ,72 A

ATOM 989 CB ARG A 121 19. ,762 -9. .437 -25. .251 1. .00 36. ,25 A

ATOM 990 CG ARG A 121 19. ,153 -8. .924 -23. .952 1. .00 39. ,04 A

ATOM 991 CD ARG A 121 19. ,272 -9. .932 -22. ,814 1. .00 41. ,76 A

ATOM 992 NE ARG A 121 20. ,665 -10. .184 -22. .453 1. ,00 44. ,83 A

ATOM 993 CZ ARG A 121 21. ,054 -10. .820 -21, .351 1. ,00 46. ,02 A

ATOM 994 NHl ARG A 121 20. ,154 -11. .274 -20, .489 1. .00 47. 03 A

ATOM 995 NH2 ARG A 121 22. ,346 -10. .999 -21, .108 1. ,00 45. ,57 A

ATOM 996 C ARG A 121 20. ,317 -9. .022 -27. .657 1. ,00 36. 14 A

ATOM 997 O ARG A 121 20. .285 -10, .268 -27. .742 1. ,00 38. 36 A

ATOM 998 OXT ARG A 121 20. ,711 -8, .275 -28. .579 1. ,00 37. 71 A

ATOM 999 OH2 TIP 1 11. .198 -0. .999 -3. ,667 1. ,00 16. 50

ATOM 1000 OH2 TIP 3 14. ,837 11, .350 0. .471 1. ,00 24. 07

ATOM 1001 OH2 TIP 5 -8. ,364 0. .382 10. .615 1. ,00 24. 14

ATOM 1002 OH2 TIP 6 17. .245 -8. ,103 -5. ,651 1. ,00 26. 42

ATOM 1003 OH2 TIP 7 25. 948 -5. ,713 3. .896 1. ,00 34. 61

ATOM 1004 OH2 TIP 8 15. ,749 -3. ,754 -10. .884 1. ,00 27. 33

ATOM 1005 OH2 TIP 10 19. 926 -5. ,911 -13. .435 1. ,00 31. 22

ATOM 1006 OH2 TIP 11 8. 852 -7. ,420 16. ,512 1. ,00 25. 93

ATOM 1007 OH2 TIP 12 27. 540 5. ,995 7. ,559 1. ,00 27. 52

ATOM 1008 OH2 TIP 13 2. 401 14. ,373 12. ,068 1. ,00 32. 79

ATOM 1009 OH2 TIP 14 4. 688 7. ,136 16. ,488 1. 00 28. 38

ATOM 1010 OH2 TIP 15 11. 736 8. ,734 -6. 213 1. ,00 28. 13

ATOM 1011 OH2 TIP 16 7. 003 1. ,948 17. ,761 1. 00 31. 18

ATOM 1012 OH2 TIP 17 7. 181 -10. 970 4. ,224 1. 00 26. 13

ATOM 1013 OH2 TIP 18 4. 436 -3. 114 19. ,148 1. 00 23. 67 ATOM 1014 OH2 TIP 19 22.291 3.052 18.651 1.00 23.91

ATOM 1015 OH2 TIP 22 32 .273 4 .681 -5 .240 1 .00 26 .41

ATOM 1016 OH2 TIP 25 12 .191 7 .381 13 .143 1 .00 29 .04

ATOM 1017 OH2 TIP 26 19 .912 -6 .081 -8 .409 1 .00 34 .06

ATOM 1018 OH2 TIP 28 12 .190 8 .045 -8 .841 1 .00 30 .04

ATOM 1019 OH2 TIP 31 27 .055 -3 .125 -0 .987 1 .00 30 .25

ATOM 1020 OH2 TIP 36 22 .899 -4 .869 -16 .239 1 .00 39 .18

ATOM 1021 OH2 TIP 37 8 .402 15 .826 14 .904 1 .00 42 .44

ATOM 1022 OH2 TIP 38 18 .991 -7 .540 23 .040 1 .00 28 .91

ATOM 1023 OH2 TIP 40 24 .165 -6 .472 0 .132 1 .00 29 .30

ATOM 1024 OH2 TIP 44 20 .825 9 .018 11 .424 1 .00 32 .38

ATOM 1025 OH2 TIP 45 23 .750 -0 .318 -17 .747 1 .00 34 .44

ATOM 1026 OH2 TIP 46 14 .046 -7 .024 13 .165 1 .00 37 .95

ATOM 1027 OH2 TIP 47 11 .923 15 .331 8 .516 1 .00 44 .09

ATOM 1028 OH2 TIP 49 6 .818 -14 .559 2 .597 1 .00 40 .19

ATOM 1029 OH2 TIP 50 0 .841 11 .981 11 .314 1. .00 29 .54

ATOM 1030 OH2 TIP 51 28 .883 2 .247 1 .519 1 .00 29 .11

ATOM 1031 OH2 TIP 55 7 .237 8 .798 -2 .364 1 .00 38 .09

ATOM 1032 OH2 TIP 57 6 .119 6 .364 -2 .871 1 .00 32 .07

ATOM 1033 OH2 TIP 61 13 .756 -6. .904 -25 .714 1 .00 28, .50

ATOM 1034 OH2 TIP 69 21. .318 -7, .573 17 .105 1, .00 33. .06

ATOM 1035 OH2 TIP 73 17, .837 10, .425 7 .338 1, .00 31, .51

ATOM 1036 OH2 TIP 74 -4, .727 6, .408 10. .688 1, .00 28, .65

ATOM 1037 OH2 TIP 75 10, .181 8, .273 17. .212 1, .00 34, .61

ATOM 1038 OH2 TIP 78 -4, .315 -9. .183 11. .067 1, .00 37. .24

ATOM 1039 OH2 TIP 79 9. .720 7. .971 13. .783 1. .00 29. .86

ATOM 1040 OH2 TIP 83 9. .180 8. .999 -5. .667 1. .00 38. .94

ATOM 1041 OH2 TIP 86 11, .722 -14. .392 16, .007 1. .00 36. .57

ATOM 1042 OH2 TIP 94 10, .671 -10. .093 12, .691 1. .00 39. .60

ATOM 1043 OH2 TIP 96 8. .960 -10. .879 14. .873 1. .00 37. .16

ATOM 1044 OH2 TIP 99 11. .475 6. .909 -12. ,538 1. .00 33. .39

ATOM 1045 OH2 TIP 107 25. .085 -0. .335 -7. ,744 1. .00 37. .69

ATOM 1046 OH2 TIP 111 26. .394 4. .235 10. .194 1. .00 40. .36

ATOM 1047 OH2 TIP 112 10. .905 15. ,847 4. .965 1. .00 37. ,42

ATOM 1048 OH2 TIP 113 23. ,131 -4. ,734 19. ,014 1. .00 37. ,43

ATOM 1049 OH2 TIP 119 12. ,854 -9. ,131 -5. ,973 1. .00 41. ,17

ATOM 1050 OH2 TIP 127 -1. ,130 12. ,301 9. ,183 1. .00 45. ,98

ATOM 1051 OH2 TIP 202 15. .105 -9. ,190 6. ,006 1. .00 14. ,26

ATOM 1052 OH2 TIP 203 6. ,809 1. ,514 -5. .999 1. .00 14. ,57

ATOM 1053 OH2 TIP 204 14. .843 -7. ,591 -4. ,536 1. .00 22. ,84

ATOM 1054 OH2 TIP 207 19. ,732 11. ,192 2. ,402 1. .00 19. ,14

ATOM 1055 OH2 TIP 208 24. ,017 -6. ,876 2. .741 1. .00 16. ,70

ATOM 1056 OH2 TIP 209 2. ,183 -5. ,119 6. ,044 1. .00 17. ,66

ATOM 1057 OH2 TIP 311 5. ,440 -6. ,806 6. ,876 1. ,00 18. ,27

ATOM 1058 OH2 TIP 312 0. ,702 0. ,426 10. ,311 1. ,00 14. 15

ATOM 1059 OH2 TIP 314 3. ,832 10. ,613 3. 536 1. ,00 14. ,13

ATOM 1060 OH2 TIP 315 8. ,123 -5. .893 8. 395 1. ,00 15. 94

ATOM 1061 OH2 TIP 318 -3. ,076 9. ,191 8. 899 1. ,00 24. 66

ATOM 1062 OH2 TIP 321 ^" 14. 851 -8. ,620 -1. 269 1. ,00 15. 76

ATOM 1063 OH2 TIP 324 22. 586 -3. 791 -7. 366 1. ,00 23. 73

ATOM 1064 OH2 TIP 326 6. 574 5. 417 -5. 224 1. ,00 23. 59

ATOM 1065 OH2 TIP 329 14. 524 8. 137 9. 934 1. ,00 18. 76

ATOM 1066 OH2 TIP 330 21. 716 -5. 838 15. 028 1. .00 25. 21

ATOM 1067 OH2 TIP 331 21. 441 10. 788 -1. 071 1. ,00 15. 88

ATOM 1068 OH2 TIP 333 20. 258 2. 895 -7. 566 1. ,00 19. 13

ATOM 1069 OH2 TIP 335 4. 651 3. 491 -5. 084 1. ,00 21. 31

ATOM 1070 OH2 TIP 336 16. 444 -1. 373 18. 473 1. .00 22. 03

ATOM 1071 OH2 TIP 337 14. 127 -1. 978 -9. 380 1. 00 27. 17

ATOM 1072 OH2 TIP 338 -1. 567 6. 462 2. 804 1. 00 21. 70

ATOM 1073 OH2 TIP 339 10. 072 -5. 751 14. 815 1. 00 23. 74

ATOM 1074 OH2 TIP 340 -0. 122 -3. 825 7. 266 1. ,00 17. 13

ATOM 1075 OH2 TIP 341 21. 458 11. 967 4. 173 1. 00 18. 92 ATOM 1076 OH2 TIP 342 16.862 8.814 12.535 1.00 22.77

ATOM 1077 OH2 TIP 343 19 .781 -3. .592 -11 .754 1 .00 24 .76

ATOM 1078 OH2 TIP 344 8 .658 0 .473 -7, .745 1 .00 19 .43

ATOM 1079 OH2 TIP 345 22 .186 -10. .806 6 .880 1. .00 23 .12

ATOM 1080 OH2 TIP 346 1. .266 4 .989 15 .641 1. .00 22 .67

ATOM 1081 OH2 TIP 347 22, .981 -3. .789 16 .372 1. .00 20 .69

ATOM 1082 OH2 TIP 348 0, .244 -1. .344 8. .337 1. .00 20, .98

ATOM 1083 OH2 TIP 349 -6, .396 -0, .280 12, .436 1, .00 28, .00

ATOM 1084 OH2 TIP 350 -0, .266 10, .492 7, .429 1. .00 19, .27

ATOM 1085 OH2 TIP 351 13, .735 3, .563 -14, .036 1. .00 22, .41

ATOM 1086 OH2 TIP 352 5, .372 14, .284 15, .899 1. .00 24, .26

ATOM 1087 OH2 TIP 353 -3. .607 4, .669 2, .510 1. .00 21, .67

ATOM 1088 OH2 TIP 354 11. .487 -1. .713 -8. .475 1. .00 21. .30

ATOM 1089 OH2 TIP 356 11. .468 -7. .239 12 .765 1, .00 28, .08

ATOM 1090 OH2 TIP 357 4. .738 -7, .244 9, .580 1, .00 35. .31

ATOM 1091 OH2 TIP 358 6. .692 7, .788 -6. .448 1, .00 27. .00

ATOM 1092 OH2 TIP 1000 22. .770 -6, .588 -27, .789 1. .00 26. .34

ATOM 1093 OH2 TIP 1001 20. .518 10. .133 6, .008 1. .00 28. .86

ATOM 1094 OH2 TIP 1002 9, .235 0, .589 17, .696 1. .00 31. .22

ATOM 1095 OH2 TIP 1003 11. .238 0. .955 -10. .291 1. .00 30. .98

ATOM 1096 OH2 TIP 1004 15. .069 7. .390 -20. .328 1. .00 37. .80

ATOM 1097 OH2 TIP 1007 27. .285 -5. .370 9. .133 1. .00 32. .33

ATOM 1098 OH2 TIP 1011 13. .241 -8. .734 15. .288 1. .00 38. .17

ATOM 1099 OH2 TIP 1012 0. .914 11. .408 3. .137 1. .00 38. ,69

ATOM 1100 OH2 TIP 1013 13. .386 -13. .602 13. .887 1. ,00 41. .55

ATOM 1101 OH2 TIP 1014 -3. .491 8, ,595 3. .105 1. ,00 38. ,34

ATOM 1102 OH2 TIP 1015 24. .992 -2. ,292 15. .219 1. ,00 27. ,67

PEAK

ATOM 1103 OH2 TIP 1016 -0 .536 8 .607 1. .504 1 .00 31 .90

PEAK

ATOM 1104 OH2 TIP 1017 17 .106 11 .428 3. .479 1, .00 41 .60

PEAK

ATOM 1105 OH2 TIP 1018 26 .988 1, .824 -0. .133 1, .00 39 .68

PEAK

ATOM 1106 OH2 TIP 1019 2 .581 -9, .242 3. .541 1, .00 48. .35

PEAK

ATOM 1107 OH2 TIP 1020 22, .468 6. .790 -8. .416 1. .00 27, .69

PEAK

ATOM 1108 OH2 TIP 1021 10, .685 -9, .337 15. .963 1. .00 35, .75

PEAK

ATOM 1109 OH2 TIP 1022 5, .938 -6, .351 -5. .441 1. .00 41, .01

PEAK

ATOM 1110 OH2 TIP 1023 7, .831 -1, .592 22. .906 1. .00 39, .60

PEAK

ATOM 1111 OH2 TIP 1024 9, .287 15, .465 2. .806 1, .00 36, .23

PEAK

ATOM 1112 OH2 TIP 1025 5, .903 3, .927 19. .001 1. .00 33, .82

PEAK

ATOM 1113 OH2 TIP 1026 11. .696 -12, .766 11. .747 1, .00 38. .79

PEAK

ATOM 1114 OH2 TIP 1027 22, .887 -9. .170 15. .909 1. .00 41. .21

PEAK

ATOM 1115 OH2 TIP 1028 -5, .803 1. .927 14. .207 1. .00 34. .19

PEAK

ATOM 1116 OH2 TIP 1029 26, .228 1. .065 -5. ,860 1. ,00 46. .31

PEAK

ATOM 1117 OH2 TIP 1030 25. .458 2. .421 18. .721 1. ,00 39, .22

PEAK

ATOM 1118 OH2 TIP 1031 1, .561 10, .203 0. .829 1. .00 30, .76

PEAK

ATOM 1119 OH2 TIP 1032 28, .466 -3, .450 16. .373 1. .00 53, .13

PEAK ATOM 1120 OH2 TIP 1033 -0.908 11.869 4.960 1.00 29.27

PEAK

ATOM 1121 OH2 TIP 1034 0.760 7.592 15.893 1.00 35.48

PEAK

ATOM 1122 OH2 TIP 1035 30.967 -2.577 -0.881 1.00 42.11

PEAK

ATOM 1123 OH2 TIP 1036 14.249 9.085 -10.448 1.00 40.00

PEAK

ATOM 1124 OH2 TIP 1037 14.519 5.999 -14.689 1.00 42.25

PEAK

ATOM 1125 OH2 TIP 1038 17.619 -1.773 22.476 1.00 44.29

PEAK

ATOM 1126 OH2 TIP 1039 9.948 -19.717 -5.206 1.00 38.48

PEAK

ATOM 1127 OH2 TIP 1040 6.848 7.773 -9.276 1.00 40.41

PEAK

ATOM 1128 OH2 TIP 1041 29.548 -10.369 16.129 1.00 43.28

PEAK

ATOM 1129 OH2 TIP 1042 1.774 -12.234 -6.072 1.00 43.14

PEAK

ATOM 1130 OH2 TIP 1202 14.025 -8.172 8.531 1.00 31.63

ATOM 1131 CB VAL 4 28.023 0.286 -3.003 0.50 26.33

AC 2

ATOM 1132 CGI VAL 4 26.641 0.246 -2.377 0.50 25.78

AC 2

ATOM 1133 CG2 VAL 4 28.152 -0.776 -4.085 0.50 27.07

AC 2

ATOM 1134 CB ASN 31 23.380 4.017 -4.574 0.50 15.56

AC 2

ATOM 1135 CG ASN 31 24.867 3.907 -4.361 0.50 15.09

AC 2

ATOM 1136 ODl ASN 31 25.419 2.812 -4.312 0.50 15.81

AC 2

ATOM 1137 ND2 ASN 31 25.532 5.053 -4.251 0.50 18.05

AC 2

ATOM 1138 CB ILE 36 21.635 -3.520 6.116 0.50 12.23

AC 2

ATOM 1139 CG2 ILE 36 21.985 -4.444 4.969 0.50 12.15

AC 2

ATOM 1140 CGI ILE 36 22.420 -2.209 6.009 0.50 12.91

AC 2

ATOM 1141 CDl ILE 36 23.920 -2.385 6.150 0.50 14.36

AC 2

END

Ins(l,3,4,5)P₄-induced conformational changes

The activation of PKB by phosphorylation by PDKl is dependent on the ability of the PKB PH domain to interact with PtdIns(3,4)P₂ or PtdIns(3,4,5)P_α. This binding was suggested to induce a conformational change exposing Thr308 so that it can be phosphorylated by PDKl. However, such Ptdlns-induced conformational changes have not been observed in any of phosphoinositide-PH domain complexes solved previously [5]. We have therefore analysed the PKB_αPH structure to see whether we could detect any regions of this domain which might participate in binding to the kinase domain. This region would be expected to undergo a conformational change upon the binding of PtdIns(3,4,5)P₃. Furthermore, these residues are also likely to be removed from the 3-phosphoinositide ligand binding pocket as the PKB kinase domain would not be expected to interact with the membrane surface. We would also expect this region of the PH domain to be unique to PKB_α as other PtdIns(3,4,5)P₃ binding PH domains that have been characterised to date do not appear to undergo major conformational changes upon ligand binding.

Analysis of the electrostatic surface potential of our PKB_αPH-Ins(l,3,4,5)P₄ complex shows that apart from the phosphoinositide binding pocket, there is a further area of clustered basic residues (Arg 15, Lys20, Arg67 and Arg69) which do not participate in Ptdlns binding. These residues form a flat, highly positively charged surface which could bind to the negatively charged lipid membrane (Fig. 4A). In a previous study, Tsichlis and colleagues observed that mutation of Arg 15 to Ala significantly impaired PKB in PDGF stimulated NIH3T3 cells, although the molecular basis of this observation was not characterised further [12]. This would be in agreement with Arg 15 playing a key role in enabling PKB to interact with the membrane surface. In addition, in our model of how the PKB_αPH domain is oriented relative to the plasma membrane (Figs. IB, 4A), the DI phosphate is pointing down towards the membrane, allowing binding of the inositol head group while the di-acyl glycerol backbone is still embedded in the hydrophobic core of the lipid bilayer, as would be expected for a PH domain-membrane interaction. This mode of interaction of the PH domain of PKB with PtdIns(3,4,5)P₃ at the plasma membrane results in two of the variable loops, VL2 and VL3, pointing away from the membrane, providing possible docking sites for the PKB kinase domain without steric hindrance from the membrane surface (Figs. IB, 4A). VL3 (Fig. 2) forms a relatively short loop carrying uncharged side chains. In contrast, VL2 contains a high concentration of negatively charged residues (Glu40, Asp44, Asp46 and Glu49, Fig. 2). Unlike any other known PH domain structures that have been solved to date, this loop contains a short α-helix (Fig. 1C), and the charged residues occupy one side of the helix, facing away from the PH domain core, towards the solvent. In order for these loops to transmit the Ptdlns-binding event to the kinase domain they would most likely have to undergo a conformational change.

We next addressed whether the binding of the 3-phosphoinositides to the PKB PH domain induced any conformational changes in the PH domain structure. This was achieved by crystallisation of the apo-PKB_αPH domain and solving its structure using molecular replacement with synchrotron diffraction data, and subsequent refinement to 1.65 A resolution (R=0.203,

Comparing the apo-PKB_αPH domain structure with the structure bound to inositol(l,3,4,5)P revealed large (up to 7.6 A) displacements in the PKB_αPH backbone occur upon ligand binding. In apo- PKB_αPH the ligand binding-pocket is occupied by a hydrogen bonding network centred around an ionic interaction between Arg86/Lysl4 (which interact with the D3 and the D4 inositol phosphate groups in the complex) and Glul7, also involving Asn53 and several water molecules (Fig. 4B). This network partially occupies the space taken up by Ins(l,3,4,5)P₄ in the complex (Fig. 4B).

Hence, when the Ins(l,3,4,5)P or inositol(l,3,4)P₃ head group binds to the PH domain, these interactions are broken. The structure reveals that Glu 17 is pushed outwards, resulting in a relatively minor conformational change of VL1, with backbone shifts up to 2.5 A. Apart from interacting with the lipid head group through the D4 phosphate, Arg86 follows the movement of Glul7 when the ligand binds (Fig. 4B). Arg86 lies at the base of VL3 and pulls the entire loop closer to the phosphoinositide binding pocket, leading to backbone shifts at the tip of VL3 of up to 7.4 A, at Trp80. Interestingly, this residue is disordered in the apo-PKB_αPH structure, and is ordered, yet fully exposed, in PKB PH-Ins(l,3,4,5)P₄ complex. The most dramatic changes, however, are observed in VL2. In apo-PKB_αPH, side chains on this loop are not well defined by the electron density maps, and the backbone does not assume ordered secondary structure. Upon ligand binding, however, the entire loop is rearranged (with backbone shifts up to 7.6 A on Glu49), forming an ordered α-helix with 3-4 negative charges (Asp44, Asp46, Glu49 and to a lesser extent Glu40) clustered together (Figs. 4A, B), facing the solvent. If VL2 in the absence of 3- phosphoinositides formed an intra-molecular interaction with the PKB kinase domain, it is possible that upon 3-phosphoinositide binding this clustering, together with the large conformational change of VL2, could dislodge this loop from the PKB kinase domain, allowing PDKl to phosphorylate Thr308. Tsichlis and colleagues reported that mutation of Glu40 (at the base of VL2) to a Lys increased 2 to 3 -fold the activity of PKB in unstimulated and wortmannin treated cells and enabled PDKl to phosphorylate this mutant efficiently at lower concentrations of PtdIns(3,4,5)P₃ in vitro than wild type PKB [12]. We interpret their finding as indicating that the PKB (E40K) mutant interacted with higher affinity with PtdIns(3,4,5)P₃. However, an alternative explanation is that in the PKB (E40K) mutant, the VL2 region of the PKB PH domain is less able to interact with the PKB kinase domain thereby promoting the ability of PDKl to phosphorylate Thr308 efficiently in the absence of PtdIns(3,4,5)P₃.

Summarising, the comparison of the apo-PKB_αPH and PKB_αPH- Ins(l,3,4,5)P₄ structures shows that there are several significant conformational changes upon Ins(l,3,4,5)P₄ binding. Such ligand induced conformational changes have not previously been observed in PtdIns(3,4,5)P₃-binding PH domains, such as DAPP1 [22], GRP1 [22, 23] and BTK [21]. VL2 and VL3, which both point away from the membrane surface and undergo large conformational changes, appear to be candidate docking sites for the kinase domain of PKB.

Mutagenesis of key residues in the binding pocket

The structure indicates that the interactions of PKB with the D3 and D4- phosphate groups of the inositol ring that are the key determinants in enabling PKB to interact with PtdIns(3,4,5)P₃ and PtdIns(3,4)P₂. To further investigate the molecular basis of the lipid binding specificity of the PKB PH domain, we constructed several full-length PKB variants with mutations in the lipid binding pocket, and evaluated their interaction for PtdIns(3,4)P₂ or PtdIns(3,4,5)P₃ using the protein-lipid overlay assay which has been used by many groups to assess the lipid binding properties of PKB and other PH domain containing proteins [17, 18, 19] (Fig. 3).

Characterisation of PKB mutants

The wild type and mutants of PKB used for the lipid binding experiments were expressed in human embryonic kidney 293 cells and purified as described before [14]. Lipid binding studies were carried out using the protein-lipid overlay assay described previously [19]. Restriction enzyme digests, DNA ligations, Polymerase Chain Reaction cloning and site directed mutagenesis were performed using standard protocols. All DNA constructs were verified by DNA sequencing (The Sequencing Service, School of Life Sciences, University of Dundee). All the phosphoinositides used in this study were dipalmitoyl derivatives obtained from Echelon. Hybond-C extra, the pGEX4T-l vector, Enhanced Chemiluminescence reagent, thrombin protease and Glutathione-Sepharose were from Amersham Pharmacia Biotech; Protease Inhibitor tablets were from Roche; Benzamidine-Agarose and monoclonal anti-Glutathione-S-Transferase (GST) antibody were from Sigma; anti-goat anti mouse-horseradish peroxidase conjugated secondary antibody was from Pierce.

Results

Full length PKB interacted with both PtdIns(3,4,5)P₃ and PtdIns(3,4)P₂ but a mutant lacking the entire PH domain (ΔPH-PKB) did not detectably interact with these phosphoinositides (Fig. 3, panel B). Affinity of PKB_α for the DI -phosphate was addressed by mutating Arg23 to Ala. The PKB(R23A) was still capable of interacting with both PtdIns(3,4,5)P₃ and PtdIns(3,4)P₂, albeit with reduced affinity compared to the wild type PKB_α (Fig. 3, panel F), indicating that the observed interaction of Arg23 with the DI -phosphate plays a role in regulating the overall affinity of PKB with 3- phosphoinositides .

A more dramatic effect is observed when Arg25, which binds the D3- phosphate, is mutated to either Ala or Cys (Fig. 3, panels C and D). Binding of PtdIns(3,4)P₂ or PtdIns(3,4,5)P₃ to these mutants is almost completely lost, confirming the importance of that this interaction plays in permitting PKB to bind Ptdins(3,4,5)P₃. Mutation of the equivalent Arg residue in the PH domain of the Bruton's tyrosine kinase has also been shown to prevent the interaction with PtdIns(3,4,5)P₃, and the corresponding mutation in humans causes X-linked agammaglobulinaemia, an inherited immune disease [20, 21]. Complete loss of the binding of PtdIns(3,4,5)P₃ and PtdIns(3,4)P₂ to PKB_α is also observed when Lys 14, which interacts with both the D3/D4-phosphate groups, is mutated to Ala (Fig. 3, panel E). Taken together, the mutations and the structure suggest that in particular the D3 and D4 phosphates play a key role in enabling PKB_α to interact specifically with PtdIns(3,4,5)P₃ and PtdIns(3,4)P₂, whereas the DI -phosphate plays only a supporting role. It is worth noting that not only in native PKB_α, but also in all mutants that we generated, PtdIns(3,4)P₂ and PtdIns(3,4,5)P₃ bind with similar affinity, further emphasising that the D5-phosphate plays no role in mediating the binding of PKB-PH to phosphoinositides.

EXAMPLE II: PH domain modulators and mimics

Introduction

As the binding of PKB-PH to membrane-embedded 3-phosphoinositides is a prerequisite for activation of PKB by PDKl, small molecules that interact with the ligand-binding pocket of the PKB-PH, could prevent PKB from interacting with PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ and thus prevent its activation in cells.

PKB activation would be expected to impair growth and promote apoptosis of cancer cell lines in which PKB activity is elevated. Recently there have been two reports on molecules that interfere with the binding to PKB-PH to phosphoinositides. In the first, it was described how treatment of cells with C2-ceramide induced recruitment of PKB to the membrane [24]. However, it is not clear how these lipids can resemble phosphoinositides, and our structure does not provide any further clues how this might work. In a second study, phosphoinositide derivatives were synthesised that contained a hydroxymethyl group at the D3 position, and/or a carbonate rather than a phosphate group at DI [25, 26, 27]. These compounds were shown to inhibit PDGF-induced PKB phosphorylation and inhibited the growth of four different cancer cell lines. Although a detailed analysis of how these compounds specifically inhibited PKB activation was not performed, our results indicate that they may function by binding to PKB-PH, thereby preventing it from interacting with PtdIns(3,4,5)P₃ without inducing the conformational change required for activation. Analysing the PKB_αPH domain structure provided herein indicates that the replacement of the D3 phosphate with either a hydrogen or a hydroxymethyl group would reduce the steric hindrance with Asn53, which partially occupies the Ptdlns binding pocket in the apo structure (Figs. 4B and C). As noted above, it appears to be the shift of Asn53, at the base of VL2, that enables the large conformational change of this loop to occur following ligand binding. Thus it is indeed possible that compounds not bearing a bulky phosphate at the D3 position but rather a shorter hydroxymethyl group could still bind PKB- PH with significant affinity, but not induce the conformational change required for activation.

It may also be desirable to develop compounds that bind to the 3- phosphoinositide ligand binding site of PKB-PH and induce a similar conformational change as the binding of Ins(l,3,4,5)P₄. This could promote the PtdIns(3,4,5)P -independent activation of PKB by PDKl which could be used to stimulate insulin dependent responses in diabetic patients or promote the survival of neuronal cells following a stroke.

Cysteine Incorporation Assay

One method for identifying compounds which modulate the interaction between PKB and PtdIns(3,4,5)P₃) or PtdIns(3,4)P₂, consists of determining whether, and optionally to what extent, a conformational change in the pleckstrin homology domain of the PKB upon contact with PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂, is enhanced or disrupted in the presence of the compound.

Similarly, one method for identifying compounds which mimic the effect of PtdIns(3,4,5)P₃ or PtdIns(3,4)P_2> on PKB comprises determining whether, and optionally to what extent, a conformational change in a PH domain of the PKB upon contact with the compound, matches a conformational change in the PH domain of the PKB upon contact with the PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂.

The conformational change could be measured indirectly by substituting an amino acid residue of the PH domain with a detectably-labelled cysteine residue, for example fluorescently-labelled, and detecting a change in fluorescence intensity or frequency, which corresponds to the conformational change.

Preferably, the substituted amino acid residue of the PH domain is not involved in binding to PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂, so when it is mutated there is no effect on the capacity/ability of PKB to bind the ligand, and would not be selected from Lys 14, He 19, Arg23, Arg25, Asn53 and Arg86 of the 123 residues of the PH domain.

Further preferably, the substituted amino acid residue of the PH domain is not involved in binding to a negatively charged lipid membrane, and would not be selected from residues Argl5, Lys20, Arg67 and Arg69 of the 123 residues of the PH domain.

It is preferred that the substituted amino acid residue of the PH domain is exposed to the solvent, and is located close to the binding pocket such that when the ligand is not bound to the PH domain, the fluorophore is located in the binding pocket. Preferably, the substituted amino acid residue of the PH domain is selected from a residue located in VL1. More preferably, the substituted amino acid residue is selected from Glu 17, Glu 18, and Tyrl9 of SEQ ID NO: 1.

A cysteine residue is incorporated into the PH domain and is covalently modified with a detectable molecule such as BADAN (6-bromoacetyl-2- dimethylaminonaphthalene) from Molecular Probes. The binding affinity is measured by titrating a known or suspected ligand into the derivatised protein solution, and measuring fluorescent changes with a fluorimeter or spectrophotometer at a relevant wavelength. Changes in fluorescence are caused by the displacement of BADAN from the ligand binding site by the ligand, and the fluorescence is proportional to the level of displacement. Thus conformational changes can be measured to identify compounds that modulate or mimic the interaction between PKB and PtdIns(3,4,5)P₃) or PtdIns(3,4)P₂. Methods for performing such an assay have been described previously [38, 39], incorporated herein by reference.

Other Methods

Other approaches that can be employed to assess protein-lipid interactions, and to measure the binding of various new compounds that could be potential inhibitors of PKB include:

1. Lipid vesicle sedimentation assays, which have been widely used to investigate the phosphoinositi de-binding properties of proteins (James et al., 1996; Stephens et al., 1998). Purified proteins are incubated with lipid vesicles that contain a mixture of phospholipids that attempt to mimic the lipid composition of the plasma membrane, and a small mole fraction of the test lipid. The vesicle also contains sucrose so that they can be sedimented by ultracentrifugation. If the protein binds to the lipid vesicle, following ultracentrifugation, this is observed as a re-distribution of the protein from the supernatant to the pellet fraction. Microgram amounts of protein are required for this approach.

2. Protein Lipid Overlay assay, which is described in Dowler et al., (2000).

3. Isothermal titration calorimetry (Kavran et al., 1998), in which the protein-lipid interaction are detected by measuring the small changes in temperature that are associated with the interaction of the protein with a lipid. The data from these experiments can be used to calculate the thermodynamic properties of the interaction, such as Gibbs free energy, and kinetic parameters such as the binding and dissociation constants. Milligram amounts of protein are required for this approach and soluble forms of lipids are usually employed.

4. Measuring the kinetics of protein binding to the test lipid by surface plasmon resonance (SPR) (Currie et al., 1999; Hodgkin et al, 2000). A biosensor chip is coated with a lipid monolayer containing a small mole fraction of the test lipid. The purified protein is washed over the chip and protein bound to the chip by virtue of interaction with the test lipid can be detected as a change in the defractive index across the cell. These experiments generate characteristic binding and dissociation curves that can be used to calculate the apparent binding and dissociation constants. Microgram amounts of protein are required for this approach.

5. Using a gel filtration-based approach to determine the ability of a PH domain to bind water-soluble forms of a lipid such as the inositol head groups of phosphoinositides (Ferguson et al., 2000; Lemmon et al., 1995). The PH domain is incubated with a radioactively labelled inositol head group and then fractionated by gel filtration chromatography. If the radioactively labelled inositol interacts with the PH domain, a peak of radioactivity that co-elutes with the protein is observed on gel filtration. Microgram amounts of protein are required for this approach.

6. The ability of proteins to interact with phosphoinositide lipids has also been analysed by incubating purified proteins with phosphoinositide lipids that have been covalently attached to agarose beads in the absence or presence of soluble phosphoinositides (Krugmann et al., 2002). The beads are then isolated by centrifugation, washed and immunoblotted to verify whether protein interacted with the resin.

In silico identification

Compounds that bind to the PH domain of PKB can be identified in silico. Several methods for so doing are made possible based upon the structure of the PH domain provided herein.

Several in silico methods could be employed, for example, via a substructure search for new ligands using programmes such as CHEM DRAW or CHEM FINDER. We take the basic structure of the natural ligand and take various structural features of it (i.e. the inositol ring) then submit this to a the programme which will searches a set of chemical company catalogues for chemicals containing this substructure.

These compounds are then screened by eye for groups that could not interact with the ligand binding site of the PH domain because, for example, they are too large or have steric or charge hindrance, and those are discarded. The remaining chemicals are submitted to a PRODRG server and topologies/co-ordinates for these chemicals are created. These chemicals are modelled into the structure, from which chemicals that are possibly able to bind to the ligand binding site of the PH domain are selected. Further details of the PRODRG programme are available at http://davapc 1.bioch.dundee.ac.uk/programs/prodrg/prodrg.html. These compounds are then ordered, crystallised with the protein and their binding capabilities assessed by techniques such as ITC, FAT BLOTS, or the fluorescently labelled protein. Compounds selected via this method for testing as modulators or mimics of 3-phosphoinositide binding to the PKB PH domain include: 4,5,-dihydroxy-l,3_benzenedisulfonic acid disodium salt monohydrate; 4 sulfophthalic acid; 1 ,2,4-benzenetricarboxylic acid; 1- O-Octyl-beta-D-glucopyranoside; myo-inositol hexasulfate; 1,3,4,6-tetra-O- acetly-2-O-trifluoromethane; and sulfonyl-beta-D mannopyranose acetobromo-alpha-D-galactose.

An alternative approach is to use PRODRG: a tool for generating GROMOS/MOL2/WHATIF topologies and hydrogen atom positions from small molecule PDB files. We take the natural ligand and computationally vary all possible groups at each site on the ligand, with a variety of new groups while the protein co-ordinates and the ligand back-bone co-ordinates remain fixed the results can then be screened for hindrance and repulsion, and the molecules are obtained either through catalogues or made.

Conclusions

In this study we have defined the key interactions that enable Ins(l,3,4,5)P₄ to bind PKB_αPH. We explained why PKB can bind both PtdIns(3,4,5)P₃ and PtdIns(3,4)P₂ with equal affinity, due to absence of any ordered interactions with the D5-phosphate. A mutagenesis strategy, rationally designed on the basis of our structure, has shown that both the D3 and D4 phosphates contribute the major share of the binding affinity. We have also shown, for the first time, that PH domains are not only static binding modules, but can respond to phosphoinositide binding by undergoing large conformational changes. The observed conformational changes mainly occur in two loops, VL2 and VL3, both pointing away from the membrane surface, one of which (VL2) not only changes conformation but also its charge distribution. We postulate that this loop is a likely candidate for transmitting the phosphoinositide binding event, leading to exposure of Thr308 on the kinase domain and subsequent phosphorylation by PDKl. Thus, our structures support previous evidence that that translocation of PKB to the membrane is in itself not enough to trigger its activation, but in addition a 3-phosphoinositide mediated conformational change is also required. Our high resolution structures also provide a defined three dimensional scaffold for the design of small molecules with anti-cancer, anti-apoptosis, or anti-diabetes properties.

REFERENCES

[1] B. Vanhaesebroeck, S. J. Leevers, K. Ahmadi, J. Timms, R. Katso, P. C. Driscoll, R.Woscholski, P. J. Parker, and M. D. Waterfield, Synthesis and function of 3-phosphorylated inositol lipids, Annu.Rev. Biochem., 70, 535- 602 (2001).

[2] S. J. Leevers, B. Vanhaesebroeck, and M. D. Waterfield, Signalling through phosphoinositide 3- kinases: the lipids take centre stage, Curr Opin Cell Biol, 11, 219-25 (1999).

[3] A. Toker and L. C. Cantley, Signalling through the lipid products of phosphoinositide-3-OH kinase, Nature, 387, 673-676 (1997).

[4] S. J. Isakoff, T. Cardozo, J. Andreev, Z. Li, K. M. Ferguson, R. Abagyan, M. A. Lemmon, A. Aronheim, and E. Y. Skolnik, Identification and analysis of PH domain-containing targets of phosphatidylinositol 3- kinase using a novel in vivo assay in yeast, EMBO J., 17, 5374-5387 (1998).

[5] M. A. Lemmon and K. M. Ferguson, Signal-dependent membrane targeting by pleckstrin homology (PH) domains, Biochem J, 350, 1-18 (2000).

[6] D. P. Brazil and B. A. Hemmings, Ten years of protein kinase B signalling: a hard Akt to follow, Trends Biochem.Sci., 26, 657-664 (2001).

[7] J. Downward, Mechanisms and consequences of activation of protein kinase B/Akt, Curr. Opin. Cell Biol, 10, 262-267 (1998).

[8] M. A. Lawlor and D. R. Alessi, PKB/Akt: a key mediator of cell proliferation, survival and insulin responses?, J.Cell Sci., 114, 2903-2910 (2001). [9] M. Freeh, M. Andjelkovic, E. Ingley, K. K. Reddy, J. R. Falck, and B. A. Hemmings, High affinity binding of inositol phosphates and phosphoinositides to the Pleckstrin homology domain of RAC protein kinase B and their influence on kinase activity, J.Biol.Chem., 272, 8474- 8481 (1997).

[10] S. R. James, C. P. Downes, R. Gigg, S. J. A. Grove, A. B. Holmes, and D. R. Alessi, Specific binding of the Akt-1 protein kinase to phosphatidylinositol 3,4,5-trisphosphate without subsequent activation, BiochemJ., 315, 709-713 (1996).

[11] M. Andjelkovic, D. R. Alessi, R. Meier, A. Fernandez, N. J. C. Lamb, M. Freeh, P. Cron, P. Cohen, J. M. Lucocq, and B. A. Hemmings, Role of translocation in the activation and function of protein kinase B, J.Biol.Chem., 272, 31515-31524 (1997).

[12] A. Bellacosa, T. O. Chan, N. N. Ahmed, K. Datta, S. Malstrom, D. Stokoe, F. McCormick, J. N. Feng, and P. Tsichlis, Akt activation by growth factors is a multiple-step process: the role of the PH domain, Oncogene, 17, 313-325 (1998).

[13] S. J. Watton and J. Downward, Akt/PKB localisation and 3- phosphoinositide generation at sites of epithelial cell-matrix and cell-cell interaction, Curr.Biol, 9, 433-436 (1999).

[14] D. R. Alessi, M. Deak, A. Casamayor, F. B. Caudwell, N. Morrice, D. G. Norman, P. Gaffhey, C. B. Reese, C. N. MacDougall, D. Harbison, A. Ashworth, and M. Bownes, 3-phosphoinositide-dependent protein kinase- 1 (PDKl): structural and functional homology with the DrosophilaDSTPK61 kinase, Curr.Biol, 7, 776-789 (1997). [15] D. Stokoe, L. R. Stephens, T. Copeland, P. R. J. Gaffney, C. B. Reese, G. F. Painter, A. B. Holmes, F. McCormick, and P. T. Hawkins, Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B, Science, 277, 567-570 (1997).

[16] R. M. Biondi, A. Kieloch, R. A. Currie, M. Deak, and D. R. Alessi, The PIF-binding pocket in PDKl is essential for activation of S6K and SGK, but not PKB, EMBO J., 20, 4380-4390 (2001).

[17] F. Kanai, H. Liu, S. J. Field, H. Akbary, T. Matsuo, G. E. Brown, L. C. Cantley, and M. B. Yaffe, The PX domains of p47phox and p40phox bind to lipid products of P1(3)K, Nat.Cell Biol, 3, 675-678 (2001).

[18] S. Krugmann, K. E. Anderson, S. H. Ridley, N. Risso, A. McGregor, J. Coadwell, K. Davidson, A. Eguinoa, C. D. Ellson, P. Lipp, M. Manifava, N. Ktistakis, G. Painter, J. W. Thuring, M. A. Cooper, Z. Y. Lim, A. B. Holmes, S. K. Dove, R. H. Michell, A. Grewal, A. Nazarian, H. Erdjument- Bromage, P. Tempst, L. R. Stephens, and P. T. Hawkins, Identification of ARAP3, a novel PI3K effector regulating both Arf and Rho GTPases, by selective capture on phosphoinositide affinity matrices, Mol.Cell, 9, 95-108 (2002).

[19] S. Dowler, R. A. Currie, D. G. Campbell, M. Deak, G. Kular, C. P. Downes, and D. R. Alessi, Identification of pleckstrin-homology-domain- containing proteins with novel phosphoinositide- binding specificities, Biochem J, 351, 19-31 (2000).

[20] C. I. E. Smith, K. B. Islam, I. Vorechovsky, O. Olerup, E. Wallin, H. Rabbani, B. Baskin, and L. Hammarstrom, X-linked agammaglobulinemia and other immunoglobulin deficiencies, ImmunolRev., 138, 159-183 (1994). [21] M. Hyvonen and M. Saraste, Structure of the PH domain and Btk motif from Bruton's tyrosine kinase: Molecular explanations for X-linked agammaglobulinaemia, EMBO J., 16, 3396-3404 (1997).

[22] K. M. Ferguson, J. M Kavran, V. G. Sankaran, E. Fournier, S. J. Isakoff, E. Y. Skolnik, and M. A. Lemmon, Structural basis for discrimination of 3-phosphoinositides by pleckstrin homology domains, Mol Cell, 6, 373-84 (2000).

[23] S. E. Lietzke, S. Bose, T. Cronin, J. Klarlund, A. Chawla, M. P. Czech, and D. G. Lambright, Structural basis of 3-phosphoinositide recognition by pleckstrin homology domains, Mol Cell, 6, 385-94 (2000).

[24] S. Stratford, D. B. DeWald, and S. A. Summers, Ceramide dissociates 3 '-phosphoinositide production from pleckstrin homology domain translocation, Biochem.J., 354, 359-368 (2001).

[25] A. P. Kozikowski, J. J. Kiddle, T. Frew, M. Berggren, and G. Powis, Synthesis and biology of lD-3-deoxyphosphatidylinositol - a putative antimetabolite of phosphatidylinositol- 3 -phosphate and an inhibitor of cancer cell colony formation, J.Med.Chem., 38, 1053-1056 (1995).

[26] Y. H. Hu, L. X. Qiao, S. M. Wang, S. B. Rong, E. J. Meuillet, M. Berggren, A. Gallegos, G. Powis, and A. P. Kozikowski, 3- (Hydroxymethyl)-bearing phosphatidylinositol ether lipid analogues and carbonate surrogates block PI3-K, Akt, and cancer cell growth, J.Med.Chem., 43, 3045-3051 (2000).

[27] S. B. Rong, Y. H. Hu, I. Enyedy, G. Powis, E. J. Meuillet, X.W.Wu, R. X.Wang, S. M.Wang, and A. P. Kozikowski, Molecular modeling studies of the Akt PH domain and its interaction with phosphoinositides, J.Med.Chem., 44, 898-908 (2001). [28] C. C. Thomas, S. J. Dowler, M. Deak, D. R. Alessi, and D. M. F. van Aalten, Crystal structure of the phosphatidylinositol (3,4)-bisphosphate binding PH domain of TAPP1 - molecular basis of lipid specificity, BiochemJ., 358, 287-294 (2001).

[29] M. S. Alphey, G. A. Leonard, D. G. Gourley, E. Tetaud, A. H. Fairlamb, and W. N. Hunter, The high resolution crystal structure of recombinant Crithidia fasciculata tryparedoxin-I, J.Biol.Chem., 274, 25613- 25622 (1999).

[30] Z. Otwinowski and W. Minor, Processing of X-ray diffraction data collected in oscillation mode, Methods in Enzymology, 276, 307-326 (1997).

[31] T. C. Terwilliger and J. Berendzen, Automated MAD and MIR structure solution, Ada Cryst., D55, 849-861 (1999).

[32] K. Cowtan, Joint CCP4 and ESF-EACBM Newsletter on Protein Crystallography, 31, 34-38 (1994).

[33] A. Perrakis, R. Morris, and V. S. Lamzin, Automated protein model building combined with iterative structure refinement, Nature Struct.Biol, 6, 458-463 (1999).

[34] T. A. Jones, J. Y. Zou, S. W. Cowan, and M. Kjeldgaard, Improved methods for building protein models in electron density maps and the location of errors in these models, Ada Cryst., A47, 110-119 (1991).

[35] A. T. Brunger, P. D. Adams, G. M. Clore, P. Gros, R. W. Grosse- Kunstleve, J.-S. Jiang, J. Kuszewski, M. Nilges, N. S. Pannu, R. J. Read, L. M. Rice, T. Simonson, and G. L. Warren, Crystallography and NMR system: A new software system for macromolecular structure determination, Ada Cryst., D54, 905-921 (1998). [36] J. Navaza, AMoRe: an automated package for molecular replacement, Ada Cryst., A50, 157- 163 (1994).

[37] G. Vriend, WHAT IF: a molecular modeling and drug design program, J. Mol. Graph., 8, 52-56 (1990).

[38] G. V. Richeire et al., A Fluorescently Labelled Intestinal Fatty Acid Binding Protein, J. Biol Chem. 267, 33, pp23495-23501.(1992).

[39] M.C.T.Wadum et al, Fluorescently labelled bovine acyl-CoA binding protein - an acyl-Co A sensor. Interaction with CoA and acyl-CoA esters and its use in measuring free acyl CoA esters and non-esterifred fatty acids (NEFA).

Currie, R.A., Walker, K.S., Gray, A., Deak, M., Casamayor, A., Downes, C.P., Cohen, P., Alessi, D.R. and Lucocq, J. (1999) Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localisation of 3-phosphoinositide-dependent protein kinase- 1. Biochem J, 337, 575-83.

Dowler, S., Currie, R.A., Campbell, D.G., Deak, M., Kular, G., Downes, C.P. and Alessi, D.R. (2000) Identification of pleckstrin-homology-domain- containing proteins with novel phosphoinositide-binding specificities. Biochem J, 351, 19-31.

Ferguson, K.M., Kavran, J.M., Sankaran, V.G., Fournier, E., Isakoff, S.J., Skolnik, E.Y. and Lemmon, M.A. (2000) Structural basis for discrimination of 3-phosphoinositides by pleckstrin homology domains. Mol Cell, 6, 373- 84.

Hodgkin, M.N., Masson, M.R., Powner, D., Saqib, K.M., Ponting, C.P. and Wakelam, M.J. (2000) Phospholipase D regulation and localisation is dependent upon a phosphatidylinositol 4,5-biphosphate-specific PH domain. Curr Biol, 10, 43-6.

James, S.R., Downes, C.P., Gigg, R., Grove, S.J., Holmes, A.B. and Alessi, D.R. (1996) Specific binding of the Akt-1 protein kinase to phosphatidylinositol 3,4,5-trisphosphate without subsequent activation. Biochem J, 315, 709-13.

Kavran, J.M., Klein, D.E., Lee, A., Falasca, M., Isakoff, S.J., Skolnik, EN. and Lemmon, M.A. (1998) Specificity and promiscuity in phosphoinositide binding by pleckstrin homology domains. JBiol Chem, 213, 30497-508.

Krugmann, S., Anderson, K.E., Ridley, S.H., Risso, Ν., McGregor, A., Coadwell, J., Davidson, K., Eguinoa, A., Ellson, CD., Lipp, P., Manifava, M., Ktistakis, Ν., Painter, G., Thuring, J.W., Cooper, M.A., Lim, Z.Y., Holmes, A.B., Dove, S.K., Michell, R.H., Grewal, A., Νazarian, A., Erdjument-Bromage, H., Tempst, P., Stephens, L.R. and Hawkins, P.T. (2002) Identification of ARAP3, a Novel PI3K Effector Regulating Both Arf and Rho GTPases, by Selective Capture on Phosphoinositide Affinity Matrices. Mol Cell *,ι 9 ^■',i 95-108.

Lemmon, M.A., Ferguson, K.M., O'Brien, R., Sigler, P.B. and Schlessinger, J., (1995) Specific and high-affinity binding of inositol phosphates to an isolated pleckstrin homology domain. Proc Natl Acad Sci USA, 92, 10472- 10476.

Stephens, L., Anderson, K., Stokoe, D., Erdjument-Bromage, H., Painter, G.F., Holmes, A.B., Gaffney, P.R., Reese, C.B., McCormick, F., Tempst, P., Coadwell, J. and Hawkins, P.T. (1998) Protein kinase B kinases that mediate phosphatidylinositol 3,4,5- trisphosphate-dependent activation of protein kinase B. Science, 279, 710-4.

Claims

1. A method of identifying a compound which modulates the interaction between protein kinase B (PKB) and phosphatidylinositol (3,4,5)-triphosphate (PtdIns(3,4,5)P₃) or phosphatidylinositol (3,4)- diphosphate (PtdIns(3,4)P₂), the method comprising determining whether, and optionally to what extent, a conformational change in a pleckstrin homology (PH) domain of PKB upon contact with PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂, is enhanced or disrupted in the presence of the compound.

2. A method of identifying a compound which mimics the effect of PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ on PKB, the method comprising determining whether, and optionally to what extent, a conformational change in a PH domain of PKB upon contact with the compound, matches a conformational change in the PH domain upon contact with the PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂.

3. The method of claim 1 or 2 further comprising the step of determining the conformational change in the PH domain of the PKB upon contact with the PtdIns(3,4,5)P or the PtdIns(3,4)P₂ in the absence of the compound.

4. A method according to any of claims 1-3, wherein the PH domain comprises the amino acid sequence of SEQ ID No: 1, or a fragment, variant, derivative or fusion thereof.

5. The method of any of claims 1-4, wherein determining the conformational change comprises using 3D structural co-ordinates of the PH domain bound to a 3-phosphoinositide or headgroup thereof, and/or the 3D structural co-ordinates of the PH domain alone, or a subset thereof, and a molecular modelling technique.

6. The method of any of claims 1-4, wherein determining the conformational change comprises directly measuring the conformational change.

7. The method of claim 6 wherein directly measuring the conformational change comprises use of one or more of NMR, X-ray crystallography, FRET, and circular dichroism.

8. The method of any of claims 1-4, wherein determining the conformational change comprises indirectly measuring the conformational change.

9. The method of claim 8, wherein at least one amino acid residue of the PH domain is substituted with a detectably-labelled cysteine residue, and wherein indirectly measuring the conformational change comprises detecting the label.

10. The method of claim 9 wherein the detectably-labelled cysteine residue is fluorescently-labelled, and detecting the label comprises detecting a change in fluorescence intensity or frequency.

11. The method of claim 9, wherein the substituted amino acid residue of the PH domain is not involved in binding to PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂.

12. The method of claim 11, wherein the substituted amino acid residue is selected from residues 1-123 of SEQ ID No 1, with the exception of Lys 14, He 19, Arg23, Arg25, Asn53 and Arg86.

13. The method of claim 9, wherein the substituted amino acid residue of the PH domain is not involved in binding to a negatively charged lipid membrane.

14. The method of claim 13, wherein the substituted amino acid residue is selected from residues 1-123 of SEQ ID No 1, with the exception of Argl5, Lys20, Arg67 and Arg69.

15. The method of claim 9, wherein the substituted amino acid residue is selected from a residue located in VL1.

16. The method of claim 15, wherein the substituted amino acid residue is selected from Glul7, Glul8, and Tyrl9 of SEQ ID NO: 1.

17. A method of selecting or designing a compound to be used in the method of any one of the preceding claims, the method comprising using the 3D structural co-ordinates of the PH domain bound to a 3- phosphoinositide or headgroup thereof, and/or the 3D structural coordinates of the PH domain alone, or a subset thereof, and a molecular modelling technique, to select the compound from a plurality of test compounds.

18. The method according to claim 17, and also comprising the steps of: identifying, in at least one database of chemical structures, a set of test compounds containing a specific structural feature; identifying a subset of test compounds by discarding from the set of test compounds those compounds that are obviously unable to bind to the PKB PH domain based upon their size, charge or steric hindrance; and using the 3D structural co-ordinates of the PH domain bound to the 3-phosphoinositide or headgroup thereof, and/or the 3D structural coordinates of the PH domain alone, or a subset thereof, and a molecular modelling technique, to identify from the subset of test compounds a compound likely to be able to bind to the PH domain.

19. The method according to claim 17, and also comprising: varying the possible atoms at each site on the 3-phosphoinositide or headgroup thereof that is identified in the 3D structural co-ordinates of the PH domain bound to the 3-phosphoinositide or headgroup thereof, as being in contact with the PH domain; and screening for compounds that minimise repulsion or hindrance while keeping the remaining protein co-ordinates and ligand co-ordinates of the PH domain bound to the 3-phosphoinositide or headgroup thereof, fixed.

20. The method according to any one of claims 5, 17, 18 or 19 wherein using the 3D structural co-ordinates of the PH domain bound to a 3- phosphoinositide or headgroup thereof, and/or the 3D structural coordinates of the PH domain alone, or a subset thereof, comprises using a molecular model of a PH domain derived from the 3D structural coordinates of the PH domain bound to a 3-phosphoinsotide or headgroup thereof, and or the 3D structural co-ordinates of the PH domain alone, or a subset thereof.

21. The method according to any one of claims 5, 17, 18, 19 or 20 wherein using the 3D structural co-ordinates of the PH domain bound to a 3-phosphoinositide or headgroup thereof, or subset thereof, comprises using the 3D structural co-ordinates of PKB_αPH-Ins(l,3,4,5)P as set forth in Table 2, or a subset thereof.

22. The method according to any one of claims 5, 17, 18, 19, 20 or 21 wherein using the 3D structural co-ordinates of the PH domain alone, or a subset thereof, comprises using the 3D structural co-ordinates of apo PKBJPH as set forth in Table 3, or a subset thereof.

23. A PKB having at least one amino acid residue of the PH domain substituted by a detectably-labelled cysteine residue.

24. A PKB having at least one amino acid residue of the PH domain substituted by a cysteine residue that can be detectably-labelled.

25. The PKB of claim 23 or 24, wherein the substituted amino acid residue is as defined in any of claims 11-16.

26. Use of the PKB as defined in claim 23 or 25, in an assay for detecting conformational change of the PH domain.

27 A kit of parts comprising a PKB as defined in claim 23, 24 or 25, and a means for carrying out the method as defined in any one of claims 1-21.

28. A nucleic acid encoding the PKB of claim 24 or 25.

29. A vector comprising the nucleic acid of claim 28.

30. A host cell comprising the vector of claim 29.

31. Use of a compound identified by the method of any of claims 1 -22 in the preparation of a medicament for the treatment of cancer.

32. Use according to claim 31 wherein the compound disrupts the conformational change in the PKB PH domain on interaction with

PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂.

33. Use according to claim 31 or 32 for impairing growth of cancer cells

34. Use according to claim 31 or 32 for promoting apoptosis of cancer cells.

35 Use of a compound identified by the method of any of claims 1-22 in the preparation of a medicament for stimulating insulin dependent responses in diabetic patients, or for promoting cellular survival following an ischaemic event, or for promoting the survival of neuronal cells following a stroke, or for reducing apoptosis.

36. Use according to claim 35 wherein the compound enhances the normal conformational change upon binding of PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ to the PKB PH domain.

37. Use according to claim 35 wherein the compound binds to the 3- phosphoinositide ligand binding site of the PKB PH domain and induces a conformational change which promotes the PtdIns(3,4,5)P₃ or PtdIns(3,4)P₂ independent activation of PKB.

38. A polypeptide comprising a PKB PH domain in which the Asn53 residue has been substituted.

39. A PKB comprising the polypeptide of claim 38.

40. A nucleic acid encoding the polypeptide of claim 38 or the PKB of claim 39.

41. A vector comprising the nucleic acid of claim 40.

42. A host cell comprising the vector of claim 41.