WO2001073444A2 - Receptor/peptide crystal structure for identification of inhibitors - Google Patents

Abstract

The crystal structure of a collagen peptide in complex with integrin α2 I-domain is provided. Coordinates for the crystal structure are useful in designing novel molecules that can be tested for binding to the receptor and other I-domains and preferably ability to inhibit I-domain binding to ligand, and I-domain function. Regions of I-domains that undergo conformation change upon ligand binding are also identified and provided as targets for binding molecules such as antibodies. Molecules that inhibit the function of polypeptides comprising I-domains are of therapeutic potential in a number of diseases and disorders.

Description

RECEPTOR/PEPTIDE CRYSTAL STRUCTURE FOR IDENTIFICATION OF INHIBITORS

Technical Field

The present invention relates to use of coordinates of peptide/receptor crystal structure in designing and obtaining molecules that inhibit protein I-domain interactions and function, especially collagen/receptor interaction, and are of therapeutic potential. The present invention relates to modulating platelet aggregation, adhesion and activation, as well as the adhesion, migration and phenotypic expression of many other cells, and inhibitors of collagen interaction with collagen receptors.

Background Art

Collagens and collagen-related peptides

The collagens provide the vertebrate organism with tensile strength; they are the major protein component of skin, bone, cartilage and other connective tissue. Collagens, for example Type IN, provide a network of protein known as the basal lamina to which cells can attach and over which cells can migrate. Such structures are found beneath endothelial and epithelial cell layers in many locations. Deeper into tissues such as the epidermis or the intimal layer of the blood vessels, fibrous collagens such as Types I and III are found [2] . The structure and precise amino acid composition of the collagens varies with type. Each type is the product of a distinct gene or genes. What characterises a protein as a collagen is that it contains, substantially or in some part, a triple-helical structure in which three polypeptide chains, each helical in its own right, are wound around one another to form a superhelix. A specific amino acid sequence, Gly-Pro- Hyp, (GPO in single-letter nomenclature) when repeated sufficiently can support triple-helical conformation. A related sequence, GPP, also adopts a triple-helical conformation.

The properties of these sequences which support triple-helical structure are :

(i) the tight bends associated with the strained ring structure of the iminoacids proline and hydroxyproline,

(ii) the presence of glycine at every third residue whose side chain, simply a hydrogen atom, positioned in the interior of the cylinder defined by the triple helix, is so small as to present no obstacle to the protein chains associating in this conformation, and

(iii) the capacity of the hydroxyproline residues in particular to support intra- or inter-chain hydrogen bonding, thus stabilising the helix.

In long peptides, where such effects may be additive over many triplets of amino acids, substantial deviation from the GPO prototypic sequence still allows triple-helical structure. Thus, in Type I collagen, where the explicit triplet GPO comprises only around 10% of the primary sequence of the molecule, which is over three hundred triplets in length, the structure exhibits a melting temperature, i.e. the temperature at which the helix will unwind, in excess of 40°C, significantly higher than physiological temperatures. In nature, the helix and its higher order assembly, the collagen fibril, is further stabilised by cross-linking.

Synthetic peptides are known where, utilising a sequence of repeating GPP triplets or repeating GPO triplets, significantly higher melting temperatures can be achieved. For example, peptides comprising [GPO] ₁₀ melt at about 60°C [3], but [GPO]_s melts at below 20°C [4-6].

Such synthetic peptides have found increasing application in biomedical research, since they may have biological activity. For example, in cross-linked form the sequence [GPO] ₁₀ will bind to a specific platelet receptor population, known as glycoprotein Nl , on human platelets and activate them, most likely by stabilising these receptors in close proximity, allowing proteins associated with their intracellular domains to interact [7-10] . Clustering of receptors in this way may be one mechanism by which signals, such as a change in phosphorylation state of intracellular proteins, may propagate within the platelet [10, 11] . This mechanism is thought to be a key activatory step in haemostatic events leading to platelet aggregation, and in pathological events including thrombosis [12-14] . Thus the peptide containing the GPO motif, known as collagen-related peptide or CRP, provides a receptor-specific peptide useful in the study of platelet activation [8] .

Peptide motifs which support triple helical structure, i.e. GPO or GPP, can be used as flanking sequences which confer triple-helical structure upon other sequences from collagen, or indeed from other proteins, which would not otherwise adopt this conformation [15-18] . Such peptides allow the researcher to investigate the properties of small sequences from the primary structure of the collagen alpha chains, such as the alpha 1 chain from type I collagen, or the alpha 2 chain from type I collagen or the alpha 1 chains of type III collagen, whilst retaining the triple-helical structure which is crucial for cell-reactivity. Such investigations have allowed other specific receptor-binding sequences to be identified.

One such is the sequence GFOGER, which binds to a further class of receptors, the integrins αlβl and α2βl [18] .

The integrins

The integrins are expressed on the surface of cells, being widespread throughout the different tissues of the body, and their functions are manifold. Integrins are heterodimeric structures, comprising two subunits, designated α and β [19]

Certain combinations of the 20 or so known α subunits with the 10 or so known β subunits are allowed, whilst many are excluded and do not occur in nature. Thus, at present, about 30 different integrins are known in man. Their selectivity for particular ligands derives primarily from the combination of subunits, but may be dependent also upon the activation state of the integrin [20, 21] .

Some integrins mediate direct cell-cell contact, as between leukocytes, or between the cells forming a cell layer or epithelium. Often, counter-receptors such as the cellular adhesion molecules (CAMS) may bind to such integrins [22] . This represents the model by which the β2 integrins found upon the leukocyte surface mediate cell-cell contact. Commonly, integrins are found to bind to extracellular proteins of the plasma (such as fibrinogen) or of the matrix (such as collagen or fibronectin) . Very often, the amino acid sequences supporting interaction with integrins include an acidic residue such as D or E. Thus the sequence RGD can bind to the fibrinogen receptor, αllbβ3, the vitronectin receptor αvβ3 , to the fibronectin receptor, α5βl and to certain other integrins [20] . Sequences elsewhere within the ligand may enhance and provide further selectivity to this primary interaction.

Integrin α subunits can be described as having a modular structure, with seven consensus repeats in their extracellular domains [23] . Some of these, known as EF-hands, bind cations, Ca²⁺, for example, (although other divalent cations such as Zn²⁺, Co²⁺ or Mn²⁺ may serve the same purpose) which support the activity of the receptor. One property of the αllb subunit of the fibrinogen receptor known to depend upon the presence of these divalent cations is the ability to associate with the β3 subunit, essential for receptor function [24] .

Integrin α subunits fall into two classes, those as described above and those which possess an additional protein module, the inserted domain or I-domain, which is sometimes known as the A-domain because it adopts the same fold and may share other properties with the A-domains of the protein, von Willebrand factor.

The collagen-binding integrins, αlβl and α2βl contain I-domains [25] . These I-domains are crucial for the capacity of the integrin to bind collagen, which resides in a characteristic structure at one end of the domain which binds a divalent cation. Several species of cation can occupy this site, for example Mg²⁺ or Co²⁺ or Mn²⁺ [26] . In physiology it is likely that Mg²⁺ may be the ion present in this specialised binding structure, known as the metal ion dependent adhesion site or MIDAS. Because of its crucial role in mediating collagen binding, the I-domain MIDAS is the subject of close scrutiny in the field.

Protein domains are defined as stretches of sequence which fold independently into the native conformation of the peptide, i.e. when separated from other regions of the parent protein. The I-domain, in suitably pure form, expressed, for example as a recombinant protein, can re-fold [26] into a structure which has the same capacity to bind cations in its MIDAS and the same capacity to bind ligands as the parent integrin [27] . For this reason, the α2 I-domain provides a ready model for studying the interaction of collagen with α2βl.

A key question has been how the binding of ligand to the I- domain may alter its structure, which various techniques have been applied to address. For example, suitable computer algorithms allow fold prediction to be made, based upon the known primary sequence and by analogy with other I-domains or A-domains, which may provide an important input to this process. Such algorithms might allow a proposed ligand- binding cleft to be visualised in 3-dimensions, and to be compared with the known shape of the ligand. Often, suitable algorithms provide an analysis of the charge density on the surface of both the ligand and the proposed binding cleft, to establish complementary sites which might provide the basis for their interaction.

Previous work has elucidated the structure of the α2 I-domain in its free, unligated form [26] . The key feature of I domains and vWf A-domains is that they contain a characteristic assembly of five parallel and one anti-parallel beta-strands which form the stable platform of the structure. This conformation, known as the dinucleotide-binding fold (or Rossman fold) is found in other proteins such as NAD hydrolase, guanine nucleotide-binding proteins and protein kinases. Common to all of these structures is that ligand binding occurs at the C-terminal surface formed by these beta- strands, although this has not hitherto been formally demonstrated. So it is with the integrin I-domains. This structure is linked by a series of peptide loops, several of which elaborate α-helices and at least one anti-parallel beta strand which substantially enclose the beta-sheet as they return to the base of the beta-sheet structure.

Another crucial feature of I-domains is that they possess an amino acid motif regarded as diagnostic of I-domains, having the sequence DxSxS, where x may represent any amino acid. These three amino acids, D151, S153 and S155, are present in the N-terminal loop arising from the first beta strand of the α2 I-domain. These, along with other oxygen-containing residues in nearby peptide loops, co-ordinate the metal ion and constitute the MIDAS.

In the case of α2 I-domain, beta-strand 5_ elaborates above it a single turn of α-helix, known as the C-helix. A C-helix is known to exist in the αl I-domain, and might be predicted in other, less well-characterised I-domains. This appears to obstruct the MIDAS in its un-ligated state. It seems very likely that similar structures may occur in other I-domains.

Structure determination

Structure prediction, based upon the primary sequence of a protein domain, although a useful adjunct to the research endeavour, needs to be confirmed by measurement. The procedures used for such purposes include nuclear magnetic resonance and X-ray crystallography. Each approach offers its own advantage: nuclear magnetic resonance allows the examination of proteins in aqueous media, and at temperatures close to physiological. However, nuclear magnetic resonance requires that the proteins be synthesised during their expression from amino acids comprising atomic nuclei with unpaired spin, such as ¹⁵N or ¹³C, in their peptide or other bonds . Protons within the structure may need to be replaced by deuterons which do not resonate. This may present a significant difficulty, especially given that quite high protein concentration, such as 1 millimolar, and volume, such as 1 millilitre, may be needed to allow the analysis to proceed. Further, the magnetic resonance are critically- dependent upon the size of the target protein, so that structures larger than about 100 amino acids are difficult to obtain, because of limitations of the field strength and frequency of the instrument .

X-ray diffraction also suffers from practical constraints, the major drawback being that the protein under examination must crystallise under laboratory conditions to provide a crystal of sufficient size and homogeneity as to be useful for subsequent analysis. Suitable instruments include quite widespread laboratory-scale X-ray diffraction units, useful in the initial examination of the crystal, or the much larger- scale synchrotron devices. The choice of instrument is governed by the size of the crystal available and the spatial resolution required of the analysis.

In the crystallisation of two structures as a complex, further constraints emerge. Firstly, the complex must adopt an appropriate, presumably physiological, conformation. Secondly, the association between the two species must be stable at solution temperatures. Thirdly, the dimensions of the complex must be such as to allow unit cells, i.e. the most fundamental level of organisation of the complex, to align in an array which can form a crystal . Where the two species are of grossly different shapes or sizes, this may be a meaningful constraint. For example, the tropocollagen molecule, the triple helical structure comprising the intact α-chains of the collagen in question, may approximate to a rod about 300nm in length, whereas the I-domain of the integrin α2βl approximates to a sphere about 3nm diameter. It is unlikely that a complex formed from single copies of such disparate structures will crystallise, although complex formation might very well occur.

Disclosure of the Invention

The present invention is based on work in which a collagen peptide was produced as a trimer, and a crystal structure obtained for the complex formed by binding of the peptide to integrin α2 I-domain. Coordinates for the crystal structure are useful in designing novel molecules that can be tested for binding to the receptor and other I-domains, and preferably ability to inhibit I-domain binding to ligand (e.g. collagen) and function. Regions of I-domains that undergo conformational change upon ligand binding are also identified and provided as targets for binding molecules such as antibodies. Molecules that inhibit the function of polypeptides comprising I-domains are of therapeutic potential in a number of diseases and disorders. The coordinates of the crystal structure for use in aspects and embodiments of the present invention are shown in Table 1. Specific contacts of additional interest are shown in Table 2. Details of interaction between peptide and receptor are shown in the Figures, described below.

The coordinates of Table 1 provide a measure of atomic location in Angstroms. The coordinates are a relative set of positions that define a shape in three dimensions. The skilled person would recognise that it is possible that an entirely different set of coordinates having a different origin and/or axes could define a similar or identical shape. Furthermore, he would recognise that varying the relative atomic positions of the atoms of the structure so that the root mean square deviation of residue backbone atoms (i.e. the nitrogen-carbon-carbon backbone atoms of protein amino acid residues) is less than 1.5 A (preferably less than 1.0 A and more preferably less than 0.5 A) when superimposed on the coordinates provided in Table 1 for the residue backbone atoms, will generally result in a structure which is substantially the same as the structure of Table 1 in terms of both its structural characteristics and potency for structure- based drug design. Likewise he would recognise that changing the number and/or positions of the water molecules of Table 1 will not generally affect the potency of the structure for structure-based drug design of I-domain inhibitors. Thus for the purposes described herein as being aspects of the present invention, it is optionally within the scope of the invention if: the Table 1 coordinates are transposed to a different origin and/or axes; the relative atomic positions of the atoms of the structure are varied so that the root mean square deviation of residue backbone atoms is less than 1.5 A (preferably less than 1.0 A and more preferably less than 0.5 A) when superimposed on the coordinates provided in Table 1 for the residue backbone atoms; and/or the number and/or positions of water molecules is varied. Reference herein to the coordinates of Table 1 thus optionally includes the coordinates in which one or more individual values of Table 1 are varied in this way.

Also, the skilled person would recognise that modifications in the α2 I-domain crystal structure due to e.g. mutations, additions, substitutions, and/or- deletions of amino acid residues could account for variations in the atomic coordinates of the complex. Therefore, atomic coordinate data of the α2 I-domain modified so that a ligand that bound to the α2 I-domain would also be expected to bind to the modified .2 I-domain are, for the purposes described herein as being aspects of the present invention, optionally also within the scope of the invention. Reference herein to the coordinates of Table 1 thus optionally includes the coordinates modified in this way.

Furthermore, the Table 2 coordinates being derived from Table 1, reference herein to the coordinates of Table 2 optionally includes the coordinates in which one or more individual values of Table 2 are changed as a result of the above- mentioned variation and/or modification of the coordinates of Table 1.

The crystal structure defined by the co-ordinates may be visualised and rendered by many molecular graphics programmes, suitable examples of which include MolView (T.J. Smith, Dept . Biology, Purdue University, In47907, USA) , RasMol Molecular Graphics (Roger Sayle, Biomolecular Structures Group, Glaxo Wellcome Research & Development, Stevenage, Hertfordshire,

UK) , Swiss PDB Viewer (Glaxo Wellcome Experimental Research) or XtalView (D.J. McRee, (1992) J. Mol. Graphics, 10, 44-47).

Many other software suites are available to the skilled researcher.

Modelling and refinement of crystallographic data can be performed using AMORE [30] and XtalView, or other suitable software, as noted in the Methods section below. The use in rational drug design of both the co-ordinates produced by these algorithms and the identity and chemical nature of the atoms involved in the interaction between I- domain and ligand, presented in Table 2, may involve use of interpretive software such as MCSS (Miranker, A. and Karplus, M., "Functionality Maps of Binding Sites: a Multiple Copy Simultaneous Search Method," Proteins: Structure, Function, and Genetics, 11 29-34 (1991)).

Use of these data in identification of chemical compounds which may be potential ligands or inhibitors of the I- domain: collagen interaction may utilise database searching software such as HOOK: A Program for finding novel molecular architectures that satisfy the chemical and steric requirements of a macromolecule binding site, (Eisen, M. B., et al., Proteins, 19 199-221 (1994)) or DOCK (Meng, E.C. et al., J. Comput. Chem. 13, 505-524 (1992)). Suitable databases of candidate ligands may include the ACD (Available Chemicals Directory; Molecular Design Limited Information Systems, San Leandro, CA, USA) or the NCI Drug Information System 3D Database (National Cancer Institute, USA) .

A binding motif within collagen was previously identified, the sequence GFOGER [17, 18] . As for the parent molecule, this amino acid sequence adopts a triple helical conformation, when flanked by suitable repeats of GPO or GPP triplets, and binds to the integrin. Evidence for this is provided by the observation that the sequence is inactive when flanked by repetitive GAP motifs [18] , so that non-helical structure is adopted, rather than the GPP or GPO motifs described above which support triple-helical conformation. The structure of the candidate peptide is determined by the various requirements for co-crystallisation. If the flanking sequences of GPP or GPO are too long, then the dimensions of the triple-helix no longer match those of the I-domain, and crystallisation will be increasingly less likely, as outlined above. But it remains important that sufficiently long flanking sequences are present to maintain triple-helical structure even at the cold-room temperature (0-8EC, typically 4EC) used for crystallisation. Hence the extent of the flanking triplets is likely to be critical, being long enough to support triple-helical structure but not so long as to impede crystallisation.

A further consideration is that the peptide should be located centrally upon the I-domain, so that the complex is approximately symmetric, a property which favours crystallisation.

In accordance with the present invention, a peptide has been synthesized comprising [GPO] ₂GFOGER [GPO] ₃ which has a melting temperature of about 22°C and allows co- crystallisation to proceed at cold-room temperatures, where 95% or more of the peptide is in triple-helical form (see Figure 1) . This peptide forms a single turn of the triple-helix after assembly in trimer. Further, the disposition of two GPO triplets at the N-terminus of the peptide and three at the C-terminus allows the crucial glutamate (E) residue to be centrally located within the resultant triple-helix, favouring a symmetrical complex with the α2 I-domain.

An important consideration in the design of this peptide is the chemical modification of charged groups at its amino- terminus and carboxy-terminus . This has the effect of rendering the ends of the peptide neutral at physiological pH, so that electrostatic repulsion between adjacent chains within a triple-helix is minimised. This permits the peptide to assemble as a triple-helix at higher temperature, so facilitating the use of shorter peptide ligands, consistent with the dimensions of the receptor, in the crystallisation process. Several chemistries may be suitable. In the present case, acetylation of the N-terminal amino group and incorporation of a C-terminal amide achieved this purpose.

Methods useful in attempts to induce crystallisation are known in the art [28] . Crucial factors may be the inclusion of suitable buffers to maintain the appropriate charge of the protein and the peptide ligand; suitable detergents to maintain the conformation of the receptor; suitable polymers to increase the effective concentration of both receptor and ligand; suitable concentration of divalent cation to saturate the MIDAS; suitable concentration of peptide; precipitants to induce the gradual precipitation/crystallisation of the complex; that the crystallisation be performed at temperatures at which the peptide is triple-helical; glycerol to stabilize the I domain and act as a cryo-protectant during the flash freezing prior to data collection.

Once the crystallisation and X-ray diffraction data have been obtained, then the 3-dimensional co-ordinates of the atoms within the crystal may be deduced by the use of suitable computer algorithms. The resultant data set allows the construction of 3-dimensional models of the ligand in complex with the receptor, which offers to the researcher a fundamental understanding of the interaction between the two. Knowledge of the structure of the ligand-I domain complex allows key processes to be established, such as a change in conformation in the receptor or ligand as the complex forms. Such information allows for the design of materials which interact with the receptor, most likely at the site of interaction, the MIDAS, but possibly elsewhere in the structure, for example in the C-Helix or near Helix α7. Such materials may be used to impede the activation process of the integrin, preventing collagen from binding to the receptor. In therapeutic use, such materials may be used to prevent cell contact with collagen, so impeding disease processes such as thrombosis, atherogenesis and metastasis.

In general aspects, the present invention is concerned with identifying or obtaining potential inhibitors of Integrin I- domain interaction with ligand (e.g. collagen) and/or function, and in preferred embodiments identifying or obtaining actual inhibitors of such interaction and/or function. Crystal structure information presented herein is useful in designing potential inhibitors and modelling them or their potential interaction with the I-domain of Integrin α2βl or other I-domain. Potential inhibitors may be synthesized and brought into contact with the relevant I-domain to test for ability to interact with the I-domain, ability to inhibit interaction of the I-domain with collagen or other ligand, or with a collagen peptide that binds the I-domain, and/or ability to affect I-domain or Integrin function. Actual inhibitors may be identified from among potential inhibitors synthesized following design and model work performed in silico . An inhibitor identified using the present invention may be formulated into a composition, for instance a composition comprising a pharmaceutically acceptable excipient, and may be used in manufacture of a medicament for use in a method of treatment . These and other aspects and embodiments of the present invention are discussed below.

Table 2 provides details of contacts between the peptides and I-domain in the crystal structure. These too may be used in design of molecules that make similar contacts with the I- do ain. Such molecules may be synthesised and tested for ability to interact with the I-domain, ability to inhibit interaction of the I-domain with collagen or with a collagen peptide that binds the I-domain, and/or ability to affect I- domain or Integrin function.

Comparison of the structure of the I-domain crystallised with the triple-helical peptide and the I-domain crystal structure without the peptide identifies a number of changes in conformation in the I-domain on peptide binding, and consequently parts of the I-domain which may be targeted for inhibition. This is discussed further below.

In accordance with a first aspect of the present invention there is provided a method of identifying a potential inhibitor of an I-domain-containing polypeptide, especially an integrin I-domain, e.g. selected from the group consisting of αl, α2, αlO, all, aD, aE, aL, aM and αX, preferably α2 or αl and most preferably α2, the method comprising either (i) employing a three-dimensional structure of the Integrin 2 I-domain as shown in Table 1 to design or select a potential inhibitor, (ii) designing or selecting a potential inhibitor that interacts with one or more points in the I-domain crystal structure shown for the I-domain in Table 2, or (iii) designing or selecting a potential inhibitor that mimics one or more (and preferably three or more) points in the peptide structure shown for the peptide structure in Table 2. In accordance with a further aspect of the present invention there is provided a method of identifying a potential inhibitor of an I -domain-containing polypeptide, especially an integrin I-domain, e.g. selected from the group consisting of αl, α2, αlO, all, aD, aE, aL, aM and αX, preferably α2 or αl and most preferably α2 , the method comprising the steps of:

(a) employing a three-dimensional structure of the Integrin α2 I-domain as shown in Table 1 to design or select a potential inhibitor;

(b) synthesizing or providing said potential inhibitor; and

(c) testing said potential inhibitor for ability to interact with an I -domain-containing polypeptide.

A potential inhibitor of an integrin or other I-domain containing polypeptide may be designed by modelling points of interaction between the trimerized collagen peptide and the α2βl I-domain, for example as shown in Table 2. One or more electrostatic interactions and/or one or more hydrogen bonds and/or one or more hydrophobic interactions may be used in the modelling. In a preferred embodiment, all the I-domain points identified in Table 2 are employed in the design, and/or all the peptide points identified in Table 2.

Thus, in a further aspect the present invention provides a method of identifying a potential inhibitor of an I -domain- containing polypeptide, especially an integrin I-domain, e.g. selected from the group consisting of αl, α2, αlO, all, aD, aE, aL, aM and αX, preferably α2 or αl and most preferably α2, the method comprising the steps of:

(a) designing or selecting a potential inhibitor that interacts with one or more points in the I-domain crystal structure shown for the I-domain in Table 2 ;

(b) synthesizing or providing said potential inhibitor; and (c) testing said potential inhibitor for ability to interact with an I-domain-containing polypeptide.

In a further aspect the present invention provides a method of identifying a potential inhibitor of an I-domain-containing polypeptide, especially an integrin I-domain, e.g. selected from the group consisting of αl, α2, αlO, all, aD, aE, aL, aM and αX, preferably α2 or αl and most preferably α2 , the method comprising the steps of:

(a) designing or selecting a potential inhibitor that mimics one or more points in the peptide structure shown for the peptide structure in Table 2;

(b) synthesizing or providing said potential inhibitor; and

(c) testing said potential inhibitor for ability to interact with an I-domain-containing polypeptide. Preferably, in step (a) the potential inhibitor mimics three or more spaced points in the peptide structure.

Step (c) of each of the above aspects may comprise bringing said potential inhibitor into contact with the I-domain-containing polypeptide to determine ability of said potential inhibitor to inhibit (i) ability of the I-domain to interact with collagen or a collagen peptide or other ligand which binds the I-domain, and/or (ii) I-domain or I-domain-containing polypeptide function. The I-domain-containing polypeptide may be an integrin (e.g α2βl) .

Integrin function may be measured in a number of different ways .

For instance, cells which express the integrin may be allowed to come into contact with a surface coated with a substrate known to bind the integrin. By illustration with reference to α2βl Integrin as a preferred embodiment without limitation to the ability to employ other integrins and I-domains 'in embodiments of the present invention, cells, such as human or other platelets, or any cell type utilising α2βl as an adhesive receptor, or cells such as HT1080 cells which use only α2βl as a receptor for collagen, may be allowed to settle upon the surface, and after suitable incubation time, e.g. from 10 minutes to 1 hour, or to 3 hours or longer, be washed from the surface [18] . Cells removed by this washing procedure may be quantitated, for example using an electronic particle counter [18] , a haemocytometer, or other suitable procedure, allowing the proportion of cells that is not removed by washing to be defined as adherent. Alternatively, such cells as remain, constituting adherent cells, may be quantitated directly, either by microscopical counting, or if radiolabelled cells were used, then the amount of radioactivity remaining may be measured, or the cells may be stained using histochemical dyes and the amount of stain retained may be quantitated colorimetrically, or cells may be lysed using suitable detergent or other procedure, and the enzymes released from the cells may then be quantitated colorimetrically as a measure of the adherent cell numbers [18] . Each of these, or other suitable procedure, allows the adhesion of cells via α2βl to be measured, which defines the function of the integrin. Such procedures are well-known to those skilled in the art [refs 3,7,16,17,18,25,27].

In another variant of the procedure, similar surfaces coated with substrate, such as peptide or collagen as defined above, may be used to support the adhesion of the purified integrin α2βl or of the recombinant α2 I-domain. In these variants, the receptor or I-domain is suitably labelled, for example with biotin [18] , or, if expressed as recombinant fusion protein, with a poly-His tag, or glutathione-S-transferase, or with a fluorescent dye or with any other suitable means of identification, each of which may readily be detected by routine methodology. Alternatively, the protein may be allowed to interact directly with a specific antibody, and its presence may then be detected immunologically. Such assays allow the extent to which the integrin or I-domain adheres to the substrate to be determined, which is a measure of integrin function.

Alternatively or additionally, step (c) of the above aspects may comprise the sub-steps of:

(i) forming a complex of the I-domain-containing polypeptide and said potential inhibitor ; and (ii) analysing said complex by X-ray crystallography or NMR spectroscopy to determine the ability of said potential inhibitor to interact with the I-domain-containing polypeptide. Detailed structural information can then be obtained about the binding of the potential inhibitor to the I-domain-containing polypeptide, and in the light of this information adjustments can be made to the structure or functionality of the potential inhibitor, e.g. to improve binding to the polypeptide .

A further aspect of the present invention (which may be used in the above-mentioned analysis sub-step (ii) ) provides a method of analysing an I-domain-containing polypeptide complex comprising employing (i) X-ray crystallographic diffraction data from the I-domain-containing polypeptide complex and (ii) atomic coordinate data according to Table 1 to generate a difference Fourier electron density map of the complex.

Therefore, an I-domain-containing polypeptide complex can be crystallised and analysed using X-ray diffraction methods, and a difference Fourier electron density map can be calculated based on the X-ray diffraction pattern of the complex and the solved structure for the I-domain of Table 1. Such a map can be used to determine whether and where a particular ligand binds to the I-domain and/or changes to the conformation of the I-domain.

Electron density maps can be calculated using programs such as those from the CCP4 computing package (Collaborative

Computational Project 4. The CCP4 Suite: Programs for Protein Crystallography, Acta Crystallographica, D50 760-763, (1994)). For map visualisation and model building programs such as O (Jones et al . , Acta Crystallographica, A47 110-119 (1991)). Structure factor data, which are derivable from atomic coordinate data (see e.g. Blundell et al . , in Protein Crystallography, Academic Press, New York, London and San Francisco, (1976) ) , are particularly useful for calculating difference Fourier electron density maps.

Analysis of the changes in conformation of the α2 I-domain allows certain residues to be identified as becoming exposed upon ligand binding: residues E318 (at the N-terminal end of Helix α7) and D292 (close to the N-terminal end of Helix α6) . Inhibitors of the I-domain and integrin function may be identified by targeting a binding molecule to the regions of the I-domain including these amino acids, for example by generating antibodies or other binding molecules to sequences comprising, for instance residues 315 to 320, or 288 to 295. Certain parts of the I-domain, for example the C-helix, residues 284 to 288, also dramatically alter their conformation upon binding. These similarly provide a target to inhibit conformational change, with therapeutic potential.

Thus, in a further aspect the present invention provides a method of obtaining a potential inhibitor of an Integrin, the method comprising the steps of: (a) providing a peptide fragment of Integrin α2 I-domain, which peptide fragment contains the E318 residue (e.g. comprises residues 315-320) , the D292 residue (e.g. comprises residues 288-295) or the residues 284-288;

(b) bringing the peptide fragment into contact with a test substance, such as an antibody molecule; and

(c) determining the ability of the peptide fragment to bind with the test substance.

A substance which binds the peptide, e.g. an antibody molecule, is a potential inhibitor of integrin function, e.g. Integrin α2βl function. Ability of a potential inhibitor actually to inhibit may be determined as discussed elsewhere herein.

Similarly, the present invention provides for identifying a molecule that interacts with any part of the integrin I-domain identified by means of the crystal structure disclosed herein as making a contact with another part of the I-domain or the peptide in the crystal, or as altering in conformation on binding of the peptide.

Data presented in Table 1 allows identification of those residues and their corresponding co-ordinates within the resting I-domain (Brookhaven Protein Database number laox, reference 26) which are critically involved in both its conformational change and ligand binding cleft. Thus, in the light of data presented in Table 1 and the additional disclosure herein, the resting I-domain co-ordinates [26] becomes a useful reference point for rational drug design. This allows certain surfaces, defined by the residues presented in Table 1, but whose resting co-ordinates are contained in laox, to be identified unambiguously as contributing to the latent ligand binding cleft. Hence an inhibitor may be designed to bind to the resting I-domain and so prevent it from binding ligand.

For other I-domains, regions corresponding to those identified for α2 I-domain as targets for antibody molecules are identified in accordance with the present invention as: αM: residues 301-304 (N-terminal end of Helix α7) , residues 272-284 (N-terminal end of Helix α6) ; αL: residues 290-295 (N-terminal end of Helix α7) , residues 258-272 (N-terminal end of Helix α6) ; αl : residues 318-324 (N-terminal end of Helix α7) , residues 292-298 (N-terminal end of Helix α6) .

Thus, an antibody molecule or other binding molecule may be obtained, e.g. by making a peptide comprising or consisting of the above residues of any of the above regions and bringing the peptide into contact with a mixture containing potential binding molecules, determining binding to the peptide and selecting a binding molecule that binds. A binding molecule such as an antibody molecule may be tested for ability to bind and inhibit an I-domain, and may be employed as an inhibitor of a polypeptide comprising an I-domain for one or more purposes as disclosed herein.

Specific residues can also be identified, such as T221 in α2 I-domain, linked to metal ion in the resting I-domain indirectly via a water molecule. Suitable inhibitors may be designed to bind T221 and prevent the metal ion from moving closer to become co-ordinated directly. Such inhibitors may be used to prevent subsequent ligand. binding.

Comparison of the crystal structure of the integrin a2 I- domain in complex with the triple-helical collagen-like peptide with that of the free, uncomplexed, I-domain [26] allows regions of the I-domain to be identified which may be exposed in the free state, but which become hidden in the complexed state. An example will be those areas of the surface of the I-domain which are obscured by the binding of the triple-helical peptide. These specific residues are identified in Table 2. Other such sites are remote from the binding cleft, and are revealed by conformational changes which occur during the transition from the free to the complexed state. Such sites may also represent therapeutic targets : agents such as inhibitors or antibodies which bind to these critical exposed regions of the complexed integrin may block the transition to the resting conformation, so maintaining the integrin in its active conformation.

The present invention allows such residues to be identified, and the co-ordinates of the I-domain surface in these regions to be used for rational drug design, as described above.

Alternatively, as noted, knowledge of these critical regions of the I-domain allows peptide sequences to be used to raise antibodies or other binding molecules by appropriate methodology, for example against short peptide sequences derived from the I-domain or by DNA vaccination of nucleotide sequences corresponding to these regions of the I-domain. The utility of such inhibitors may be tested as described above, in suitable adhesion or other assays.

Reference to an Aantibody molecule® describes an immunoglobulin whether natural or partly or wholly synthetically produced. The term also covers any polypeptide or protein having a binding domain which is, or is substantially homologous to, an antibody binding domain. Thus, antibody molecules for use in the present invention include fragments which comprise an antigen binding domain such as Fab, scFv, Fv, dAb, Fd and diabodies, all of which are well known in the art.

Comparison of the two forms of the integrin I-domain allows sites to be identified upon its surface which are hidden in the free integrin, and which are exposed only after complex with suitable ligand, for example the triple-helical peptide described above, Ac- (GPO) ₂GFOGER(GPO) ₃-NH₂_ . Such sites, when targeted by inhibitors may have two possible effects: if sufficiently close or within the binding cleft, they may inhibit ligand binding, but if sufficiently remote so as not to impede ligand binding, they may stabilise the integrin in its active conformation and so enhance ligand binding. Such activity may be identified by binding assays as described herein, and each class of agent, whether inhibitory or activatory towards integrin function, may have its own therapeutic use or other application.

Regions of interest within the α2 I-domain binding cleft are identified in Table 2, which also lists residues of the I- domain (E318 and D292) which are exposed upon ligand binding and are not obscured by the triple-helical peptide.

A collagen peptide employed in testing for ability of a potential inhibitor to inhibit binding of the I-domain to the peptide may be a triple-helical peptide, of sequence GFOGER known to bind the α2 I-domain [18] , or other sequence which binds to the I-domain, flanked by suitable repeats of GPO or GPP triplets to ensure triple-helical structure. Alternatively, physiological substrates such as collagens, for example type I or type III or type IV or type VI or other collagens, readily coat and adhere to the surface of tissue culture dishes or 96-well plates, and are known to bind to α2βl. Alternatively, other substrates such as the extracellular protein laminin, also known to bind the I-domain of α2βl, may be used for the same purpose. Specificity of interaction in this and other assays may be verified by using antibodies against either the immobilised substrate or the receptor on the surface of cells under test.

In any aspect of the present invention a potential inhibitor that tests positive when brought into contact with the I- domain, that is fulfils one or more of the specified criteria, is considered an actual inhibitor.

Thus further aspects of the present invention provide methods of identifying and/or obtaining inhibitors of a polypeptide which contains an I-domain, especially an Integrin, which may be selected from the group consisting of αl, α2, αlO, all, aD, aE, aL, aM and αX, especially α2 or αl, most preferably α2.

Another aspect of the present invention provides a crystal of α2 I-domain complex having a space group P2₁2₁2₁, and unit cell dimensions of a = 42.0 A, b = 48.4 A, and c = 114.5 A. Or more generally a = 42.0+0.2 A, b = 48.4±0.2 A, and c =

114.5+0.2 A.

Alternatively or additionally, the present invention provides a crystal of α2 I-domain complex having the three dimensional atomic coordinates of Table 1.

Further aspects of the present invention provide (i) a computer system, intended to generate structures and/or perform rational drug design for I-domain-containing polypeptides or I-domain-containing polypeptide complexes, the system containing atomic coordinate data according to Table 1 or Table 2, and (ii) computer readable media for use in the computer system, having atomic coordinate data according to Table 1 or Table 2 recorded thereon.

By a "computer system" we mean the hardware means, software means and data storage means used to analyse atomic coordinate data. The minimum hardware means of the computer-based systems of the present invention comprises a central processing unit (CPU) , input means, output means and data storage means. Desirably a monitor is provided to visualise structure data. The data storage means may be RAM or means for accessing computer readable media of the invention. Examples of such systems are microcomputer workstations available from Silicon Graphics Incorporated and Sun Microsystems running Unix based, Windows NT or IBM OS/2 operating systems.

By "computer readable media" we mean any media which can be read and accessed directly by a computer e.g. so that the media is suitable for use in the above-mentioned computer system. Such media include, but are not limited to: magnetic storage media such as floppy discs, hard disc storage medium and magnetic tape; optical storage media such as optical discs or CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media.

By providing such a system or such computer readable media, the atomic coordinate data can be routinely accessed to model I-domain-containing polypeptides and complexes thereof, e.g. using the molecular graphics programs discussed above.

Another aspect of the present invention provides an inhibitor of an I-domain identified or obtained by any method disclosed herein.

An inhibitor may be formulated into a composition comprising at least one additional component.

Following identification of an inhibitor it may be manufactured and/or used in preparation, i.e. manufacture or formulation, of a composition such as a medicament, pharmaceutical composition or drug. These may be administered to individuals.

Thus, the present invention extends in various aspects not only to an inhibitor as provided by the invention, but also a pharmaceutical composition, medicament, drug or other composition comprising such an inhibitor, a method comprising administration of such a composition to a patient, e.g. for treatment (which may include preventative treatment) of a disorder or disease, use of such an inhibitor in manufacture of a composition for administration, e.g. for treatment of a disorder or disease, and a method of making a pharmaceutical composition comprising admixing such an inhibitor with a pharmaceutically acceptable excipient, vehicle or carrier, and optionally other ingredients.

Disorders and diseases which may be treated in accordance with aspects of the present invention include the thrombotic disorders, myocardial infarction and stroke, acute thrombosis associated with angioplasty and with coronary bypass grafting, and with liver fibrosis or thrombotic complication of liver necrosis each of which is prone to occur after hepatitis infection. Inhibition of platelet α2βl may be used to treat longer-term occlusion of arteries, restenosis which commonly occurs after angioplasty as well as atherogenesis as a consequence of arterial vascular smooth muscle cell migration from the medial to the intimal space. Collagen receptor antagonism may be used to provide a novel means of anti- platelet therapy, and to be of benefit in clinical situations where conventional anti-platelet therapy is also effective.

The integrin α2βl, and the closely-related αlβl, for which GFOGER-containing triple-helical peptide is also a ligand, are widely expressed in mammalian cells. These integrins each provide a means of adhesion and migration of cells over the underlying collagen-containing extracellular matrix, and as such, may be essential for the metastasis of tumour cells. Inhibitors of α2 and αl I-domain function may be used to inhibit metastasis.

As discussed herein, the present invention will also apply to other I-domains, such as those of αL and αM, inhibition of which will lead to down-regulation of those aspects of leukocyte function which depend upon cell adhesion. Therapeutically, such aspects of the present invention may be used to prevent excessive leukocyte (both monocyte and neutrophil) infiltration across vascular endothelia which may result in excessive tissue necrosis in sepsis; inhibition may be valuable in controlling inflammation.

An inhibitor of a polypeptide (e.g. Integrin α2βl) may be used in treatment of a disease or disorder in which the polypeptide has a role, and may be administered to any individual, human or non-human, in need thereof.

When an inhibitor according to the present invention is to be given to an individual, administration is preferably in a Aprophylactically effective amount® or a "therapeutically effective amount" as the case may be, although prophylaxis may be considered therapy) , this being sufficient to show benefit to the individual. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors .

A composition may be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.

Pharmaceutical compositions according to the present invention, and for use in accordance with the present invention, may include, in addition to active ingredient, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g. cutaneous, subcutaneous or intravenous.

Pharmaceutical compositions for oral administration may be in tablet, capsule, powder or liquid form. A tablet may include a solid carrier such as gelatin or an adjuvant. Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.

For intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection. Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required.

Examples of techniques and protocols mentioned above can be found in Remington=s Pharmaceutical Sciences, 16th edition, Osol, A. (ed) , 1980.

The basis for considering that the principles established here for α2 I-domain will be applicable to other receptors is two- fold. Firstly, the surface of the several I-domains under consideration is very similar. On these grounds alone it is anticipated that antagonists of α2 I-domain will also inhibit other I-domains. Secondly, experiment has demonstrated that this principle does extends to the αl I-domain, since the triple-helical GFOGER-containing peptide supports adhesion of Ruggli cells mediated by αlβl, and inhibits adhesion of these same cells to collagen and of the purified receptor to collagen [18] . Other collagen-binding I-domains αlO, all are expected to follow suit.

Receptor antagonists of α2 I-domain provide for identification of antagonists of other I-domains, and the surface of the α2 I-domain embodied in Table 2 will provide valuable assistance in the model building exercise needed for rational drug design targeting these ubiquitous cellular adhesion receptors.

Further aspects and embodiments of the present invention will be apparent to those skilled in the art. The invention will now be illustrated further with reference to experimental support and use of aspects and embodiments of the invention.

Brief Description of Drawings

Figure 1 shows the melting curve for peptide Ac-

[GPO]₂GFOGER[GPO]₃-NH₂. The Figure shows the variation in optical rotation with temperature of a solution of the peptide, indicating the transition from triple helical to random coil conformation as temperature increases.

Figure 2 shows the structure of the α2 I-domain in complex with the triple helical synthetic peptide. Beta strands within the I-domain are shown as broad arrows, and alpha- helices as coiled ribbons. The backbones only of other loops of the I-domain and of the strands of the triple helical peptide are shown.

Figure 3 shows that interaction of α2 I-domain and peptide is confined to two strands of triple-helix. The Figure shows the surface of the α2 I-domain in complex with the triple helical synthetic peptide. The footprint of the triple helical peptide on the I-domain surface is shaded, and both sidechains and peptide carbonyls which interact with the I-domain are indicated by arrows .

Figure 4 shows that carbonyl groups on Middle and Trailing strands of the triple-helix interact with I-domain Y185 and H258. Interactions are shown as dashed lines.

Figure 5 illustrates principal conformational changes in I- domain upon binding of peptide. The Figure shows the three- dimensional structure of the α2 I-domain in its resting, un- ligated form (grey) superimposed on the structure after ligation (dark) with triple-helical Ac- [GPO] ₂GFOGER [GPO] ₃-NH₂.

The peptide is not shown. I-domain α-helices (with their numbers above them) are shown as coiled ribbons, and β-strands as broad arrows. Conformational changes are indicated by outlined arrows.

Figure 6 shows details of the α2 I-domain MIDAS after ligation with triple-helical Ac- [GPO] ₂GFOGER [GPO] ₃-NH₂. The peptide glutamate (E) is shown, along with the residues of the I- domain which also co-ordinate the metal ion in the ligated (peptide-bound) state of the I-domain. Amino acids of the I- domain involved in metal ion co-ordination are indicated by letters (single amino-acid nomenclature) and numbers defining their position within the I-domain sequence. Interactions are indicated by dashed lines.

Experimental Support and Use of Aspects and Embodiments of the Invention

Design, Production and Analysis of a Triple Helical Peptide that Binds and Crystallises wi th Integrin I Domain

The peptide Ac- (GPO) ₂GF0GER (GPO) ₃-NH₂ was synthesized (see below for materials and methods) and shown to adopt triple helical conformation, as demonstrated by the melting curve (Figure 1) . This indicated that at cold-room temperature, i.e. below 10°C, more than 90 % of the peptide was in triple helical conformation, determined by optical polarimetry. Other methods such as circular dichroism may be used to provide further confirmation of the triple-helical state of the peptide.

Crystallisation of the Peptide of Example 1 and the I-domain of Integrin α2 and Determination of Atom Co-ordinates

Materials and methods are described below.

The co-ordinates of the atoms comprising: (i) the triple-helical structure of peptide Ac- (GPO) ₂GFOGER (GPO) ₃-NH₂ , (ii) the I-domain of the integrin α2 subunit, comprising residues 143 to 326 of the integrin sequence,

(iii) water molecules forming part of the crystal complex, and

(iv) a metal ion bridging the I-domain and collagen. are shown in Table 1.

The deduced 3 -dimensional structure of the complex is shown in Figures 2 - 6.

The collagen-like peptide adopts its characteristic triple- helical structure with a 1-residue displacement between strands, these being in parallel rather than anti-parallel alignment. This allows us to define the strands as leading, middle and trailing, with the trailing strand being displaced towards the N-terminus of the triple-helix, relative to the middle strand, and the leading strand displaced towards the C- terminus of the trimeric structure. This is illustrated in Figure 2.

In turn, this allows the strands to be seen as non-equivalent ; the environment of any specific amino acid is defined by its relationship with different amino acids in each adjacent strand, and so the structure is lacking in radial symmetry. The significance of this is that, if the amino acids interacting with the I-domain were confined to a single strand, any of the three strands could serve this function, and crystallisation would be unlikely, given that there would be three, non-equivalent peptide: I-domain complexes as a consequence of the stagger between the different strands.

If two strands engage the I-domain, then two of the three possible orientations of the helix will suffice (after axial rotation by 120° and translation of the helix by one residue) but the third orientation will be non-identical and unfavourable .

If three strands engage the I-domain, then a unique complex will result.

Surprisingly, given that crystal formation of the α2 I- domain:peptide complex is observed, the second possibility proves to be the case. Complex formation could in principle occur in either of two conformations, therefore. The successful crystallisation shows that only one of the two possible orientations occurs within the complex is allowed and suggests that interaction between the ends of adjacent triple- helices within the crystal lattice favours one of the two possible complexes.

This helix:helix interaction is permitted by the unique overlap between the C-termini of triple-helical peptides in adjacent unit cells, which are related by a two-fold axis.

This may be the cause of the bend seen in the complexed helix, although it is also possible that interactions of the triple- helix with the I-domain support this perturbation of the triple-helix linear structure.

Interaction with the I-domain is restricted to the middle and trailing strands. Multiple sites of interaction are shown in Figure 3. These include interactions of carbonyl groups from the peptide bonds of the triple helix with specific residues within the I-domain (some of which are shown in detail in Figure 4) , as well as the key interactions of the middle strand E (which co-ordinates the metal ion) and R residue (which forms a salt-bridge with I-domain D219)and trailing strand F residue. An inhibitor of receptor interaction with collagen and/or function may inhibit one or more of these interactions, and this may be by making the interactions.

The changes in the α2 I-domain upon ligation by the GFOGER- containing peptide may be summarised thus:

Upon complex formation between the I-domain and the collagenlike peptide, the C-Helix unwinds while the connecting loop coils up to form an extra turn of Helix α6.

Helix α7 undergoes a remarkable displacement upon ligand binding. This helix translates axially towards the base of the I-domain (the C-terminal end of the beta-sheet) by almost its own length, a distance of about 1 nm.

The residues responsible for co-ordinating the cation in the MIDAS are re-arranged, allowing the glutamate residue of the collagen sequence GFOGER to approach the apex of, and so complete, the octahedral co-ordination shell of the divalent cation.

An overview of these changes is shown in Figure 5.

The detail of these changes is provided as follows:

Comparison between the collagen-bound and unligated α2 I- domain shows that the central beta-sheet does not change its conformation upon ligation (RMSD = 0.03 nM) , providing a convenient reference frame for structural comparison.

The structural changes on binding ligand may be described as follows. The metal ion moves 0.26 nm towards MIDAS Loop 2 in order to make a direct bond with T221. MIDAS Loop 1 follows the movement of the metal in order to maintain its direct bonds via S153 and S155. MIDAS Loop 3 undergoes a radical rearrangement: the sidechain of D254 moves laterally so that its direct bond to the metal is lost; the G255 peptide bond flips by 180E so that its Cα moves -0.4 nm away from the metal ion; and E256 forms a new water-mediated bond to the metal. The outcome of these events is shown in Figure 6. The movement of Loop 1 towards Loop 3 brings the side chains of Y157 and H258 0.3 nm closer together such that they both fit into grooves of the triple helix.

The shift of Loop 1 and the rearrangement of Loop 3 trigger a reorganization of the C-helix and Helix α7. Loop 1 is packed against α7 in the unliganded structure, and the large concerted movement of Loop 1 and Helix al appears to Asqueeze out® the α7 helix, and it drops downwards by 1 nm. This movement breaks a partly buried salt bridge between E318 from α7 and R288 from the C-helix. The flip of Loop 3, which is packed closely against Helix α6, forces a rearrangement of the sidechain of the buried L296 that would create a close contact with L286 from the C-helix. In response to the steric pressure between these leucines, and the loss of the stabilizing E318-R288 salt-bridge, the C-helix unwinds while the connecting loop coils up to form an extra turn at the N- terminus of helix α6. The uncoiling of the C-helix produces a dramatic 180E rotation and shift of Y285, such that its hydroxyl oxygen moves by 1.7 nm from its location above the MIDAS motif to form a hydrogen bond with S316 at the top of the repositioned α7. By contrast, L286 moves 0.4 nm towards the collagen, where it makes van der Waals contacts with the trailing strand phenylalanine, and R288 moves 0.6 nm closer to the MIDAS motif, where it forms a water-mediated salt-bridge to D254.

Inhibition of any one or more of these structural changes may be used to inhibit receptor interaction with collagen and/or function. An inhibitor or receptor function may inhibit totally or partially one or more of the conformational changes .

Discussion

Several notable features of the structure are revealed, which shed light upon the function of the I-domain as a dynamic piece of cellular machinery, capable of regulating cell function, and whose own function may be regulated by the cell. These conclusions arise from the comparison of the ligated and unligated structures of the α2 I-domain, detailed above.

Firstly, it appears that the role of the C-helix is to regulate ligand binding, since it controls access to the MIDAS. Secondly, the translation of Helix 7 upon ligand binding could serve either of two functions, to regulate the position of the C-helix from within the cell, i.e. to increase the affinity of the integrin, or to transmit signals from the ligated MIDAS to the body of the integrin and thence to the cell. Plausibly, the same molecular movement could serve both purposes .

This level of understanding supports several approaches to rational drug design, assuming that the therapeutic intent is to inhibit integrin function.

Firstly, small molecule analogues of collagen may be designed, of similar shape and charge distribution to the key residues of the sequence GFOGER, which bind to the complementary structure, the binding cleft of the α2 I-domain. Solution of the complex structure provided here enables establishment of the critical determinants of ligand binding, location of key atomic interactions and assignment of binding energies. This information provides for in silico construction of integrin α2βl antagonists, preferably focussing upon the integrin MIDAS .

Secondly, molecules that inhibit the conformational changes described may be designed. For example, small molecule ligands may be designed for regions adjacent to the C-helix to stabilise it in the closed conformation so preventing ligand binding, as discussed already herein. This approach offers an alternative to direct antagonism of the MIDAS.

Similarly, the regions of the I-domain at the C-terminus of Helix α7 (close to the interface between the I-domain and the rest of the integrin α2 subunit) may be targeted. This enables design of small molecules which prevent translation of the helix from occurring, with the consequence of locking the integrin in its inactive conformation, preventing both collagen binding and inwards signal transduction from taking place .

Furthermore, the different integrins characterised to date parallel one another in both structure and function. Hence, the other I-domain-containing integrins, known at present to include αl, α2 , αlO, all, aD, aE, aL, aM and αX, may be targetted in accordance with the present invention. For instance an inhibitor of α2 or αl identified using the present invention may be tested for ability to inhibit one or more other integrins containing an I-domain. Additionally, the data presented here allow predictions to be made concerning the active (ligated) form of the integrin based upon the conformation of the resting integrin, or from primary sequence using the co-ordinates of known structures such as α2 I-domain or αL I-domain as a model. Thus a region of an I-domain considered by analogy with the ligated α2 I-domain crystal structure information presented herein to be involved in ligand binding and/or involved in a conformational change on ligand binding, may be targeted, for instance by means of an antibody or other specific binding molecule.

These concepts may be extended to other, non-integrin proteins, such as von Willebrand factor, which contain I- domains and which might undergo activation in an analogous fashion.

The knowledge of the structural changes occurring in the integrin upon ligation presented here provides such proteins as targets for rational drug design.

Materials and Methods

Crystallization and data collection Recombinant α2-I domain and a synthetic collagen-like peptide, Ac-GPO)₂GFOGER(GPO)₃-NH₂, were produced [18, 26]. See also WO99/50281. Crystallization experiments were performed at 4EC using the sitting drop vapor diffusion method. Initial conditions were established using a 2 ml sample of protein in buffer 0.1 M Tris pH 7.5, 0.15M NaCl, 2 mM MgCl₂ (or MnCl₂) and peptide in 10 mM acetate pH 5.0 mixed in a ratio of 1:4 added to 2 ml of well solution consisting of 25 mM sodium cacodylate pH 6.5, 20% glycerol and 20-30% PEG 5K MME. Small bunched crystals appeared after 2-4 days and had flattened rod-like morphology with dimensions 0.025 x 0.025 x 0.1 mm³. The crystals adopt space group P2₁2₁2₁ with cell dimensions a = 4.2 nm, b = 4.84 nm, c = 11.45 nm. Crystal growth was dependent on the presence and concentration of divalent cation but was unaffected by the cation species. Similar crystals grew in the presence of Mg²⁺, Mn²⁺, Co⁺, Cd²⁺, Ni²⁺ and Zn⁺ ions . Larger single crystals were rare and improved only marginally by making small changes in the cation concentration and the protein:peptide ratio. Data were collected at the Daresbury Synchrotron Radiation Source using a single crystal flash frozen in a cryo-stream of nitrogen at a temperature of 100 K. Data set Native I was collected from station 9.6 using the Quantum4 CCD detector to 0.25 nm resolution. This crystal was grown in 1 mM ZnCl₂ using a protein to triple helical peptide ratio of 1:2.5. A high resolution data set to 0.21 nm resolution (Native II) was subsequently collected on SRS station 7.2 using a MAR345 scanner. This crystal was grown in 1 mM CoCl₂ using a protein to peptide ratio of 1:1.6. Data were reduced with DENZO and scaled with SCALEPACK [29] . The overall I/si for Native II is 12.0 (2.9 in 2.17-2.1 A shell) with an R_merge of 8.9% (34.4% in outer shell), an average redundancy of 2.9 and completeness of 98.2% in the range 20-2.1 A (14483 reflections) .

Structure determination and refinement

Molecular replacement was performed on the Native I data set with AMORE [30] using the crystal structure of the uncomplexed α2-I domain as the search model. A clear solution was found in the cross rotation function and subsequent translation function. The initial R_W0RK was 52.0% with an R_FREE of 54.2%. A 2F₀-F_C electron density map calculated at 0.25 nm was of high quality with changes in the MIDAS motif readily apparent.

Little density for the collagen peptide could be observed in the 2F₀-F_C or F₀-F_c map at this stage. Several rounds of model building and refinement of the I domain using XTALVIEW [31] resulted in greatly improved density for several regions of the domain which had undergone structural change. Following rebuilding of the I domain some density for the collagen peptide was apparent in the 2F₀-F_C and F₀-F_c electron density maps. Solvent flattening using a molecular mask constructed to encompass the predicted peptide region provided unbiased improvement of the peptide electron density, and 24 alanine residues were inserted. At this stage the identification of hydroxyproline hydroxyl groups in the C-terminal GPO triplets allowed the correct assignment of the collagen chain direction. Identification of GFOGER sidechain density and the C-terminal ends of each chain allowed correct positioning of the leading, middle and trailing strands. Several rounds of model building and refinement allowed complete identification of the collagen peptides. At this stage data to 0.21 nm resolution became available from the native II data set showing an initial R_W0RK of 38.6% and an R_FREE of 47.1% against the refined model . Further cycles of model building and refinement, including the insertion of 398 water molecules, gave a final R_W0RK of 0.203 and R_FREE of 0.276 (5% of the reflections) . The RMS deviations from ideal bond length and angles are 0.0006 nm and 1.41E. Good density is observed for I domain residues 142 to 326 and for all collagen residues, although the N-terminal GPO triplet of each strand is more mobile than the others. The coordinates and structure factors have been deposited with the PDB (code assigned; Idzi) . References

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27. Dickeson et al . (1997) J. Biol. Chem. 272:7661-7668.

28. Ducruix & Giege (1992) in Crystallisation of nucleic acids and proteins : A practical approach . IRL press: Oxford. 29. Otwinowski (1993) in Data collection and processing, L. Sawyer, N. Isaacs, andS . Bailey, Ed. SDERC: Daresbury, UK. p. 59-62.

30. Navaza (1994) Acta Cryst . A50:157-163. 31. McRee (1999) J. Struct. Biol. 125:156-165.

All documents cited anywhere in this text are incorporated by reference .

TABLE 1 - Co-ordinates of the crystal formed from the α2 I- domain and triple-helical peptide Ac- (GPO) ₂GFOGER (GPO) ₃-NH₂ in compl ex.

The sequence of each molecular component of the crystal complex is provided:

Fifteen consecutive lines define the amino acid sequence beginning with the N-terminal Alanine (ALA) of the recombinant I-domain, which contains 185 amino acid residues and is defined as A.

Two consecutive lines define the sequence of the 21 amino acids and C-terminal amide of the first chain of the triple helical peptide, defined as B.

Four further consecutive lines define identically the sequence of the second and third chains of the triple-helical peptide, defined as C and D.

Thirty-one lines show the water molecules (HOH) which are comprised within the structure of the complex as water of crystallisation, defined collectively as E.

One line defines the cobalt ion (CO) as F.

One line (CRYST1) defines the dimensions of the crystal cell, and its spacegroup.

Atoms comprising the crystal complex are listed sequentially, identified in Columns 1 and 2; Column 3 defines each specific atom within an amino acid residue; Column 4 defines the identity and position of the amino acid within the sequence, or of other chemical species such as water (HOH) , and the chain (defined above as A, B, C, D, E or F) containing the specific atom; Columns 5, 6 and 7 provide the X, Y and Z coordinates respectively of the specific atom; Column 8 provides the occupancy, that is presence or absence for the purposes of analysis; Column 9 provides a parameter of thermal mobility known as the B-factor; Column 10 provides an alternative means of identifying the chain in which the atom resides, useful for certain computer software packages (A defines atoms as being within Chain A, the I-domain: CA, CB and CD identify atoms as residing within the triple-helical peptide chains, Collagen A, Collagen B or Collagen C: W defines an atom as belonging to water, and M as being the metal ion) .

SEQRES 1 A 185 ALA LEU ILE ASP VAL VAL VAL VAL CYS ASP GLU SER ASN

SEQRES 2 A 185 SER ILE TYR CPR TRP ASP ALA VAL LYS ASN PHE LEU GLU

SEQRES 3 A 185 LYS PHE VAL GLN GLY LEU ASP ILE GLY PRO THR LYS THR

SEQRES 4 A 185 GLN VAL GLY LEU ILE GLN TYR ALA ASN ASN PRO ARG VAL

SEQRES 5 A 185 VAL PHE ASN LEU ASN THR TYR LYS THR LYS GLU GLU MET

SEQRES 6 A 185 ILE VAL ALA THR SER GLN THR SER GLN TYR GLY GLY ASP

SEQRES 7 A 185 LEU THR ASN THR PHE GLY ALA ILE GLN TYR ALA ARG LYS

SEQRES 8 A 185 TYR ALA TYR SER ALA ALA SER GLY GLY ARG ARG SER ALA

SEQRES 9 A 185 THR LYS VAL MET VAL VAL VAL THR ASP GLY GLU SER HIS

SEQRES 10 A 185 ASP GLY SER MET LEU LYS ALA VAL ILE ASP GLN CYS ASN

SEQRES 11 A 185 HIS ASP ASN ILE LEU ARG PHE GLY ILE ALA VAL LEU GLY

SEQRES 12 A 185 TYR LEU ASN ARG ASN ALA LEU ASP THR LYS ASN LEU ILE

SEQRES 13 A 185 LYS GLU ILE LYS ALA ILE ALA SER ILE PRO THR GLU ARG

SEQRES 14 A 185 TYR PHE PHE ASN VAL SER ASP GLU ALA ALA LEU LEU GLU

SEQRES 15 A 185 LYS ALA GLY

SEQRES 1 B 22 GLY PRO HYP GLY PRO HYP GLY PHE HYP GLY GLU ARG GLY

SEQRES 2 B 22 PRO HYP GLY PRO HYP GLY PRO HYP NHH

SEQRES 1 C 22 GLY PRO HYP GLY PRO HYP GLY PHE HYP GLY GLU ARG GLY

SEQRES 2 C 22 PRO HYP GLY PRO HYP GLY PRO HYP NHH

SEQRES 1 D 22 GLY PRO HYP GLY PRO HYP GLY PHE HYP GLY GLU ARG GLY

SEQRES 2 D 22 PRO HYP GLY PRO HYP GLY PRO HYP NHH

SEQRES 1 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 2 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 3 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 4 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 5 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 6 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 7 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES δ E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 9 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 10 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH SEQRES 11 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 12 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 13 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 14 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 15 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES IS E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 17 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 18 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 19 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 20 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 21 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 22 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 23 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 24 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 25 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 26 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 27 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 28 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 29 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 30 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 31 E 400 HOH HOH HOH HOH HOH HOH HOH HOH HOH HOH

SEQRES 1 F 1 CO

CRYST1 41.994 48.377 114.545 90.00 90.00 90.00 P 21 21 21 24

ATOM 1 CB ALA A 142 11.648 -13.520 47.836 1 .00 34 .96 A

ATOM 2 C ALA A 142 9.671 -12.738 49.142 1 .00 34 .94 A

ATOM 3 0 ALA A 142 8.835 -13.081 49.983 1 .00 35 .57 A

ATOM 4 N ALA A 142 9.402 -13.644 46.820 1 .00 35 .53 A

ATOM 5 CA ALA A 142 10.165 -13.735 48.096 1 .00 34 .99 A

ATOM 6 N LEU A 143 10.173 -11.504 49.092 1 .00 33 .30 A

ATOM 7 CA LEU A 143 9.763 -10.523 50.085 1 .00 30 .95 A

ATOM 8 CB LEU A 143 10.863 -10.384 51.155 1 .00 30 .60 A

ATOM 9 CG LEU A 143 12.286 -9.955 50.765 1 .00 31 .70 A

ATOM 10 CD1 LEU A 143 12.375 -8.444 50.664 1 .00 32 .35 A

ATOM 11 CD2 LEU A 143 13.275 -10.423 51.811 1 .00 30. .98 A

ATOM 12 C LEU A 143 9.304 -9.133 49.630 1 .00 29 .03 A

ATOM 13 0 LEU A 143 8.144 -8.776 49.845 1 .00 28 .59 A

ATOM 14 N ILE A 144 10.174 -8.354 48.992 1 .00 26 .76 A

ATOM 15 CA ILE A 144 9.788 -6.988 48.623 1 .00 24, .45 A

ATOM 16 CB ILE A 144 10.354 -5.982 49.660 1 .00 24 .71 A

ATOM 17 CG2 ILE A 144 9.884 .583 49.339 1 .00 24 .79 A

ATOM 18 CGI ILE A 144 9.898 .365 51.072 1 .00 25, .36 A

ATOM 19 CD1 ILE A 144 10.517 .520 52.173 1 .00 25, .41 A

ATOM 20 C ILE A 144 10.151 .446 47.238 1. .00 22. .83 A

ATOM 21 0 ILE A 144 11.317 .426 46.842 1. .00 22. .87 A

ATOM 22 N ASP A 145 9.135 -5.980 46.520 1. .00 19, .93 A

ATOM 23 CA ASP A 145 9.330 -5.386 45.210 1, .00 18. .20 A

ATOM 24 CB ASP A 145 8.371 -6.002 44.181 1. .00 17. .90 A

ATOM 25 CG ASP A 145 8.865 -7.340 43.639 1. .00 18. .99 A

ATOM 26 ODl ASP A 145 10.071 -7.645 43.799 1 .00 21, .43 A

ATOM 27 OD2 ASP A 145 8.056 -8.077 43.034 1. .00 16. ,50 A

ATOM 28 C ASP A 145 9.056 -3.886 45.363 1. .00 17. ,28 A

ATOM 29 o ASP A 145 7.903 -3.463 45.478 1, .00 16. .93 A

ATOM 30 N VAL A 146 10.120 -3.087 45.383 1. .00 16. ,46 A

ATOM 31 CA VAL A 146 9.981 -1.644 45.542 1. .00 15. ,31 A ATOM 32 CB VAL A 146 10.946 -1.092 46.615 1.00 16.68 A

ATOM 33 CGI VAL A 146 10.681 0.395 46.826 1.00 17 .60 A TOM 34 CG2 VAL A 146 10.780 -1.846 47.916 1.00 17 .29 A

ATOM 35 C VAL A 146 10.231 -0.848 44.268 1.00 14 .93 A

ATOM 36 o VAL A 146 11.275 -0.984 43.630 1.00 14 .75 A

ATOM 37 N VAL A 147 9.270 -0.002 43.916 1.00 13 .85 A

ATOM 38 CA VAL A 147 9.385 0.846 42.741 1.00 13 .06 A

ATOM 39 CB VAL A 147 8.215 0.624 41.751 1.00 14 .12 A

ATOM 40 CGI VAL A 147 8.284 1.650 40.628 1.00 12 .57 A

ATOM 41 CG2 VAL A 147 8.270 -0.797 41.184 1.00 13 .32 A

ATOM 42 C VAL A 147 9.384 2.309 43.165 1.00 12 .08 A

ATOM 43 o VAL A 147 8.431 ,784 43.791 1.00 12, .23 A

ATOM 44 N VAL A 148 10.468 ,004 42.831 1.00 11, .18 A

ATOM 45 CA VAL A 148 10.625 ,424 43.130 1.00 9 .94 A

ATOM 46 CB VAL A 148 12.106 .779 43.401 1.00 10, .37 A

ATOM 47 CGI VAL A 148 12.258 ,282 43.621 1.00 10, .02 A

ATOM 48 CG2 VAL A 148 12.608 ,016 44.615 1.00 11, .21 A

ATOM 49 C VAL A 148 10.144 254 41.942 1.00 10. .76 A

ATOM 50 o VAL A 148 10.622 078 40.822 1.00 11. .23 A

ATOM 51 N VAL A 149 9.195 6.152 42.192 1.00 10. .14 A

ATOM 52 CA VAL A 149 8.650 7.027 41.154 1.00 9. ,36 A

ATOM 53 CB VAL A 149 7.099 6.991 41.177 1.00 8. ,62 A

ATOM 54 CGI VAL A 149 6.523 7.938 40.130 1.00 6. .99 A

ATOM 55 CG2 VAL A 149 6.617 5.553 40.929 1.00 5. 19 A

ATOM 56 C VAL A 149 9.186 8.421 41.493 1.00 10. 37 A

ATOM 57 o VAL A 149 8.677 9.099 42.392 1.00 12. 43 A

ATOM 58 N CYS A 150 10.207 8.844 40.757 1.00 8. ,87 A

ATOM 59 CA CYS A 150 10.890 10.108 41.027 1.00 9. 53 A

ATOM 60 CB CYS A 150 12.389 9.812 41.159 1.0 000 7. 66 A

ATOM 61 SG CYS A 150 13.406 11.182 41.672 1.0000 8. 78 A

ATOM 62 C CYS A 150 10.678 11.283 40.073 1.0000 8. 89 A

ATOM 63 o CYS A 150 11.035 11.229 38.895 1 .00 10 .33 A

ATOM 64 N ASP A 151 10.115 12.356 40.618 1 .00 9 .37 A

ATOM 65 CA ASP A 151 9.822 13.591 39.890 1 .00 9 .11 A

ATOM 66 CB ASP A 151 9.110 14.552 40.840 1 .00 11 .54 A

ATOM 67 CG ASP A 151 8.410 15.689 40.129 1 .00 11 .85 A

ATOM 68 ODl ASP A 151 8.906 16.171 39.091 1 .00 14 .28 A

ATOM 69 OD2 ASP A 151 7.357 16.113 40.634 1 .00 12 .34 A

ATOM 70 C ASP A 151 11.105 14.256 39.356 1 .00 10 .14 A

ATOM 71 0 ASP A 151 12.012 14.575 40.120 1 .00 8 .58 A

ATOM 72 N GLU A 152 11.176 14.470 38.045 1 .00 9, .69 A

ATOM 73 CA GLU A 152 12.349 15.100 37.454 1 .00 10 .74 A

ATOM 74 CB GLU A 152 13.097 14.106 36.548 1, .00 12, .08 A

ATOM 75 CG GLU A 152 12.376 13.735 35.251 1 .00 12, .78 A

ATOM 76 CD GLU A 152 13.161 12.738 34.402 1, .00 13. .97 A

ATOM 77 OE1 GLU A 152 14.400 12.675 34.534 1, .00 12. .78 A

ATOM 78 OE2 GLU A 152 12.540 12.024 33.588 1, .00 14. .91 A

ATOM 79 C GLU A 152 11.949 16.344 36.661 1, .00 11, .12 A

ATOM 80 o GLU A 152 12.709 16.830 35.823 1. .00 11. .48 A

ATOM 81 N SER A 153 10.758 16.865 36.942 1, .00 10. .14 A

ATOM 82 CA SER A 153 10.266 18.048 36.252 1, .00 9, .70 A

ATOM 83 CB SER A 153 8.803 18.306 36.624 1. .00 10. ,82 A

ATOM 84 OG SER A 153 8.654 18.418 38.025 1. .00 7. .53 A

ATOM 85 C SER A 153 11.128 19.264 36.589 1. .00 10. .23 A

ATOM 86 o SER A 153 11.912 19.235 37.539 1. .00 10. ,08 A

ATOM 87 N ASN A 154 10.976 20.327 35.801 1. .00 8. .89 A ATOM 88 CA ASN A 154 11.760 21.548 35.973 1.00 9.70 A

ATOM 89 CB ASN A 154 11 .320 22 .621 34 .959 1 .00 9 .07 A

ATOM 90 CG ASN A 154 11 .755 22 .300 33 .524 1 .00 12 .54 A

ATOM 91 ODl ASN A 154 12 .534 21 .373 33 .284 1 .00 13 .50 A

ATOM 92 ND2 ASN A 154 11 .262 23 .084 32 .568 1 .00 11 .08 A

ATOM 93 C ASN A 154 11 .713 22 .144 37 .369 1 .00 9 .06 A

ATOM 94 0 ASN A 154 12 .723 22 .629 37 .870 1 .00 7 .54 A

ATOM 95 N SER A 155 10 .539 22 .093 37 .997 1 .00 10 .29 A

ATOM 96 CA SER A 155 10 .352 22 .672 39 .327 1 .00 9 .98 A

ATOM 97 CB SER A 155 8 .874 22 .642 39 .710 1 .00 9 .88 A

ATOM 98 OG SER A 155 8 .513 21 .362 40 .193 1 .00 11 .38 A

ATOM 99 C SER A 155 11 .159 22 .002 40 .435 1 .00 10 .21 A

ATOM 100 0 SER A 155 11 .381 22 .601 41 .483 1 .00 9 .99 A

ATOM 101 N ILE A 156 11 .595 20 .766 40 .211 1 .00 9 .91 A

ATOM 102 CA ILE A 156 12 .364 20 .047 41 .219 1 .00 9 .61 A

ATOM 103 CB ILE A 156 12 .462 18 .546 40 .861 1 .00 8 .85 A

ATOM 104 CG2 ILE A 156 13 .467 17 .846 41 .775 1 .00 8 .95 A

ATOM 105 CGI ILE A 156 11 .070 17 .898 40 .980 1 .00 8 .39 A

ATOM 106 CD1 ILE A 156 10 .482 17 .937 42 .394 1 .00 2 .79 A

ATOM 107 C ILE A 156 13 .761 20 .647 41 .406 1 .00 9 .78 A

ATOM 108 0 ILE A 156 14 .466 20 .922 40 .439 1, .00 9 .93 A

ATOM 109 N TYR A 157 14 .140 20 .849 42 .667 1, .00 8 .74 A

ATOM 110 CA TYR A 157 15 .426 21 .448 43 .028 1. .00 9 .40 A

ATOM 111 CB TYR A 157 15 .376 22 .955 42 .766 1, .00 13 .35 A

ATOM 112 CG TYR A 157 16 .677 23 .689 43 .009 1. .00 14 .09 A

ATOM 113 CD1 TYR A 157 17 .557 23 .943 41. .964 1. .00 14. .70 A

ATOM 114 CE1 TYR A 157 18, .757 24 .621 42 .182 1. .00 15 .23 A

ATOM 115 CD2 TYR A 157 17, .026 24, .127 44, .289 1. .00 15, .58 A

ATOM 116 CE2 TYR A 157 18. .222 24, .802 44, .520 1. ,00 14. .41 A TOM 117 CZ TYR A 157 19. ,080 25. .047 43. .465 1. ,00 15, .28 A

ATOM 118 OH TYR A 157 20, .258 25, .725 43, .687 1. .00 14, .42 A

ATOM 119 C TYR A 157 15. .662 21. .217 44. .523 1. ,00 9. .98 A TOM 120 0 TYR A 157 14. .727 21, .322 45. .318 1. ,00 8. .35 A

ATOM 121 N CPR A 158 16. .903 20. .875 44. .924 1. 00 10. ,14 A

ATOM 122 CD CPR A 158 17. .241 20. .924 46. .358 1. ,00 8. .97 A

ATOM 123 CA CPR A 158 18. ,121 20. .678 44. ,124 1. 00 11. ,99 A

ATOM 124 CB CPR A 158 19. .218 21. .139 45. .071 1. 00 10. ,42 A

ATOM 125 CG CPR A 158 18. ,726 20. ,604 46. ,372 1. 00 10. ,37 A

ATOM 126 C CPR A 158 18. ,256 19. ,195 43. ,781 1. 00 11. ,98 A

ATOM 127 0 CPR A 158 17. ,978 18. ,347 44. 618 1. 00 13. 30 A

ATOM 128 N TRP A 159 18. ,695 18. ,879 42. 569 1. 00 13. ,37 A

ATOM 129 CA TRP A 159 18. ,816 17. ,481 42. ,177 1. 00 14. ,62 A

ATOM 130 CB TRP A 159 19. ,273 17. ,364 40. ,716 1. 00 13. ,17 A

ATOM 131 CG TRP A 159 19. 038 16. 001 40. 141 1. 00 12. 86 A

ATOM 132 CD2 TRP A 159 17. 773 15. 328 40. 002 1. 00 12. 49 A

ATOM 133 • CE2 TRP A 159 18. 039 14. 052 39. 453 1. 00 12. 27 A

ATOM 134 CE3 TRP A 159 16. 447 15. 680 40. 286 1. 00 12. 37 A

ATOM 135 CD1 TRP A 159 19. 982 15. 135 39. 682 1. 00 11. 66 A

ATOM 136 NE1 TRP A 159 19. 391 13. 960 39. 269 1. 00 10. 69 A

ATOM 137 CZ2 TRP A 159 17. 022 13. 122 39. 183 1. 00 12. 98 A

ATOM 138 CZ3 TRP A 159 15. 433 14. 755 40. 019 1. 00 12. 83 A

ATOM 139 CH2 TRP A 159 15. 731 13. 490 39. 471 1. 00 12. 43 A

ATOM 140 C TRP A 159 19. 760 16. 713 43. 098 1. 00 14. 85 A

ATOM 141 0 TRP A 159 19. 552 15. 530 43. 352 1. 00 16. 17 A

ATOM 142 N ASP A 160 20. 789 17. 388 43. 603 1. 00 15. 74 A

ATOM 143 CA ASP A 160 21. 748 16. 761 44. 514 1. 00 17. 53 A ATOM 144 CB ASP A 160 22.715 17.808 45.077 1.00 20.00 A

ATOM 145 CG ASP A 160 23 .797 18 .194 44 .090 1 .00 25 .18 A

ATOM 146 ODl ASP A 160 24 .384 19 .282 44 .269 1 .00 28 .54 A

ATOM 147 OD2 ASP A 160 24 .071 17 .414 43 .148 1 .00 25 .23 A

ATOM 148 C ASP A 160 21 .029 16 .077 45 .676 1 .00 15 .95 A

ATOM 149 0 ASP A 160 21 .381 14 .967 46 .065 1 . 00 14 .81 A

ATOM 150 N ALA A 161 20 .032 16 .757 46 .232 1 .00 13 .82 A

ATOM 151 CA ALA A 161 19 .265 16 .213 47 .342 1 .00 13 .97 A

ATOM 152 CB ALA A 161 18 .284 17 .260 47 .863 1 .00 13 .79 A

ATOM 153 C ALA A 161 18 .513 14 .963 46 .897 1 .00 13 .98 A

ATOM 154 0 ALA A 161 18 .370 14 .005 47 .660 1 .00 13 .02 A

ATOM 155 N VAL A 162 18 .033 14 .973 45 .658 1 .00 14 .83 A TOM 156 CA VAL A 162 17 .303 13 .826 45 .128 1 .00 14 .59 A

ATOM 157 CB VAL A 162 16 .614 14 .190 43 .794 1 .00 15 .34 A

ATOM 158 CGI VAL A 162 15 .829 12 .991 43 .254 1 . 00 14 .23 A

ATOM 159 CG2 VAL A 162 15 .679 15 .372 44 .011 1 .00 13 .44 A

ATOM 160 C VAL A 162 18 .236 12 .621 44 .934 1 .00 14 .98 A

ATOM 161 0 VAL A 162 17 .923 11 .511 45 .365 1 .00 15 .96 A

ATOM 162 N LYS A 163 19 .380 12 .840 44 .290 1 .00 15 .39 A

ATOM 163 CA LYS A 163 20 .347 11 .764 44 .074 1 .00 15 .08 A

ATOM 164 CB LYS A 163 21 .593 12 .289 43 .358 1 .00 18 .00 A

ATOM 165 CG LYS A 163 21. .405 12 .638 41 .892 1, .00 21 .39 A

ATOM 166 CD LYS A 163 22 .710 13 .194 41 .333 1 .00 24 .66 A

ATOM 167 CE LYS A 163 22, .648 13. .384 39 .837 1, .00 26. .80 A

ATOM 168 NZ LYS A 163 23, .850 14 .103 39 .348 1, .00 29, .83 A

ATOM 169 C LYS A 163 20 .781 11 .158 45 .409 1, .00 14, .49 A

ATOM 170 0 LYS A 163 20, .870 9, .936 45, .553 1. .00 11. .86 A

ATOM 171 N ASN A 164 21, .067 12, .020 46, .380 1, .00 13, .30 A

ATOM 172 CA ASN A 164 21, .494 11, .555 47, .691 1. .00 13. .86 A TOM 173 CB ASN A 164 21. .719 12, .731 48, .633 1. .00 13, .54 A

ATOM 174 CG ASN A 164 22. .110 12. .286 50. .018 1. ,00 13. .56 A

ATOM 175 ODl ASN A 164 21. .273 12. .193 50, .918 1. .00 12. .49 A

ATOM 176 ND2 ASN A 164 23. ,386 11. .985 50. .195 1. ,00 13. ,32 A

ATOM 177 C ASN A 164 20. .462 10. .618 48. .296 1. ,00 14. ,39 A

ATOM 178 0 ASN A 164 20. .797 9. ,564 48. .847 1. ,00 14. .01 A

ATOM 179 N PHE A 165 19. 201 11. 013 48. 194 1. 00 14. 20 A

ATOM 180 CA PHE A 165 18. 123 10. ,202 48. ,721 1. 00 13. 04 A

ATOM 181 CB PHE A 165 16. ,785 10. ,899 48. ,509 1. 00 12. 24 A

ATOM 182 CG PHE A 165 15. ,613 10. ,061 48. ,911 1. 00 11. ,89 A

ATOM 183 CD1 PHE A 165 15. 289 9. 896 50. 250 1. 00 12. 66 A

ATOM 184 CD2 PHE A 165 14. ,882 9. ,370 47. ,954 1. 00 12. 19 A

ATOM 185 CE1 PHE A 165 14. 251 9. 050 50. 630 1. 00 12. 76 A

ATOM 186 CE2 PHE A 165 13. 848 8. 524 48. 323 1. 00 12. 35 A

ATOM 187 CZ PHE A 165 13. 536 8. 363 49. 664 1. 00 11. 87 A TOM 188 C PHE A 165 18. 093 8. 835 48. 036 1. 00 13. 02 A

ATOM 189 o PHE A 165 18. 173 7. 808 48. 695 1. 00 14. 50 A

ATOM 190 N LEU A 166 17. 975 8. 834 46. 711 1. 00 13. 00 A

ATOM 191 CA LEU A 166 17. 925 7. 594 45. 937 1. 00 13. 67 A

ATOM 192 CB LEU A 166 18. 004 7. 911 44. 445 1. 00 12. 12 A

ATOM 193 CG LEU A 166 16. 904 8. 863 43. 968 1. 00 12. 57 A

ATOM 194 CD1 LEU A 166 17. 103 9. 207 42. 508 1. 00 9. 74 A

ATOM 195 CD2 LEU A 166 15. 552 8. 217 44. 203 1. 00 11. 27 A

ATOM 196 C LEU A 166 19. 077 6. 681 46. 319 1. 00 14. 74 A

ATOM 197 o LEU A 166 18. 899 5. 488 46. 561 1. 00 15. 55 A

ATOM 198 N GLU A 167 20. 260 7. 277 46. 357 1. 00 15. 63 A

ATOM 199 CA GLU A 167 21. 496 6. 606 46. 700 1. 00 17. 13 A ATOM 200 CB GLU A 167 22.623 7.637 46.626 1.00 20.43 A

ATOM 201 CG GLU A 167 24 .034 7 .105 46 .610 1 .00 25 .09 A

ATOM 202 CD GLU A 167 24 .977 8 .066 45 .899 1 .00 28 .66 A

ATOM 203 OE1 GLU A 167 26 .207 7 .859 45 .974 1 .00 31 .85 A

ATOM 204 OE2 GLU A 167 24 .482 9 .024 45 .254 1 .00 29 .06 A

ATOM 205 C GLU A 167 21 .410 5 .993 48 .095 1 .00 16 .74 A

ATOM 206 o GLU A 167 21 .658 4 .802 48 .265 1 .00 16 .83 A

ATOM 207 N LYS A 168 21 .053 6 .814 49 .084 1 .00 16 .30 A

ATOM 208 CA LYS A 168 20 .936 6 .373 50 .480 1 .00 15 .74 A

ATOM 209 CB LYS A 168 20 .725 7 .580 51 .406 1 .00 13 .90 A

ATOM 210 CG LYS A 168 21 .932 8 .493 51 .548 1 .00 14 .49 A

ATOM 211 CD LYS A 168 23 .035 7 .809 52 .330 1 .00 15 .70 A

ATOM 212 CE LYS A 168 24 .143 8 .773 52 .698 1 .00 16 .32 A

ATOM 213 NZ LYS A 168 24 .818 9 .345 51 .512 1 .00 14 .90 A

ATOM 214 C LYS A 168 19 .795 5 .379 50 .698 1 .00 15 .80 A

ATOM 215 o LYS A 168 19 .860 4 .528 51 .586 1 .00 15 .98 A

ATOM 216 N PHE A 169 18 .744 5 .506 49 .897 1 .00 15 .19 A

ATOM 217 CA PHE A 169 17 .602 4 .615 50 .011 1 .00 15 .65 A

ATOM 218 CB PHE A 169 16 .452 5 .097 49 .112 1 .00 12 .98 A

ATOM 219 CG PHE A 169 15 .290 4 .146 49 .059 1 .00 12 .73 A

ATOM 220 GDI PHE A 169 14 .530 3 .892 50 .192 1. .00 12 .13 A

ATOM 221 CD2 PHE A 169 14 .988 3 .465 47 .886 1 .00 13 .61 A

ATOM 222 CE1 PHE A 169 13, .485 2 .971 50. .158 1. .00 14 .03 A

ATOM 223 CE2 PHE A 169 13, .943 2 .542 47 .846 1, .00 13 .89 A

ATOM 224 CZ PHE A 169 13 .193 2 .294 48 .983 1 .00 12 .36 A

ATOM 225 C PHE A 169 18. .022 3, .198 49. .618 1, .00 16, .17 A

ATOM 226 o PHE A 169 17. .779 2, .245 50. .354 1. .00 15, .90 A

ATOM 227 N VAL A 170 18, .664 3, .066 48, .462 1, .00 17, .23 A

ATOM 228 CA VAL A 170 19, .112 1, .762 47. .984 1. .00 18, .56 A

ATOM 229 CB VAL A 170 19. .707 1. .881 46. .553 1. .00 18. .42 A

ATOM 230 CGI VAL A 170 20. .408 0. .591 46. .154 1. .00 17. .54 A

ATOM 231 CG2 VAL A 170 18. .593 2. .199 45. ,560 1. , 00 17. .05 A

ATOM 232 C VAL A 170 20. .148 1. .132 48. .926 1. ,00 20. .05 A

ATOM 233 o VAL A 170 20. 217 -0. 090 49. ,058 1. 00 20. ,58 A

ATOM 234 N GLN A 171 20. ,942 1. ,971 49. 584 1. 00 21. ,43 A

ATOM 235 CA GLN A 171 21. ,973 1. ,504 50. ,511 1. 00 22. ,80 A

ATOM 236 CB GLN A 171 22. ,786 2. .697 51. ,034 1. ,00 25. .64 A

ATOM 237 CG GLN A 171 24. ,255 2. ,721 50. 617 1. 00 27. ,27 A

ATOM 238 CD GLN A 171 25. 057 1. 580 51. 214 1. 00 29. 69 A

ATOM 239 OE1 GLN A 171 25. 020 1. 346 52. 423 1. 00 31. 25 A

ATOM 240 NE2 GLN A 171 25. 794 0. 864 50. 367 1. 00 29. 08 A

ATOM 241 C GLN A 171 21. 389 0. 736 51. 698 1. 00 22. 06 A

ATOM 242 o GLN A 171 21. 986 -0. 227 52. 182 1. 00 19. 91 A

ATOM 243 N GLY A 172 20. 219 1. 158 52. 162 1. 00 22. 43 A

ATOM 244 CA GLY A 172 19. 604 0. 498 53. 301 1. 00 21. 98 A

ATOM 245 C GLY A 172 18. 805 -0. 749 52. 975 1. 00 22. 83 A

ATOM 246 o GLY A 172 18. 207 -1. 361 53. 862 1. 00 21. 01 A

ATOM 247 N LEU A 173 18. 797 -1. 141 51. 706 1. 00 22. 94 A

ATOM 248 CA LEU A 173 18. 041 -2. 315 51. 304 1. 00 23. 99 A

ATOM 249 CB LEU A 173 17. 292 -2. 041 50. 000 1. 00 22. 59 A

ATOM 250 CG LEU A 173 16. 303 -0. 875 49. 986 1. 00 21. 28 A

ATOM 251 CD1 LEU A 173 15. 742 -0. 728 48. 580 1. 00 21. 16 A

ATOM 252 CD2 LEU A 173 15. 186 -1. 109 51. 000 1. 00 17. 99 A

ATOM 253 C LEU A 173 18. 903 -3. 555 51. 132 1. 00 25. 00 A

ATOM 254 o LEU A 173 20. 073 -3. 471 50. 772 1. 00 23. 71 A

ATOM 255 N ASP A 174 18. 303 -4. 707 51. 407 1. 00 27. 54 A ATOM 256 CA ^' ASP A 174 18.973 -5.993 51.264 1.,00 30.47 A

ATOM 257 CB ASP A 174 18.435 -6.980 52.299 1.00 33.48 A

ATOM 258 CG ASP A 174 19.424 -8.072 52.630 1.00 37.17 A

ATOM 259 ODl ASP A 174 20.025 -8.635 51.691 1.00 38.86 A

ATOM 260 OD2 ASP A 174 19.597 -8.372 53.831 1.00 38.36 A

ATOM 261 C ASP A 174 18.590 -6.451 49.858 1.00 30.22 A

ATOM 262 0 ASP A 174 17.644 -7.216 49.677 1.00 29.33 A

ATOM 263 N ILE A 175 19.328 -5.957 48.870 1.00 30.40 A

ATOM 264 CA ILE A 175 19.066 -6.258 47.467 1.00 31.71 A

ATOM 265 CB ILE A 175 20.031 -5.453 46.570 1.00 31.30 A

ATOM 266 CG2 ILE A 175 19.507 -5.383 45.148 1.00 30.95 A

ATOM 267 CGI ILE A 175 20.155 -4.027 47.112 1.00 31.50 A

ATOM 268 CD1 ILE A 175 18.828 -3.300 47.254 1.00 31.58 A

ATOM 269 C ILE A 175 19.146 -7.747 47.123 1.00 32.27 A

ATOM 270 0 ILE A 175 19.241 -8.594 48.009 1.00 33.75 A

ATOM 271 N GLY A 176 19.089 -8.056 45.831 1.00 32.64 A

ATOM 272 CA GLY A 176 19.143 -9.437 45.386 1.00 32.16 A TOM 273 C GLY A 176 17.826 -9.910 44.790 1.00 31.98 A

ATOM 274 0 GLY A 176 16.761 -9.471 45.222 1.00 31.33 A

ATOM 275 N RO A 177 17.866 -10.796 43.779 1.00 32.34 A

ATOM 276 CD RO A 177 19.062 -11.093 42.969 1.00 32.81 A

ATOM 277 CA PRO A 177 16.664 -11.328 43.126 1.00 32.50 A

ATOM 278 CB PRO A 177 17.237 -12.152 41.977 1.00 31.55 A

ATOM 279 CG PRO A 177 18.462 -11.390 41.612 1.00 32.20 A

ATOM 280 C PRO A 177 15.762 -12.167 44.035 1.00 32.37 A

ATOM 281 0 PRO A 177 14.625 -12.478 43.673 1.00 33.30 A

ATOM 282 N THR A 178 16.267 -12.536 45.209 1.00 32.01 A

ATOM 283 CA THR A 178 15.493 -13.342 46.150 1.00 30.96 A

ATOM 284 CB THR A 178 16.220 -14.650 46.^'484 1.00 30.93 A

ATOM 285 OG1 THR A 178 17.517 -14.355 47.019 00 29.20 A

ATOM 286 CG2 THR A 178 16.363 -15.498 45.235 00 30.68 A

ATOM 287 C THR A 178 15.213 -12.599 47.448 00 30.22 A

ATOM 288 0 THR A 178 14.569 -13.126 48.355 00 31.00 A

ATOM 289 N LYS A 179 15.710 -11.372 47.536 00 28.83 A

ATOM 290 CA LYS A 179 15.500 -10.549 48.716 00 27.14 A

ATOM 291 CB LYS A 179 16.849 -10.160 49.321 00 27.31 A

ATOM 292 CG LYS A 179 17.589 -11.369 49.871 00 27.60 A

ATOM 293 CD LYS A 179 18.955 -11.561 49.240 00 27.00 A

ATOM 294 CE LYS A 179 20.026 -10.827 50.025 00 28.86 A

ATOM 295 NZ LYS A 179 21.395 -11.054 49.489 00 30.25 A

ATOM 296 C LYS A 179 14.692 -9.331 48.287 00 25.60 A

ATOM 297 o LYS A 179 13.507 -9.463 48.000 00 24.62 A

ATOM 298 N THR A 180 15.314 -8.157 48.221 00 23.79 A

ATOM 299 CA THR A 180 14.580 -6.966 47.795 00 22.88 A

ATOM 300 CB THR A 180 14.745 -5.798 48.790 00 22.04 A

ATOM 301 OG1 THR A 180 14.234 -6.182 50.070 00 23.16 A

ATOM 302 CG2 THR A 180 13.979 -4.576 48.304 00 20.65 A

ATOM 303 C THR A 180 15.002 -6.473 46.414 00 21.26 A

ATOM 304 o THR A 180 16.191 -6.322 46.130 00 21.51 A

ATOM 305 N GLN A 181 14.018 -6.225 45.558 00 20.39 A

ATOM 306 CA GLN A 181 14.282 -5.722 44.215 00 19.27 A

ATOM 307 CB GLN A 181 13.526 -6.552 43.173 00 19.23 A

ATOM 308 CG GLN A 181 14.235 -7.832 42.766 00 21.63 A

ATOM 309 CD GLN A 181 13.460 -8.635 41.738 00 22.21 A

ATOM 310 OE1 GLN A 181 14.044 -9.370 40.946 00 25.69 A

ATOM 311 NE2 GLN A 181 12.139 -8.506 41.750 00 22.55 A 01 LΠ ω t to H U1 o U1 o LΠ o LΠ o LΠ o LΠ

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to o LΠ en LO O to en μ-¹ en o ] it* it* LO ~J it* -J to LO μ-¹ o LO H to LO H

> > >' ! t >^, !> | ' | ' | ^{| |} |> >

ATOM 480 CB THR A 202 25.406 -6.698 42.692 1.00 39.50 A

ATOM 481 OG1 THR A 202 26 .042 -5 .675 41 .916 1 . 00 39 .36 A

ATOM 482 CG2 THR A 202 25 .787 -8 .062 42 .131 1 .00 38 .99 A

ATOM 483 C THR A 202 23 .576 -5 .092 43 .112 1 .00 39 .86 A

ATOM 484 ^•0 THR A ■202 23 .195 -4 .222 42 .328 1 .00 40 .54 A

ATOM 485 N LYS A 203 23 .766 -4 .880 44 .408 1 .00 39 .50 A

ATOM 486 CA LYS A 203 23 .531 -3 .598 45 .053 1 .00 39 .14 A

ATOM 487 CB LYS A 203 23 .718 -3 .775 46 .561 1 .00 39 .00 A

ATOM 488 CG LYS A 203 23 .223 -2 .641 47 .432 1 .00 38 .99 A

ATOM 489 CD LYS A 203 23 .210 -3 .101 48 .881 1 .00 38 .85 A

ATOM 490 CE LYS A 203 22 .743 -2 .017 49 .823 1 .00 38 .65 A

ATOM 491 NZ LYS A 203 22 .657 -2 .540 51 .210 1 .00 39 .40 A

ATOM 492 C LYS A 203 24 .495 -2 .540 44 .516 1 .00 39 .51 A

ATOM 493 0 LYS A 203 24 .171 -1 .350 44 .462 1 .00 39 .55 A

ATOM 494 N GLU A 204 25 .681 -2 .990 44 .118 1 .00 39 .07 A

ATOM 495 CA GLU A 204 26 .715 -2 .110 43 .582 1 .00 38 .48 A

ATOM 496 CB GLU A 204 28 .023 -2 .886 43 .406 1 .00 38 .84 A

ATOM 497 CG GLU A 204 27 .969 -4 .318 43 .910 1 .00 39 .73 A

ATOM 498 CD GLU A 204 27 .896 -4 .399 45 .421 1 .00 40 .43 A

ATOM 499 OE1 GLU A 204 27 .004 -5 .107 45 .943 1 .00 39 .63 A

ATOM 500 OE2 GLU A 204 28 .740 -3 .756 46 .085 1 .00 41 .63 A

ATOM 501 C GLU A 204 26 .295 -1 .538 42 .234 1 .00 37 .65 A

ATOM 502 0 GLU A 204 26 .323 -0 .326 42 .019 1 .00 37 .61 A

ATOM 503 N GLU A 205 25. .917 -2 .429 41 .326 1, .00 36, .53 A

ATOM 504 CA GLU A 205 25 .496 -2 .043 39 .989 1, .00 36 .06 A

ATOM 505 CB GLU A 205 25. .192 -3 .298 39, .176 1, .00 37, .10 A

ATOM 506 CG GLU A 205 26 .288 -4 .343 39, .278 1, .00 39, .86 A

ATOM 507 CD GLU A 205 25 .919 -5 .646 38 .607 1, .00 41 .30 A

ATOM 508 OE1 GLU A 205 25. .768 -5, .656 37. .368 1. .00 42. .71 A

ATOM 509 OE2 GLU A 205 25. .778 -6, .660 39. .324 1. .00 42, .41 A

ATOM 510 C GLU A 205 24, .267 -1, .144 40, .046 1. .00 34, .97 A TOM 511 0 GLU A 205 23. .984 -0. .402 39. .102 1. .00 34. .32 A TOM 512 N MET A 206 23, .542 -1, .209 41. .158 1. .00 33. .42 A

ATOM 513 CA MET A 206 22. .349 -0. .396 41. .333 1. ,00 32. .37 A

ATOM 514 CB MET A 206 21. ,351 -1. ,094 42. ,260 1. ,00 32. ,31 A

ATOM 515 CG MET A 206 20. .103 -0. .266 42. ,541 1. ,00 31. ,24 A

ATOM 516 SD MET A 206 18. .839 -1. .174 43. .439 1. ,00 31. .05 A

ATOM 517 CE MET A 206 18. ,222 -2. ,247 42. ,128 1. ,00 30. ,66 A

ATOM 518 C MET A 206 22. ,694 0. ,978 41. ,891 1. ,00 32. ,05 A

ATOM 519 o MET A 206 22. ,024 1. .960 41. 576 1. 00 32. ,40 A

ATOM 520 N ILE A 207 23. 726 1. 044 42. 730 1. 00 31. 87 A

ATOM 521 CA ILE A 207 24. ,159 2. ,317 43. 307 1. 00 31. 74 A

ATOM 522 CB ILE A 207 25. ,070 2. ,111 44. 543 1. 00 33. ,09 A

ATOM 523 CG2 ILE A 207 25. 792 3. 411 44. 893 1. 00 32. 55 A

ATOM 524 CGI ILE A 207 24. ,226 1. ,642 45. 730 1. 00 33. ,77 A TOM 525 GDI ILE A 207 23. 174 2. 655 46. 162 1. 00 34. 33 A

ATOM 526 C ILE A 207 24. 926 3. 092 42. 248 1. 00 30. 68 A

ATOM 527 o ILE A 207 24. 890 4. 325 42. 210 1. 00 29. 86 A

ATOM 528 N VAL A 208 25. 623 2. 355 41. 391 1. 00 30. 42 A

ATOM 529 CA VAL A 208 26. 381 2. 964 40. 311 1. 00 31. 48 A

ATOM 530 CB VAL A 208 27. ,281 1. 918 39. 612 1. 00 31. 48 A

ATOM 531 CGI VAL A 208 27. 992 2. 544 38. 432 1. 00 32. 42 A

ATOM 532 CG2 VAL A 208 28. 301 1. 369 40. 602 1. 00 31. 32 A

ATOM 533 C VAL A 208 25. 383 3. 547 39. 305 1. 00 32. 02 A

ATOM 534 o VAL A 208 25. 626 4. 595 38. 706 1. 00 33. 11 A

ATOM 535 N ALA A 209 24. 253 2. 869 39. 135 1. 00 32. 28 A LΠ LΠ ** O ω t to LΠ o LΠ o LΠ σ LΠ o LΠ LΠ

H H >-3 ^μ3 ^μ3 ^μ3 ^μ3 H H ^μ3 3 ^μ3 3 Ω H H H ^μ3 H3 3 >-3 >-3 ι-3 ι-3 3 ι-3 ι-3 ^ H 3 Ω 4 H ^μ3 ;5 S P G P G G P O P P P P P P P P P G G P G G P G O G G G P P G G P G P P G P P P G P P P G P P G P P G P P P G G P

2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 2 2 3 3 3 3 3 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 2 3 3 3 3 3 3 3 2

CΠ CΠ CΠ LΠ CΠ LΠ LΠ LΠ LΠ m Lπ cπ Lπ cπ Lji Lπ Lπ ui Lπ cπ cπ Lπ Ln cn cπ cπ cπ Lπ Lπ Lπ Lπ Lπ cπ cπ cπ cπ cπ cπ cπ Lπ iπ OT cn cn cn cn en cn en en en Lπ Lπ Lπ uι Lπ Lπ Lπ Lπ ιt* ιf* ιt_* ιl* ιf_* ιt* ιt_* ιf* ιf* ιf_* Lo co co co μ o io co -j m ui ^ u i μ o vo co vα en ιπ rt_* ιo co o ιo ∞ vi cn ιn rt* ι ιo H o ιo oo vi θ iπ ιt_* ιo to μ-» o ιo oo -vi cn ιπ ιt_* ιo to μ-" θ io co vi cn Ω

μ3 μ3 ^μ3 H ^μ3 >-3 ^μ3 ^μ3 Ω Ω Ω Ω Ω Ω Ω Ω Ω ω co co Q Co ω ι-3 H ^μ3 H ^μ3 3 ι-3 Ω Ω Ω Ω Ω Ω Ω Ω Ω o co c co o o ^μ3 H ^μ3 H ^μ3 3 H Kj ^ Kj i Kj Ki ^ F F lr' ' F F E F K H M M tS M ω ffi W W K W ffi ^

^ ^ ^ » ^ ^ w ^ a a a a a a ^ ^ ^ ^ » ^ w pa ^ w ^ ι« w a a a a ^ ^ ^ ^ ι« !« to ?3 f^β !« ?3 ?c fo

IS³* ϊϊ³*

H H H ^ I-' H H H' l-' H H H H H H R H R H H H H R H H H R H H H H l-' l-' H' O O O O m en m en en cn cn cn ιπ ιπ ιπ ιn ιn uι rt* rt* ιf* rt ιf* ιf* w ω ιo co ιo ιo ιo to to t M W M co to to μ^j μ-' H μ-' μ^J

j-> j-¹ μ-¹ H μ-¹ μ-» μ-¹ H μ-> μ-> to to M co to to HJ H NJ to to to to co to to co to to to to co co to to to to to to to to to t to to to

-j -j en Lπ in rt* in en en i it* in o o o o θ io co ιo o to ιo ω -j v] v] cn ιπ rt* ιf* ιπ rt cn ιπ rt* ιo μ-» to μ-' o μ-' μ-> to μ-' to to ιo ιo H H io co ∞ m o ι^ iD o co co ιo ιo co cn e» CQ ιt Lo to ω ιt* ιo cn ιn vi iD Co ιo ιo ιt ιo H cn co cn rt* ω vj en ιo cn M Lθ Lπ o co o H LD in ιt* co M tθ ιl^ e (n μ-' o o ιt* Lo o o H M ω M μ-' o ^ en ιt* ω H ω ι oo ω o Lπ o ιt* o M Lo cn o tθ LD Cπ ~j to ] it_* tO it_* it* M M o M H it_* w en en D ] oo ii*. Lo o ] co co cn tO i o H oo t o to M ] W M oo i^ ii* oo v] M o m ] i^ μ-¹ H H H H R I-' H H H I-' H H H J-' h' H H H H R H t co to co ιt* ιn ιπ cn ιn co co oo -o. cn ιπ ιt* to ιo to co to μ-> LD Lo co LD Cθ LD CD ιt* en Lπ en --j cD vi Lo co en vi v] en v] en cn ιt* Lπ Lπ ιi_* cπ ιf* to ιo Π

CXI o o M tθ H h-> ιo o cn v] -vi ιo ιo μJ iπ M cn uι co N} μJ co ιo cn cD cn o c» ιo ιo ιo ιo cn o co Lθ ιli rt* co cn ιτι cn iD v] Lo ro to ω ιt* H iθ vα rt ιo cn o oo tθ v] io cn ιt* H iD Cn v] Φ. o o θ v] o co m vi ex> cn μ-» ] iπ ιo cn en μ-' iπ ιo ιθ v] oo M o Lo to ιo ιπ t^ i ιo co t w ι co ] θ Lπ Lπ Lπ tθ i μJ W ] Lo M ^ μ-¹ co θ tθ LD ιt. Lπ o ] ιt* ιt* i Lθ ] tθ M t v] cD en ] co o Lπ co co tO t CO LO LO LO LO LO LO LO CO CO LO co co CO CO CO CO O H KD KD O K tO LO CO it* CO •J -J cn en LΠ LΠ en LO v] -J vl v] cπ en H μ-> o o co cπ to H vl LD tO tO LO OO H O OO CO tO o vi in if* cπ it* H rt* 00 O Ul l0 l0 H 00 H D it* in on cn vl co LO cn lo oo to iπ cn iπ io o μ-'

H μ-¹ μ-> H t-¹ μ-> H μ-¹ μ-> H t-> H μ-> ¹ I-* μ-» μ-> μ-¹ μ-» H H o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o O O O O O O O O O o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o O O O O O O O O O to H to μ-> H H H H μ-> μ-> H to to to to to to LO CO CO CO io to t to t t O LD H oo in *. to o H -J v] cπ -j LD o to H LO en in oo oo cn if* o vi o to to

ID en o co o in to ^ rt* vl co CO CO 00 CO 00 rt* rt* H CO CO LO tO LO co cπ cπ vi cn rf* cπ to en lO tO CO LO H CO Lπ -J v] cn cn l-¹ vl cn in μ-» o 10 co tO 00 O v] O oo cn in LD μ^j H 00 cn in co o to LO cn in vl to ιo ιπ ι-' ιt* to oo' ιo o

LΠ LΠ LO LO to to H¹ LΠ o LΠ o LΠ o LΠ o LΠ o LΠ

P Ω P P P P P O Ω P Ω P Ω Q P P P Ω Ω P P P P Ω P P P Ω P P O O P P Ω P P P P P Ω P P P P P P P P P P P Ω P O P

3 3 3 3 3 3 3 3 2 3 3 3 2 2 3 2 3 2 2 2 3 2 2 2 2 2 3 3 3 3 2 2 2 3 2 2 3 2 3 2 3 2 2 2 2 2 3 3 2 3 2 3 2 3 3 3 cn en en cn cn cn cn en cn o^ o cn en σ cn cn cn cn en cn en o^ c^ cn cn cn cn cn en en cn cn cn cn cn en cn cn en cn cn cn cn cn cn cn en en iπ Ln in cπ ιf* ιt* rf* ιt* rf* rt* ιf* ιf* l0 l l0 l l0 C0 C0 C0 C0 l0 t0 C0 t0 t0 M J M W t0 μ-' H H H H H H H μ-' O O O O O O O O O O LD LD L0 L0 L0 v] cn ιπ rt* co M μ^j θ Lo oo v3 en rt* ιo to μ-^l o LD θθ vi cn Ln ιt* co M H θ LD θo vi en uι rt* Lo tθ H θ Lo ex) vi cn ιt* ω tθ H

Ω Ω Ω Ω Ω 3 P Ω Ω P Ω Ω S P Ω a P Ω Ω a P Ω P Ω Ω a P Ω Ω Ω Ω Ω Ω P Ω P P Ω Ω Ω 3 P Ω Ω a P Ω Ω a P Ω O Ω

D α Ω to Ω Ω tO 9 O Ω tfl Ω Ω tO O O Ω tO O O Q B > W N tO H w μ to μ-¹ to H to μ->

W fl W ⁱιJ iιJ fl H H ^ H ^ > H H H H3 ^ H ^< t^l t^, t t^l t^l t^, t^< >ι ^ 0 (l Q O O Q O O H 4 ^

W W K W fif W ffi W ffi W ffi W ffi co w w ω co tα co cn κ ffi W W «

M M M M ta ts ^ » » ^ ^ ^ ^ a a a a a a !s w ^ ^ » !« ^ o Q α c α α 3 'd >ti >α 'd tO tO tO CO M M tO tO tO CO M M tO tO tO tO tO tO tO tO CO tO tO M M M tO tO tO M CO tO CO CO tO M tO CO M CO tO M tO tO tO tO M t C t tO tO N3 t t tO t t M tO tO tO CO t tO t C M M t tO t C CO t C CO W NJ CO W C M μ-^> H μ^J H H μ^J H H μ^J H H K rf* lt* rt* lt* rt* lf* C - CO l C lO CO tO t tO tO CO M t tθ μ-' H μ^J μ^J H μ-' O O O O O O O O LD LD LO LO LD LO LO LD CO Oθ ra CO vl vl vl

to μ^J H H θ o to κ to co to to to to to o μ^j μ^j to ιo co Lo ιt* rt* ιt* rt* C M i ιt* ιn cπ ιn en cn

o en ιo ιo ιn > μ^j cn cπ cπ ιf* ιπ ιo cn ω ιf* cn M oo o μ-' to μ^j H cn cn ιo H LD Lθ LD M U) cn ιπ vi H Lo o M rt* H iΛj μ^j θ LD Cθ H C^ o M J oi si uι u oι U ιt> si si μ o oι o μ i iJ o ιo W j μ ιθ Λ io * Λ in co u μ κ si «) μ vi ϋi ⁽» ^ u w m μ oι iιJ uι o oi ϋi «ι iιi u H «) o c v] H Lo c M H v] μ^J M in LD v] ι^ μ-' o cn H cn co ι v3 Lo ιn c e» to o H ln ι^, cπ tθ H cπ o μ^j co vi μ^j o H rt* vi ιt* o H oo ι oo rt^

H μ-> H μ^j μ-' μ-' i-' μ^j μ-' μ-' μ^j μ^J μ-¹ μ-¹ μ-¹ μ-¹ μ-> H H> H H to H H H H t to CO M M M M M i u i μ μ μ μ H H H H H μ ω μ o ^j to tf* ιo to ιo to ιo ιπ cπ in *■ rt* in en cn vi LO 00 00 vl CO O LD LD LO LO O CO o to to to μJ o o o LO Lo on vi v -j cn o LΠ

H to co H oΛ vi rt* w rt* ιt* ιl^ v] vα to co Lo μ-' o o cπ ιf* oo H H H ιt* ιt* LD cn cD H Lo o on to u ιπ LD θo H ex3 oo vi μ-' o o ∞ L^ o rt* o^ Lθ vi oo to m vi to co co co oi LD θ i vj o ιo vj ιt» cπ o μ^j ιo o v] iπ tθ LD H vi en iD μ-' cn o Lo ιπ v] iθ v] rt* H cn H e» rt* LD LD Lθ rt* co vi o LD C^ co ω M Lθ vi to tθ vi en to μ^j Lo Lπ vi ιf* oo cπ vi LD W cn i i Ln cn W M Co co oo ω o co Lo Lo w ι» ^ » ω u u u u ιt< ^ ιt> ι u u u u u u ω ι>ι u ω u u ω u u u u u u u u u u u ω ω ι J U u u u u u u u u u u u u u M kj H θ o Lo co co Lθ Lo μ-^, o o co v] en en ιo co ιo ιt* ijι cπ vj en co v] v] cn ιt* ιt* θ H Co ω co to t LD Co LD θ H H io to μ^j M to oo vi cn iO LO LD H O cn cπ iO Lo LD Co en oo μ^j ιo to cn cn H rt* vi en ιo to o co ) H μ^j μ-' μ-' iπ cπ ιo ιf* to ιo ιπ v] io ιt* co -j ιo co ιn co o μ^j ιo co t-» ln rt* O CO O O O O O v] LO H C lO lO H o ιo ιn tf* ιo o o o m o cn ιn μ-' v] co oo rt* VD Co co μ-' θ LD to μ-' o co o co co -o co co cn ι-' rt* ι--' ιt* vi μ^j o rt* co Lo rt* co ιt* oo cn o ιo cn cn ι-' iπ en co ιn ιt* vi ιn ιt* to cn en H iπ o co o cn o co LD v] to co cn t rt* cn ιo to co co v] θ tθ vi v] μ-' to co ι--' rt* μ-> M M H H H R H H H I-' H μ-' μ-' H μ-' μ-' μ^j μ-' μ-' μ-' H H H H H μ-» μ-^, μ-> μ^j μ-' μ-' H μ-^, μ-' H μ-> μ-» μ-' H μ-' μ-' o o o o o o o o o o o o o o o o O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O o o o o o o o o o o o o o o o o o o o o o O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O o o o o o o o o o o μ-¹ μ-> H H μ-> H μ^ μ-' H μ^j μ-' μ-' H μ^j μ-' H μ^j to to

O O H rt* l0 CO C0 CO tO CO lO |-> C0 J-' lD O O 00 00 OO vO LO CO CO LO CO LD LO LO H LD LO LD vl μ-¹ o co to to co co to co io co it* cn co

CO it* rt* H vl CO rt* tθ Lo cn ιθ v] H io oo ιπ ιo oo ιji Lθ vθ io ιπ ιo ιn en LD ιt* o H θo ιn cn cn rt* vi ιo cπ ιn to oo rt* O H lo cn in cn iD io iD CO O co in oo cn to o H Ul lf* W H CO LO O Cn Cπ O H CO ιt* tO lO CO LD O rt* CO en CO CO v] rt* Cn ιt* LO LD Cn θ rt* LO v] μ to co o co Lo cn ~j cn vi o μ^j rf*

5a to ι ι ι ι ι ta

LΠ LΠ LO LO t to LΠ o LΠ o LΠ o LΠ o LΠ o LΠ

P P P P P P P P Q P P P P Q P P P P P P P P P P P P P P P P P P P P P O P P P P P P P P P P P P P P P P P P P P

3 2 2 2 2 2 2 2 2 33 3 2 2 2 3 33 2 233 3 3 3 2 3 3 3 2 3 3 2 3 3 3 2 3 3 2 2 2 2 2 2 3 3 2 2 3 3 3 3 3 3 3 v3 vj vi vj m en cn cn cn en cn cn en cn cn en cn cn cn cn c^ en en en cn cn cn cn en en cn cn en cn cn cn cn cn cn cn cn cn cn en cn cn cn cn cn cn cn en cn cn en cn o o o o vo Lo LD LO Lo LO LD LO Lo LD co exj oo oo ∞ oo oo oo co oo vj vi vi vi vi vi vi v vi vi en cn cn en cn en cn cn in cn Lπ cπ iJi Lπ ω ω w M θ io co vi m ιπ ιf* c ^j μ^J o u3 Cθ v3 OT in ιf* ι Nj H θ Lo cθ v] c ιn ιt* ιo t μ^J θ Lo co v] m ιji ιt* ι tθ R θ LD ∞

Ω Ω Ω Ω Ω Ω Ω Ω Ω H ^tti >ϋ >ϋ > >tf

Ω Ω Ω Ω Ω Ω Ω Ω a a a a a a a a W M H t?3 t t? to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to

to to to to to

M tO M CO CO tO tO CO tO tO M M CO tO M tO CO tO M tO M M M tO tO tO CO CO tO tO CO tO CO tO tO tO CO tO CO tO tO M M M tO tO W lO lO lO CO lO CO lO LO lo CO lo tO lo CO M CO CO M M M tO t W NJ tO tO tO W tO to tO W tO NJ tO M μ-' μ^J H H H H μ-' O O O O O LD LO VO LO LD LO LD LD LD ) LD LD CO <XI OO CO CO CO CO CO CO vl vl l l v] vl l 1 0Λ Cn cn m Cn cπ ln in rt* rt^

co o co co H o H co ω rt* rt* ω to tθ v] cn en ιπ rt* ιo rt* to H μ-' o o co rt* ιo co H θ o H μ-' μ-' C o μ-' μ^j to co co rt* co to o H θ o o o H μ^j H

0 -J v] -J rt* lO O lO Cn CO v^] ιθ v^] j M ω ι LD Lθ H LD Lo μ^j ι o vi ∞ o vi v] vi M to o rt* ^j ιt* H Lo ιo rt* o rt* co μ-' Lo o o μ^j Lo ιπ vi oo c co LD θ co to μ-' o cn rt* μ-' to L CO L ιf* ιf* O OO CO M LD v3 lO O ιf* ιt* O vl v3 rt* ιt* LO CO CO O rt* rf* lf* O O O vJ μJ rt* lπ lπ v] Cn CO CO O Cn CO

>o o\ μ o u j μ co (> μ ω OD O ιt* θ m H Cn iO CO CO LD O l m Cπ O^ O vl v] H Ln Cn CO tO LD Lθ μ-' LD lO rt* ω tO lO OO LO LO v] vJ CO lt* lO CO

H H H to μ-« o o o μJ θ H θ μ-' Cθ Cθ io M to μ^j M to co M Co ιo ι^ co rt* M rt* cn cn ιn σι ιπ ιt* ιπ ex) co cn vj en vi cn vi Lo oo Lθ vi co L^ o LO LO H lo

O μ-» o rt* co co H rf* ιt* O H LD to μ-' iπ vi io j-^J co cn Lo to oo cn vi cn μ-> co co D o co o LD LO Lπ LD H CO co cn cn o μ^j μ-" co μ-» rt* cn n rt* cn co o vi

CO CO vl CO H vl ιo rt* oo o ιo Lo ιo ιπ cn ιo o o o cn vi co co in cπ μ-> t-> rt* co v] cσ rt* ι-' cn μ^J cn o v] rt* co o IO CO LD O rt* O LO LO rt* it* co cπ co co vi rt* μ-' cσ vi ιt* cn cn it* in H t O rt* to cn o to o co io en LD O O rt* co ω co io io io co io ω co co co lo co co io ω co co _* ιo ιo ιo co ιo co ιo io co co io io ω it- it^, LD Co co oo oo vi en cπ ιn co co ιo rt* μ^j to co ιt* cπ cn cn cn io in in in cn -J oo co IO H H O Lo co vi vi en en cn cπ in in en vl v io co in vl o LO rt* O Cn lO tO LO -J LD lt* co μ-' en oo ι LD rt* cn co o co io rt* co oo H ~j cn io o H cn cπ cπ cn ιn cn co rt* ιo rt* μ-» ι-> cπ co cπ -j cn H o LD o oo cn co o en LD O OO CO H Cn H H μ co m . co io oj oi si μ co co vl vi in in co to en vl H o co to in ex> ιπ μ-> ∞ ιt* to to ιπ rt* co it* en μ-¹ it* in en en oo rt* co vo LO Cn rt* vl O CO vl θ LD Cθ μJ iπ co o Lθ rt* cn ιo 00 CO LO IO vl co co H vl μ-¹ vl o LO co o en μ^J v^] rt* cn ιo co cπ K co co co co co in μ-> μ-¹ μ^j H M H H i-' μ-' μ^j H H μ-' μJ i-' μ-' M H H H M μ-' l-' H H H μ^j μ-" o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o O O O O o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o σ o o o o o o o o o o σ o a o o o o o o o o o o o o o o o o o o io to to to CO l-> H μ μ μ μ μ μ μ w w io to iJ io io io μ μ μ μ io M io io io μ-> H μ- i rt* to co cn ιt* rt* H rt* rf* ιπ cn ιn cπ rt* ιt* ιo co H θ vi vi rt* cπ co cn cn to o cπ co LD θ ιt* ιπ co o cn μ-" ιt* vα ιπ cn rt* cn en en cn ιt* cn Lo cn co rt* cπ o oo ιπ Lo rt* co t LD rt* vi Lo co LD Co σ\ o H en oo co vi cn in if* co co Lo co cn o o rt* o rt* cn rt* Lo cn vi cn co co io cn vi to cn H to co ιo o cn Lθ vi to co LD i Lo oo cn co to σι rt* cn o co tθ LD

> > to to to to to to > ' to to to ' to ι to to > to to > to to to > to > to >< to to

to to to to to to > to to to to to to to to to to to to to to to to to to to to > to to to to to to to to to to > > to to to to to to to to to to to to to to 3 3 ^μ3 ^μ3 ι-3 3 3 3 H 3 ^μ3 H 3 ^μ3 3 ^μ3 3 >-3 ^μ3 ^μ3 ^μ3 H H Q Ω H ^μ3 H 3 3 Ω H 3 4 4 fi fi !5 3 H H ^μ3 fi 4

O Ω P O P P P P P P O P P P P P P P P P O P P P P P P Ω P P P P Ω P P P P P P Ω P P P P P Ω P P P P P P P P P P 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 2 3 3 3 3 3 3 3 2 2 3 3 3 3 3 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 2 2 2 2 3 2

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Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω to to to to to to to to to to to to to to to to to to to to to to tD tό to tD to to to to tύ to to to to tO M

ATOM 1654 CD ARG C 12 3..098 26.164 38.356 00 25.19 CB

ATOM 1655 NE ARG C 12 2. .324 25.099 37.725 00 25.98 CB

ATOM 1656 CZ ARG C 12 1. .444 24.341 38.371 00 27.02 CB

ATOM 1657 NH1 ARG C 12 1. .229 24.535 39.665 00 26.61 CB

ATOM 1658 NH2 ARG C 12 0. .780 23.390 37.728 00 26.52 CB

ATOM 1659 C ARG c 12 4. .586 29.843 36.299 00 18.11 CB

ATOM 1660 0 ARG C 12 4. .235 30.912 36.807 00 18.92 CB

ATOM 1661 N GLY C 13 4. .198 29.459 35.086 00 16.77 CB

ATOM 1662 CA GLY C 13 3. .317 30.300 34.297 00 15.62 CB

ATOM 1663 C GLY C 13 2. .003 30.595 34.998 00 16.24 CB TOM 1664 0 GLY C 13 1. .769 30.107 36.105 00 15.03 CB

ATOM 1665 N PRO C 14 1. .128 31.412 34.388 00 16.73 CB

ATOM 1666 CD PRO c 14 1.348 32.224 33.174 00 16.28 CB

ATOM 1667 CA PRO C 14 -0.162 31.736 35.007 00 16.91 CB

ATOM 1668 CB PRO C 14 -0.526 33.065 34.359 00 17.54 CB

ATOM 1669 CG PRO c 14 -0.009 32.879 32.957 00 17.17 CB

ATOM 1670 C PRO c 14 -1.190 30.646 34.702 00 16.45 CB

ATOM 1671 0 PRO c 14 -0.983 29.820 33.820 00 13.87 CB

ATOM 1672 N HYP c 15 -2.313 30.637 35.433 00 17.28 CB

ATOM 1673 CD HYP c 15 -2.597 31.470 36.615 00 17.85 CB

ATOM 1674 CA HYP c 15 -3.370 29.639 35.224 1.00 16.58 CB

ATOM 1675 CB HYP c 15 -4.470 30.097 36.174 1.00 18.24 CB

ATOM 1676 CG HYP c 15 -3.696 30.684 37.300 1.00 18.18 CB

ATOM 1677 C HYP c 15 -3.863 29.580 33.784 00 15.70 CB

ATOM 1678 0 HYP c 15 -4.031 30.612 33.137 00 15.03 CB

ATOM 1679 OD HYP c 15 -3.209 29.719 38.215 00 19.41 CB

ATOM 1680 N GLY c 16 -4.088 28.363 33.292 00 15.59 CB

ATOM 1681 CA GLY c 16 -4.586 28.171 31.943 00 12.51 CB

ATOM 1682 C GLY c 16 -6.038 28.619 31.839 00 13.38 CB

ATOM 1683 o GLY c 16 -6.658 28.942 32.861 00 10.23 CB

ATOM 1684 N PRO c 17 -6.616 28.637 30.624 00 12.36 CB TOM 1685 CD PRO c 17 -5.984 28.233 29.354 00 12.72 CB

ATOM 1686 CA PRO c 17 -8.003 29.056 30.396 00 13.23 CB

ATOM 1687 CB PRO c 17 -8.023 29.337 28.900 00 14.02 CB

ATOM 1688 CG PRO c 17 -7.154 28.252 28.377 00 10.82 CB

ATOM 1689 C PRO c 17 -9.041 28.003 30.791 00 13.57 CB

ATOM 1690 o PRO c 17 -8.714 26.821 30.965 00 11.15 CB

ATOM 1691 N HYP c 18 -10.313 28.425 30.926 00 12.83 CB

ATOM 1692 CD HYP c 18 -10.797 29.804 30.744 00 11.99 CB

ATOM 1693 CA HYP c 18 -11.418 27.532 31.298 00 13.95 CB

ATOM 1694 CB HYP c 18 -12.636 28.460 31.291 00 11.62 CB

ATOM 1695 CG HYP c 18 -12.048 29.793 31.565 1.00 12.88 CB

ATOM 1696 C HYP c 18 -11.569 26.406 30.279 00 14.31 CB

ATOM 1697 o HYP c 18 -11.328 26.611 29.093 00 15.44 CB

ATOM 1698 OD HYP c 18 -11.810 30.040 32.943 00 13.37 CB

ATOM 1699 N GLY c 19 -11.968 25.227 30.742 00 14.55 CB

ATOM 1700 CA GLY c 19 -12.143 24.102 29.846 00 13.79 CB

ATOM 1701 C GLY c 19 -13.352 24.277 28.942 00 14.74 CB

ATOM 1702 o GLY c 19 -14.112 25.234 29.098 00 13.65 CB TOM 1703 N PRO c 20 -13.564 23.368 27.980 00 15.70 CB

ATOM 1704 CD PRO c 20 -12.694 22.250 27.562 00 15.16 CB

ATOM 1705 CA PRO c 20 -14.725 23.500 27.093 00 16.72 CB

ATOM 1706 CB PRO c 20 -14.347 22.622 25.912 00 15.89 CB

ATOM 1707 CG PRO c 20 -13.562 21.518 26.567 00 17.28 CB

ATOM 1708 C PRO c 20 -16.004 23.036 27.774 00 17.49 CB

ATOM 1709 o PRO c 20 -15.962 22.474 28.870 00 18.83 CB LΠ LΠ Φ Φ LO LO to to H μ-> LΠ o LΠ o LΠ o Π o LΠ o LΠ to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to to ^μ3 to to to to to to to

J-j !-^ ;-3 !-3 ;-3 ^μ ₃ ;-₃ ;-^ ^μ3 ^μ3 ^μ3 3 ^ ₁-3 3 ^μ ₃ 3 ^μ ₃ ^μ3 ^μ3 ^μ3 ,-3

P P Ω P Ω P P P Ω Ω Ω P P P P Ω Ω Ω Ω Ω Ω P Ω Ω P P P P Ω Ω P Ω Ω P P O Ω P P Ω Ω P Ω P Ω Ω tO Ω Ω P Ω P P P P P

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 2 2 3 2 2 3 2 3 3 3 3 2 3 2 3 3 3 3 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 3 2 3 2 μ-' μ-' μ-' μ-' H μ-' H H μ-¹

-J vI vl vI vI vI ~J vl vI m m w oι oι ijι w ijι ιn iJi iΛ iιι iJi iJ Ui * ιt> ^ ιt> ιi> ft ιt' * (' ιlι ω u u u u u u ) u u u ιo ιo ιo ιo ιo u tJ io ιo μ ι^ co co H θ Lθ cθ vi on ιπ ιi* ιo cθ H θ LD CD vi cn Lπ rf* lo cθ H θ LD θθ v3 cn rt* ω to ι-> o LD Cθ vi cn cπ rf* ιo to μJ o ω oo -o cn ιπ rf* co co ι-> o

Ω Ω Ω a Ω a Ω Ω Ω a Ω P Ω Ω Ω Ω Ω a P Ω Ω Ω Ω Ω a Ω a P Ω a P Ω Ω Ω Ω Ω Ω a

Ω t to ° ° 9 a g P Ω Ω Ω Ω Ω a Ω Ω Ω Ω Ω

Ω tO to O Ω to to to a Ω to to α Ω tO to D to α Ώ to a

O O O iT. Ω Ω Ω Ω B a a a B a B 'd ⁱd O O O O O Ω Ω Ω Ω a a a a ffi B O O O *I O >ti ^td Ω Ω Ω Ω ZI B B B B B B B

B B a B t' ^< t^< t→ κi ! ! κj κ; κ! μ< tO tO t0 t0 tO t0 t lr¹ t¹ t t κ! κ! κ! ! KS to t t fϋ to to fO F F F F B KJ KJ KJ J J J KJ H M Kj Kj μ< ! iO tl τ3 τJ 'θ 3 τ3 τ3 P P P P Ω P κ! ι KJ tl τJ 'tl 'O ^fO >0 Ό P P P Ω Ω P P KJ KJ KJ K! d d d d d d d d d d d d d d d d d d d d d d d d d d d d d α d d d d d α d d d d d d d d d d Ω Ω Ω Ω Ω Ω Ω Ω Ω

' r-' T-' r-' i^ T-' f-' l-'

oo rf* oo en co o in LO co cn rt* t CO CO CO to CO CO co to cπ in rt* in rt* ιπ cn en co ιπ m ιo co LO on vl cπ as ~J cπ v] to ιo to rf* O cn CO ID κo in en LO o CO H> cπ in CO o o o o μ-¹ vl CO o v r* cn l f CO o vl rf* LO

M K H μ-> o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o to rt* in cn rt* o o o cπ to co μ-> en cn cn o cn o o

Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω to to to to to to tii to to

LΠ LΠ Φ Φ LO LO to t μ-¹ (JI o LΠ o LΠ o LΠ o Lπ LΠ to3 to4 toι-3 to^μ3 >H H ^μ3 H toH 3 to3 3 to3 3 toι-3 3 >>-3 to3 to3 to3 3 toH to3 ^ to3 to3 >H H to3 H >H to^μ3 3 toH toH to to3 to3 toH toι-3 to toH to toι-3 to3 to4 to to to to to to to to to to

P P Ω P P P P Ω P P P P P P Q P P P P O P Ω P Ω P P P Ω P P Ω P P Ω P Ω P Ω Ω P P P Ω Ω P P Ω P Ω P P P P P Ω P 3 2 2 2 3 3 3 2 2 2 2 2 2 3 3 3 3 2 2 2 2 2 2 3 3 3 2 2 2 2 2 2 2 2 2 3 2 3 3 3 3 3 3 3 3 3 3 2 2 2 2 2 3 3 3 3

H H M μ-' H H H H μ^j H H M μ-' μ^j μ-⁴ μ-' μ-' μ^j μ^j H μ-' H μ-' μ-' H H H μ-' μ-' μ-' μ-' H H H μ-' μ-' μ-^, μ^j μ^j H μ^j μ-' μ-' μ-' H μ-' μ^j μ-' μ-' μ-> H H μ^j H oo eD m co oo ∞ oo ∞ co co co co CD CD CD CD cn oo eo co oo vi vi vi vα vi vi vi vi v vi vi vi vi vi vi vi vi vi vi vi vi vi vi vi ^ t H μ^j μ^j κ μ-' μ^j M H θ o o o o o o o o o ιo Lθ LD LD Lθ Lθ Lθ Lo ιo LD co co co co oo co oo oo co oo vi vi vi vi vi vi vi vi -j vi on cn en cn cn θ Lo oo v on ιn ιt_* co M θ Lo co vj cn ιπ ιi*. ω to μ^j θ Lo co ι cn ιt* ιo co H θ Lo co vi cn ιπ rt* co to μ^j o Lo cιι

Ω Ω Ω Ω Ω 3 Ω Ω Ω Ω Ω a P Ω Ω a P Ω a Ω a Ω Ω Ω Ω P Ω Ω P Ω Ω Ω Ω a Ω Ω

Ώ m to d Ω to to d to a N to Ω to to t a P o Ω Ω Ω Ω Ω a Ω Ω Ω Ω Ω Ω Ω M D Ω CO to > d Ω to to D N t to d to μ-¹ ato μ-¹ κ| κj ; κ; !θ tΗ t to fo to t tr^, tr^, lr^, tr^l IΛ |o |a t t o to ?d ιo tl τ3 τj τJ d Ω P Ω P Ω P μ< i ^μ< ^μ! Ω Ω Ω Ω Ω Ω Ω Ω

d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d d

H H H tn in cn in in rf* rf* rf* rt* rt* rt* it* co co co co co co to co co co co to to co co H o o o

H H μ-¹ μ-> μ-¹ cn rf* Lπ rf* co Lo co ω co co μ^j μ^J o o θ H Cθ to co μ-' Co ιo to ιo to ιo rf* Lπ ιn ιπ vi vi vj cn en vi oo oo vo o rf* rf_* ID H o tf> co

CO CO CO CO CO CO tO to to O to to to to to to to co co to to co co to t to t co co to to to to co co to co to to to to to to to to co co to to to to co co co rf* μ-^» to co co co cπ rt* en in rf* -j cn ιn en -j en ιπ ιn μ^j μ-' μ-' to co rf* cn cπ cn in H H μ^j to co cπ in en en vi co on in vi vi vi vi cn en i en o o H co co o o o μ^j Lo co ιo μ^j cπ co co on rf* LD θo H LD oo ιo to vl LD LO O io en vi cn o oo io H co cπ cπ in to rf* rf* vo μ-¹ H rf* cn vi co cn μ^j vi o vi cn ιo Lo Lo en cn ιo θ v] iπ to co rf* μ-' μ^j ι-¹ to H H ϋl vl oo io in in co rf* rf* co cπ oo in oo rf* μ-> LD H o co cn ω it* cn oo en o μ-' LD O Lo Lo co co μJ LD Co co co co o co co cπ rt* io μ-> rt* vl CO cπ on co oo co rf* cn CO rt* o cn oo o vi on in co co co co co co co co ω Co co co CO CO CO CO CO CO CO Co co to o CO IO CO CO IO CO CO CO CO CO CO CO CO rf* cπ rt* rf* on cπ cπ cπ oo co cn vi cn cπ cn rf* rt* to rt* rt* rt* IO rf* co μ-> ^j to co cn rt* rf* co in co cn

00 O vl to co H cn o co rf* cπ vj vi oo o oo vi on LO rt* vi co cn cn vi o CO LO vl LD co co o μ-^» oo cπ vo v] vl CO rf* vl vl co on o o co oo vo rf* on co j On LD vl LD 00 O rf_* vi cπ cπ o

H H i-' H H j-' μ-' H H μ-' H H μ-' μ-' H μ-' l-' l-> R H H H H H I-> l-' l-" μ^J μ-' μ-' μ-' μ-' μ-> H μ-' μ-' H H H H H l-> H o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o

H μ-¹ H oo co on o ιo cπ ω co Lo o ιf* cn Lo oo co cπ ιo co o to cn rf* cn _v] cσ oo rf- θ _vj _v] μ- ιo -j o cn co rf* iD v] co ιo μ-> cn j-> vi vo co vi cn H vo rt* vi ιπ rf* o co to t vi co o co vi co co cn tO vi co vo cπ vD vo if*

Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω Ω

ATOM 1821 0 HYP D 15 -5.971 25.268 36.130 1.00 12.18 CC

ATOM 1822 OD HYP D 15 -3 .452 20 .982 34 .490 1 .00 15 .74 CC

ATOM 1823 N GLY D 16 -6 .623 25 .237 33 .973 1 .00 13 .68 CC

ATOM 1824 CA GLY D 16 -7 .619 26 .277 34 .165 1 .00 13 .35 CC

ATOM 1825 C GLY D 16 -8 .887 25 .737 34 .808 1. .00 15 .22 CC

ATOM 1826 0 GLY D 16 -9 .015 24 .529 35 .002 1 . 00 14 .14 CC

ATOM 1827 N PRO D 17 -9 .858 26 .604 35 .130 1 .00 16 .78 CC

ATOM 1828 CD PRO D 17 -9 .857 28 .062 34 .923 1 .00 15 .74 CC

ATOM 1829 CA PRO D 17 -11 .110 26 .166 35 .760 1 .00 17 .75 CC

ATOM 1830 CB PRO D 17 -11 .840 27 .484 36 .045 1 .00 17 .60 CC

ATOM 1831 CG PRO D 17 -10 .729 28 .522 36 .051 1 .00 17 .99 CC

ATOM 1832 C PRO D 17 -11 .945 25 .237 34 .884 1 .00 18 .61 CC

ATOM 1833 0 PRO D 17 -11 .758 25 .172 33 .667 1 .00 18 .40 CC

ATOM 1834 N HYP D 18 -12 .876 24 .489 35 .498 1 .00 19 .66 CC

ATOM 1835 CD HYP D 18 -13 .157 24 .363 36 .939 1 .00 19 .82 CC

ATOM 1836 CA HYP D 18 -13 .720 23 .580 34 .715 1 .00 19 .63 CC

ATOM 1837 CB HYP D 18 -14 .608 22 .924 35 .778 1 .00 21 .13 CC

ATOM 1838 CG HYP D 18 -13 .760 22 .991 37 .010 1 .00 20 .32 CC

ATOM 1839 C HYP D 18 -14 .529 24 .432 33 .746 1 .00 18 .79 CC

ATOM 1840 0 HYP D 18 -14 .809 25 .592 34 .033 1 .00 18 .95 CC

ATOM 1841 OD HYP D 18 -12 .787 21 .962 37 .083 1 .00 23 .21 CC

ATOM 1842 N GLY D 19 -14. .893 23 .863 32 .602 1, .00 18 .88 CC

ATOM 1843 CA GLY D 19 -15 .668 24 .613 31 .631 1, .00 18 .26 CC

ATOM 1844 C GLY D 19 -17, .104 24 .824 32, .078 1. .00 18, .68 CC

ATOM 1845 0 GLY D 19 -17, .477 24 .399 33, .174 1, .00 16, .61 CC

ATOM 1846 N PRO D 20 -17. .938 25 .502 31 .265 1, .00 19 .16 CC

ATOM 1847 CD PRO D 20 -17, .561 26, .245 30, .055 1. .00 19, .89 CC

ATOM 1848 CA PRO D 20 -19, .342 25, .752 31, .604 1. .00 20, .26 CC

ATOM 1849 CB PRO D 20 -19, .732 26, .886 30, .660 1. .00 20, .83 CC

ATOM 1850 CG RO D 20 -18, .412 27, .463 30. .179 1. .00 20, .62 CC

ATOM 1851 C PRO D 20 -20. .162 24. .491 31. .300 1. ,00 21. ,06 CC

ATOM 1852 o PRO D 20 -19. .697 23, .616 30. .577 1. .00 20. .72 CC

ATOM 1853 N HYP D 21 -21. .378 24. .377 31. ,859 1. ,00 21. .33 CC

ATOM 1854 CD HYP D 21 -21. .927 25. .146 32. ,992 1. ,00 21. .67 CC

ATOM 1855 CA HYP D 21 -22. ,215 23. ,189 31. ,590 1. ,00 21. .74 CC

ATOM 1856 CB HYP D 21 -23. 468 23. ,451 32. 440 1. 00 22. ,13 CC

ATOM 1857 CG HYP D 21 -22. ,878 24. ,155 33. 631 1. 00 21. ,33 CC

ATOM 1858 C HYP D 21 -22. ,551 23. ,036 30. .094 1. 00 21. ,48 CC

ATOM 1859 o HYP D 21 -22. ,726 24. ,026 29. .378 1. 00 22. ,03 CC

ATOM 1860 OD HYP D 21 -22. 228 23. ,265 34. 516 1. 00 23. ,21 CC

ATOM 1861 N NHH D 22 -22. ,657 21. ,806 29. 613 1. 00 20. ,91 CC

TER

ATOM 1862 o HOH E 401 16. 330 14. 217 61. 265 1. 00 7. 27

ATOM 1863 o HOH E 402 19. 752 18. 951 37. 584 1. 00 15. 74 w

ATOM 1864 o HOH E 403 2. 016 10. 266 32. 905 1. 00 23. 77

ATOM 1865 o HOH E 404 4. 266 11. 763 34. 068 1. 00 9. 44

ATOM 1866 o HOH E 405 10. 519 11. 274 32. 006 1. 00 21. 51

ATOM 1867 o HOH E 406 1. 504 12. 266 29. 042 1. 00 21. 77 w

ATOM 1868 o HOH E 407 20. 908 16. 308 36. 153 1. 00 17. 64 TOM 1869 o HOH E 408 17. 091 20. 929 39. 613 1. 00 12. 14

ATOM 1870 o HOH E 409 8. 326 -0. 946 34. 265 1. 00 26. 84 w

ATOM 1871 . o HOH E 410 10. 585 22. 363 46. 723 1. 00 11. 87

ATOM 1872 o HOH E 411 25. 378 10. 794 55. 016 1. 00 24. 26

ATOM 1873 o HOH E 412 20. 406 16. 105 51. 398 1. 00 11. 61 w

ATOM 1874 o HOH E 413 16. 878 25. 139 38. 620 1. 00 14. 37

ATOM 1875 o HOH E 414 -0. 842 16. 913 58. 285 1. 00 16. 87 LΠ LΠ φ φ. LO ω to to H LΠ o LΠ o LΠ o LΠ o LΠ o LΠ to3 toH toι-3 H toH 3 to toH toι-3 toH to>-3 to3 toH toH toι-3 toι-3 H toι-3 to3 toι-3 toH to3 to3 toH to^μ3 to>-3 to3 H to>-3 toH >-3 toH to^μ3 toH toH to to4 to3 toH toι-3 toΩ toι-3 toΩ to to to to to to to to to to to to to P Ω Ω Ω Ω P P P P Ω P P P Ω Ω Ω P P Ω Ω P P Ω Ω Ω Ω Ω P Ω P P P P P P P P Ω P P P Ω P Ω Ω Ω P Ω Ω P Ω P Ω Ω P

2 3 2 33 2 2 2 2 33 3 22 2 3 3 3 3 2 2 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 2 3 3 3 3 3 3 3 3 3 3 2 2 2 2 2 2 2 μ-¹ H M μ-> μ-¹ H » H R H μ-> H H H μ-¹ H μ-¹ μ^Λ μ^j μ-' μ-> μ-' μ-» μ-> μ-> μ-> μ^J H H μ-' H μ^j μ-^, μ^j μ-^, μ-^l μ-' μ-' H H' μ-¹

VO LO LD VO VD VO VD VD VO VO VO VO LO VO VD VO IO LO LO VD VO VO V LOO L LDD VO V vo LO LO VoO LO VO OO CD CO CO OO OO CO CO OO oo co co co co co co co co co oo oo oo oo co lo co co co co to co co co to to co o O O O O o o o O O VO VD VO VO ID LO VO ID LO LO OO CO CD OO CO CO CO CO CO OO vj Vl μ^J o vo oo vi on cn rf* co to μ-» o VO CO on in rf* co to o LD 00 -0 cn cn CO CO μ-» o iD θθ vi cn cπ rf* co co μ-' vo oo ~J cn in rf* co to H O

Ω P Ω P Ω Ω Ω Ω Ω Ω P P Ω P Ω P Ω P Ω Ω Ω Ω Ω P Ω Ω P Ω Ω Ω P P P P Ω Ω P Ω P Ω P P P Ω P Ω Ω Ω Ω Ω Ω P P P P P a a o a o a o a p a a a a

P P Ω P Ω P Ω P P K a w ffi a a a K ffi

Ω a Ω a Ω Ω p a a P a Ω a P Ω P P P P P P Ω_ P_ Ω P Ω Ω Ω Ω Ω P Ω Ω P P P P P P μ-J pπ' ffi K w ffl K W B B B B B K B B B B B K B B a a a a a a a a a a a a a a ffi ffi H w a a a a j-H a ffi a a ta ia ta w ta to to to ia to w to to to to to to to to to tO M to ta to to ta to to to to to to to to w to ta to M rf* rf tf* rf- rf* rt* ιl* rf* rf ιf* rf* rf* lt rt* rf* rf* rt* rf* rf* lf* rt* rf* rt* rt* rt* ιt* rf* rt* rt* rt rt* rf* rf* rf* tf ιf* ιf* rf* rf- rt* rf* rf* rf* rf* rf* rf rf* rt ιt* ιf* it* rt* it* if* rf* vi on en en cn cn cn en cn cn cn iπ iπ cπ cn cπ cπ cπ cπ cπ cn rt* rf* rf* rf* rf* rf* ιf* rf* rt* lO C LO LO LO CO C LO C C t t tO IO t t t t t IO μ-¹ μ-¹ μ-> μ-> μ-¹ O Lo co vi on cn rf* co to M o vD CD vi cn cn it* co co o iD OO vi cn iπ it- io to o vD θo vi cn cπ rf_* co co ι-' θ LD co v] cn cn rt* ιo co μ-' o vo co vi cn cπ

μ μ μ to co μ-> μ-> μ-¹ i μ-> H i μ-¹ to i to i H i ι-» μ-> μ μ μ

O 00 CO o o in vo to o vi o to cn μ^j cπ oo cπ co vD VD cn to cπ co cn o cπ j j on cπ rf* rf* in rf* cπ to to co μ-> en co cπ to o CO LO o rt* v_ ιt* rt* vo H to cn ω o o vi cn ω ro !i. v] H θ vo to to μ^j θ v] ∞ H H rt* ω vo H m cn o o v] v] vo ω ιjι o vo to ∞

LD H VD H θ Lo vi cn oo ιn μ-' ω co ιn cn cn vo co vo μ-' vo cn co o en e» M cn vD vi o co ιn ιf* cn va μ-< cn co vi o co cπ co M i^ in io iti J o vD O vi co co oo co vi o o co μJ Co o co co H t vo co cπ i ^i L vo w i^ VD O co vo H Lo vo μJ vo vo o i^ tO H v^ v! o μ-¹ co cπ w ιo ιo co ιo ιo co cn rt* co cn ιo co vi o o vo ι-' H cn vo co cn co o vrι o rf* M o co cn to o rf* co vi Lo vo vi ιt* to ω c^ 00 to vi cn rt_* cn H ui rf_* o to o ιo vi o ι-' in μ-' oo vo ιπ vi ιo o co rf_* o μ^j ιt* ιo Lo μ-' μ-' oo LD θ cn o vi vo co μ-' io vD μ^j tO Cn rt* tO t O CJ CO tO it* CO rt_* rt* co vo co cn H cn cn rf* co o o vo ιf* o eD cn Vo ιo ιo vj co CD v] io cn t vi vo ιo μ-' vo co cn co co oo o rt_* co μ^J vo o μ-> ι-^, lo oo cπ rf* co cn o vo rt_* o cπ on oo tθ v3 oo vι oo H l θ v] Cθ i-' oo LD co cn rt* o ~j ιn Lo co o cn vi LD vi μ-> o ιπ cπ v] vi vo co co o ιπ μ-> to o o to rt* v] vo o v]

Lπ CO rf* rf* tO CO lO lO CO rt* LO L0 L0 ω co cπ ιo Lθ co ω co cπ cπ rt*, ιo w ιo u co ω ιo en co co cπ ω co co co co co cπ co rt_* oo μ-> o vD rt* to co cπ cn vD to co rf* rf* lπ ιo ιo rt* σ\ ιf* rt* vi vi M cn ιπ ιπ vo rf_* en rf* ιo co μ-' θ Lo o co to to cn o o μ-¹ VD io ιo ιπ ιo tθ vi co co cn rt* CO C v] O v] CO v] LD co vi co ιo o co vi cn co o co co ιi* μ^j rt* ιl* rf* co cn cπ cπ ιo μ-' vo cn H cn co Lo co vio cn to co v3 ι^ vi o co co H cn ιf* en ui ι^ vi ι^ v: ιo co vo o o v] cn ω ω vi H to ι cn ι ιt* w co μ-' e» vo vi co Lo cn vj o i v] ∞ θ Lo o ιo vo oo ι vo vχ⁾ θo H Co o cπ ιπ ιπ o α) in tf* W Lo co cn co co to cn co co H ιi^ vj H θo ιt* θ vi cn co v] vo rt^

J-' H H H H H H H R H H H I-' J-' l-' H H μ^j μ^j μ-' μ-' μ-« μ-' μ-' μ-' μ-' H> μ-> μ^j μ-> μ-' μ-» μ-' μ-> μ-> μ-' μ-' μ-' μ^j μ-' H H H H μ-' μ-' μ-' μ-' μ-' o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o to co to rt* to t rt_* rt* co to t cπ CO rt_* vl t cn cn -0 o t rt* rt* o vo vl o o to cπ o rf* o cn rt* rt_* vo in rf* cn vl

Cπ H O rf* VO VD VD O CO lO CO O H to μ- to cn en -o iD to i-' in μ-' μ-' co μ-' Co cπ iD to co io cn o on ι cn vi Lo co cπ μ-> co vo Lo μ-' vi cn μ-> ιt* co rt* ι o LD co cπ o vi LD CO Ln cπ oo cn io co co o κ-> v^] in ιθ v^] co co co ιo cn vi co rt* co co v^] to co ιn to ιn on μ^J cπ μ-> ιn rf* cπ cπ v] θθ v3 vo rf* ιt* o vo vD LD rt* v] v]

≤ S S S ≤i S S Si S Si -€i ≤ S Si Ej Sl Sj Si S S Si S Sj SJ S ≤ SJ S Si S S S S -g sj S S SJ S Si S si S Si S sj Sj SJ S SJ S S S Sj Sj S!

LΠ LΠ φ. Φ LO LO to to ι-> LΠ o LΠ o LΠ o LΠ o LΠ o LΠ to H to4 toι-3 toH to^ to- toH toH toι-3 to3 to toH toH3 to>-3 to toH to3 to3 to3 to to toι-3 toβ to^ to^μa to>-3 toH to3 to to3 toH3 to3 to^μ3 to^ toι-3 toH to>-3 toH toι-3 toH toι-3 to^μ3 to to^μ3 to3 to4 to to to to to to to to P P P P P Ω P P P P P Ω Ω Ω P Ω P P P P Ω Ω P P P P P P P P P P P P P P P P Ω P P P Ω Ω P P Ω P P O P Ω P P P P

2 2 3 2 2 2 2 2 2 2 2 2 3 3 3 3 2 2 2 2 2 3 3 3 3 3 3 3 2 2 2 3 3 3 3 3 3 3 3 3 3 3 2 2 2 2 3 3 3 3 3 3 3 3 3 3

H H h» H H μ^j μ-' H H μ-' μ-' μ-> ι-» μ-' μ-' i-' H H H μ-¹ μ-» μ-> μ-¹ H H H μ-¹ H μ-> H H μ-> μ-' H μ-' t-> μ-' H H H μ-' lO ω tO lD W tø lO UJ Ifl Ul VO W lD W W ^ W ω ϊO VO VO VO lD W ^ ^ V V ^ ^ lD ^ VO VO VO VO VO O W - ω W tø ω W VO VO Ul VO W VO VO lO IO lO lO oo oo oo oo oo co co co cn cn cn cn en en en en cn cn iπ iπ cπ iπ iπ cπ cn cπ cπ cn v] on ιn rt* co co ι-' θ vo on in rf* co co o vo co vi on cn rt* co co H o vo oo vi on in rt* io co o n in io co H O LD Co i cn cn it* Lo to

Ω P Ω P Ω P P P Ω Ω Ω P P P P P P P Ω Ω Ω Ω P P P P P Ω Ω Ω P Ω Ω P P P P P P P P P P Ω P P Ω P P P P P P P P P a ffi ffi p a P Ω Ω P P P_ Ω- Q- Q- P_ P_ P- Ω_ P_ O- P_ P- Ω a Ω a Ω a Ω a P a P a P a P Ω Ω Ω Ω Ω P P a Ω Ω a Ω P Ω P P P Ω Ω Ω P P P P p P

K K E ffi ffi K ffi E W HH ffi ffi ffi W ffi pH HH p-t

M M M t?_I M M M M M M M M tø t? t?d M M in in cn in cπ cπ in in cn cπ cn in cn in cπ in cπ cπ cπ in in cπ cn in cπ cπ cn rt* rf* rt* rt* rt* rt* rf* ιf* rt* rt* rf* rt* rt* rt* rt* rt* tt* rt* rf* rf* rf* rf*

CO CO t μ-> μ-> μ-¹ μ-¹ H H¹ μ-> o o o o o o o o o lo vo vo vo vo vo vo i^β iσ io co co eo co cσ co co ∞ co co on cn o vo on cπ rt* t o vo co -o. on cπ co to o vD co -o en in rf co to H o io co v] cn cn rf* co tO H O vo cn in rf* μ-¹

t-> co co μ-¹ t IO I CO I μ-> H I I H CO CO tO H I on μ-> o o to o in o on vo vo 00 rf* 00 it* rf* μ-> rt* cπ vo o to cn o cn vo iπ io io co io cn to oo oo io vi iπ cπ v] rt* co ω co co M vi cn o va ιo co o co on iΛJ M ιi* on μ-' VD H en vi oo o ιo oo ιo oo M vi H oo Lo oo cn o cn v] vi co v] v] H Lθ vo t^ en co^' H co ω o o ω Lo rf* co o ιo ιn cπ vi cD θ v] Co co cπ o ιo ιjι ω ω μ^j vo μ^j v] θ vi H in vi cn vD U Co vo cn ω rf* μ-> co Lo vo ω co rt* w o H co co co υ3 H iπ o ω cn vi co ιn ιo σ ι μ-' ω tθ Lo ιo to ιo o oo H vo ω co to co to w μ-¹ μ^j i to co to to to t to co i co μ-> co co I co I K r* H M co μ-> H co ID cπ on co ι-> vo in on vo t cn μ-¹ to to rt* cn cπ co o co o in cn co o H cπ co co rf* co to to o vo co rf* vo on co on co oo on CD LO co μ^j ιo cn rf* ιt>. cn co vi M ω rt* rt* ιf* co μ-> cπ cn m cn rf* VD o cn o LD v] Lo to to cn to to ιt* en oo O LD cn o vo co cn M vo vo rt* co μ -j oi

*> ιi* o αι μ oι μ ιn ^ ιιι oι co ιi) μ u -o ιt> oι co ιo oι u u co iJ iπ co * H θ co oι iι) oι .j *, o o ω O 0D v1 fO rf* l-' C0 O rf* vl rf* ] o μ-¹ rf* co Lo tn rf* vi it* iO vj o io iA) O io en o it* cn it* vi co to H co LD M LD cn in it* VD Co co v] rt* vi j--' H to cπ to co o oo H Co ~j vi vo co -J ri-. IO rf* tO t rt* rt* tO tO C ιt* Lo ω cn cπ ω rf* ιo cn co cπ cπ co rf* cn to cπ co co ιt* cπ rt* rt* co rt* rt_* f* rf_* co ιo co ιπ lo en vo Lo cn cπ vo o rt* co co rf* ιθ ιt* r en ιf* ιt* μ-^l rf* cxi θ vi en vi μ-' Lo ιo co ιo cn μ-^l co rf* co cn co vD μ^j μ-' en vo rt* o co cn o oo oo o rf* Lo o vo

H vo o cn M ω co vi uη ιn cn vo co o vo v3 Cθ cn vo ι cn co ιi* ιt* ιt* ιf* θ vi cn co vi cn co oo o to cn vi co vi i-' cn to o LD cn cn to cn μ-' ui cn io H en vi H vi co io Lo M vi μ-' to cπ vi to co oo vi cn μ-' vo en μ-' tO Lo co cn rt* o co ιo co co ιt* co vo co on vo co vo o co cπ cn vi co cn to ιi* LD vo ω vi co ιo

vi vo rt* cn μ-' ~J o M vι oo ιn cn to o o oo co to rf_* on o co vi co cn o co io co io Lo vo iπ oo vo cπ o co l-' H' J-' H h' H H H H M H I-' l-' H H H i-' H μ-' μ-' μ-' μ-' μ-' μ-' μ-' μ-' H μ-' μ-' H μ-> μ-¹ μ-> μ-> \-> ^ o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o O O O O O O O O O O O O O O O O O O O O O O O O O O O, o

H io to co to on co ω co to rf* rf* vi to μ u μ μ (n ω μ u ιo ιo » ιo ιo ι* ω ιo ι>i ω u ijι ιιι » M io (ιi ^ μ ιo ιo μ ^ » ω u ιo ιn μ ω ιo u cπ cπ vo co vi o vD H vi μ-' ιo co Cθ vo o o oo vi o vo vo cπ vo co vo cπ cπ cn en o ιo vo vo rt* co cn co en v] vo vo uι cD H M vi ιπ ω cn m o ω ι^ μ^j vi oo cn rf* cn on rf* Lo rt* μ-' v] co v] rf* co rf* Cn rt* Cn VD O CO LD vl vJ LO rf* CO LD vl OO rt* l-' H O CO Cn i Cn cn en ιo ιo ιπ μ-^I rt* ιo cn ιo μ-^> to ιo rf* ιπ rf ιo ιπ co co rf* co to co cn μ-' cπ μ-' io co v3 ln rf* σi LO CO VD lO v] OO OO vl O rt* 0 1-' O vl θn LO LD CO LO o μ^ o oo oo on on vD iπ cπ vo o rf*

s s -g ≤ ≤ si S ≤ g si sj S S g ≤ s g si ≤ si s si s g ≤ g si s s ≤ -ϋ ≤ si sj ≤ -Ei ≤ g sj s g s g sj S g sj ≤ si si si S Ei si s s

ATOM 1988 0 HOH E 527 1.957 19.483 58.941 1.00 44.43

ATOM 1989 0 HOH E 528 -7 .641 5 .258 33 .722 1 .00 42 .72

ATOM 1990 0 HOH E 529 9 .446 17 .350 65 .141 1 .00 58 .61

ATOM 1991 0 HOH E 530 26 .874 39 .005 45 .593 1 .00 38 .89

ATOM 1992 0 HOH E 531 21 .700 9 .818 32 .431 1 .00 29 .79 w

ATOM 1993 0 HOH E 532 19 .909 37 .845 37 .897 1 .00 45 .65 w

ATOM 1994 0 HOH E 533 -4 .483 18 .944 32 .657 1 .00 29 .09

ATOM 1995 0 HOH E 534 5 .879 18 .842 61 .111 1 .00 25 .87

ATOM 1996 0 HOH E 535 14 .645 -14 .638 53 .958 1 .00 34 .91

ATOM 1997 0 HOH E 536 10 .758 23 .693 29 .607 1 .00 39 .53

ATOM 1998 0 HOH E 537 14 .338 29 .236 52 .072 1 .00 23 .79

ATOM 1999 0 HOH E 538 -1 .741 9 .523 54 .031 1 .00 15 .67

ATOM 2000 0 HOH E 539 37 .974 28 .457 47 .538 1 .00 37 .53 w

ATOM 2001 0 HOH E 540 -4 .043 22 .878 40 .941 1 .00 24 .51 w

ATOM 2002 0 HOH E 541 -10 .067 3 .093 33 .051 1 . 00 39 .04

ATOM 2003 0 HOH E 542 23 .692 16 .947 40 .249 1 . 00 37 . 69

ATOM 2004 0 HOH E 543 •14 .538 18 .262 36 .711 1 .00 25 .98

ATOM 2005 0 HOH E 544 •21 .782 25 .567 27 .128 1 .00 22 .21 w

ATOM 2006 O HOH E 545 -6 .512 24 .664 43 .761 1 .00 24 .02

ATOM 2007 0 HOH E 546 0 .663 -12 .626 51 .997 1 .00 21 .29

ATOM 2008 O HOH E 547 5 .183 -4 .422 55 .353 1 .00 28 .59 w

ATOM 2009 0 HOH E 548 15. .427 -11 .562 53 .600 1, .00 41 .82

ATOM 2010 0 HOH E 549 -6 .105 0 .971 34 .469 1 .00 33 .69

ATOM 2011 0 HOH E 550 24, .009 14 .010 45 .618 1, .00 31 .33 w

ATOM 2012 0 HOH E 551 28, .845 1 .189 53, .843 1. .00 25 .92 w

ATOM 2013 0 HOH E 552 22, .693 -2 .757 30 .748 1, .00 39 .50 w

ATOM 2014 0 HOH E 553 14, .366 8 .993 63, .904 1, .00 27 .99 w

ATOM 2015 0 HOH E 554 -2, .851 7, .676 50, .104 1. .00 6, .24 w

ATOM 2016 0 HOH E 555 •21. .496 18, .740 25. .299 1. .00 37, .92 w

ATOM 2017 0 HOH E 556 -4. .586 -0. .965 54. .920 1. .00 32. .72

ATOM 2018 0 HOH E 557 28. .684 7, .487 39. .407 1. .00 38, .90 w

ATOM 2019 0 • HOH E 558 -4. .261 27. .809 42. .326 1. .00 38. .34

ATOM 2020 o HOH E 559 27. ,593 12. .602 39. .403 1. ,00 33. .36 w

ATOM 2021 0 HOH E 560 5. .408 21, .728 39. .073 1. .00 18, .41

ATOM 2022 0 HOH E 561 4. ,934 33. .417 35. ,974 1. 00 41. ,20

ATOM 2023 0 HOH E 562 20. ,940 -9. ,117 33. 600 1. 00 37. ,49 w

ATOM 2024 0 HOH E 563 25. ,023 4. .235 34. ,909 1. ,00 32. ,12 w

ATOM 2025 0 HOH E 564 -7. ,915 31. ,142 34. 213 1. 00 20. ,,84 w

ATOM 2026 0 HOH E 565 25. ,443 21. .564 41. ,029 1. ,00 29. ,81

ATOM 2027 0 HOH E 566 7. ,224 3. ,183 57. ,981 1. 00 18. ,29

ATOM 2028 0 HOH E 567 11. 011 17. ,891 38. 676 1. 00 54. 99

ATOM 2029 o HOH E 568 27. 552 -6. 668 34. 568 1. 00 57. 12 w

ATOM 2030 0 HOH E 569 -9. 431 19. .864 28. 498 1. 00 33. .60

ATOM 2031 0 HOH E 570 -9. 953 33. 734 35. 439 1. 00 38. 58 w

ATOM 2032 0 HOH E 571 15. 884 -3. 180 55. 349 1. 00 42. 47 w

ATOM 2033 0 HOH E 572 9. 077 20. 453 25. 079 1. 00 34. 23

ATOM 2034 0 HOH E 573 27. 196 8. 842 33. 494 1. 00 28. 68

ATOM 2035 0 HOH E 574 3. 622 -14. ,068 39. 777 1. 00 40. 01

ATOM 2036 0 HOH E 575 22. 780 -6. 705 48. 821 1. 00 35. 65

ATOM 2037 0 HOH E 576 20. 461 14. 459 53. 991 1. 00 7. 42 w

ATOM 2038 0 HOH E 577 27. 952 24. 030 44. 546 1. 00 49. 20

ATOM 2039 0 HOH E 578 2. 048 26. 398 43. 059 1. 00 38. 93 w

ATOM 2040 0 HOH E 579 18. 772 13. 735 50. 322 1. 00 14. 30 w

ATOM 2041 0 HOH E 580 28. 890 4. 103 47. 890 1. 00 39. 36

ATOM 2042 0 HOH E 581 16. 438 0. 081 60. 966 1. 00 45. 15

ATOM 2043 0 HOH E 582 6. 734 26. 793 26. 473 1. 00 55. 90 ATOM 2044 0 HOH E 583 1.207 4.137 65.627 1.00 45.41

ATOM 2045 o HOH E 584 7.326 -9.176 55.828 1 .00 55 .37 w

ATOM 2046 o HOH E 585 -5.971 -6.427 38.603 1 .00 31 .68 w

ATOM 2047 o HOH E 586 3.834 -8.745 40.456 1 .00 20 .37

ATOM 2048 o HOH E 587 18.895 -15.206 53.910 1 .00 36 .75

ATOM 2049 o HOH E 588 10.278 12.294 61.398 1 .00 49 .20

ATOM 2050 o HOH E 589 23.956 15.507 34.852 1 .00 41 .12 w

ATOM 2051 o HOH E 590 -0.393 16.534 29.704 1 .00 50 .39 w

ATOM 2052 o HOH E 591 28.619 -2.738 54.840 1 .00 60 .38

ATOM 2053 o HOH E 592 16.294 -17.370 59.916 1 .00 37 .59

ATOM 2054 o HOH E 593 26.970 17.196 40.746 1 .00 51 .31

ATOM 2055 o HOH E 594 19.730 -17.598 48.544 1 .00 40 .50 w

ATOM 2056 o HOH E 595 1.326 0.954 59.482 1 .00 34 .91 TOM 2057 o HOH E 596 -9.799 9.892 37.138 1 .00 33 .55

ATOM 2058 o HOH E 597 -0.061 -9.253 45.965 1 .00 50 .81

ATOM 2059 o HOH E 598 -9.383 16.434 31.738 1 .00 80 .11 w

ATOM 2060 o HOH E 599 28.769 8.640 42.670 1 .00 43 .27

ATOM 2061 o HOH E 600 -0.063 -14.933 49.352 1 .00 49 .59 w

ATOM 2062 o HOH E 601 -3.092 19.360 39.749 1 .00 10 .48

ATOM 2063 o HOH E 602 2.098 30.090 44.138 1 .00 33 .04

ATOM 2064 o HOH E 603 16.517 -5.223 41.821 1 .00 13 .16

ATOM 2065 o HOH E 604 13.725 -15.908 43.046 1 .00 50 .39 w

ATOM 2066 o HOH E 605 -8.398 -0.815 36.648 1 .00 44 .78 w

ATOM 2067 o HOH E 606 -11.723 16.827 35.869 1 .00 45 .21

ATOM 2068 o HOH E 607 21.277 -5.651 56.343 1 .00 29 .34

ATOM 2069 o HOH E 608 0.385 28.090 25.264 1 .00 30 .39

ATOM 2070 o HOH E 609 22.972 36.785 37.710 1 .00 61, .85

ATOM 2071 o HOH E 610 -22.932 23.819 37.010 1. .00 35, .16

ATOM 2072 o HOH E 611 -0.053 32.476 43.573 1 .00 47, .38 w

ATOM 2073 o HOH E 612 16.349 -4.295 32.442 1, .00 11, .94 w

ATOM 2074 o HOH E 613 8.944 17.294 55.291 1 .00 38. .30

ATOM 2075 o HOH E 614 -12.696 5.454 42.347 1, .00 24. .01 w

ATOM 2076 o HOH E 615 9.177 8.214 28.044 1 .00 14. .97

ATOM 2077 o HOH E 616 0.445 33.900 38.846 1, .00 49. .81

ATOM 2078 o HOH E 617 21.274 -2.650 56.811 1. .00 51. .42 w

ATOM 2079 o HOH E 618 -10.014 10.985 40.675 1. .00 19, .46

ATOM 2080 o HOH E 619 -0.454 23.829 44.924 1. .00 45. .60 w

ATOM 2081 o HOH E 620 11.214 19.178 21.651 1. .00 43. .14

ATOM 2082 o HOH E 621 0.405 -9.345 49.102 1. .00 29. ,74 w

ATOM 2083 o HOH E 622 12.410 20.925 30.282 1. ,00 32. ,22

ATOM 2084 o HOH E 623 1.346 -7.579 51.489 1. .00 37. .32 TOM 2085 o HOH E 624 0.952 -1.848 62.790 1. ,00 40. ,55

ATOM 2086 o HOH E 625 25.065 35.727 35.689 1. .00 49. .74 w

ATOM 2087 o HOH E 626 -0.370 -8.630 31.015 1. ,00 29. .03 w

ATOM 2088 o HOH E 627 -16.728 15.876 25.532 1. .00 30. .88

ATOM 2089 o HOH E 628 6.938 -5.411 53.020 1. .00 42. .93 w

ATOM 2090 o HOH E 629 24.380 1.854 32.909 1. 00 47. 21

ATOM 2091 o HOH E 630 -8.097 -0.898 58.999 1. ,00 26. 17 w

ATOM 2092 o HOH E 631 6.349 26.620 30.559 1. 00 19. 66

ATOM 2093 o HOH E 632 -2.843 -4.402 37.498 1. ,00 36. ,21 TOM 2094 o HOH E 633 -11.910 13.215 48.308 1. 00 38. 00 w

ATOM 2095 o HOH E 634 -3.324 -7.892 37.394 1. ,00 38. ,68

ATOM 2096 o HOH E 635 24.398 -13.158 48.927 1. ,00 43. ,76 w

ATOM 2097 o HOH E 636 -8.198 -5.459 47.003 1. 00 27. 11

ATOM 2098 o HOH E 637 -8.309 2.465 36.126 1. ,00 41. ,61 w

ATOM 2099 o HOH E 638 11.803 20.581 62.626 1. 00 35. 46 w ATOM 2100 0 HOH E 639 10.945 19.084 58.586 1.00 45.01

ATOM 2101 0 HOH E 640 24 .849 29 .419 47 .628 1 .00 43 .17

ATOM 2102 0 HOH E 641 29 .935 -2 .937 50 .468 1 .00 46 .17

ATOM 2103 o HOH E 642 -13 .168 15 .458 33 .377 1 .00 44 .29 w TOM 2104 o HOH E 643 30 .171 -8 .396 50 .663 1 .00 44 .09 w

ATOM 2105 o HOH E 644 -3 .800 -10 .918 49 .026 1 .00 42 .03 w

ATOM 2106 o HOH E 645 -11 .802 13 .503 31 .227 1 .00 32 .17 w

ATOM 2107 o HOH E 646 25 .724 15 .828 32 .256 1 .00 47 .08

ATOM 2108 o HOH E 647 23 .197 36 .930 41 .760 1 .00 59 .31

ATOM 2109 o HOH E 648 6 .297 13 .476 62 .219 1 .00 20 .21

ATOM 2110 o HOH E 649 26 .923 39 .279 48 .907 1 .00 38 .82

ATOM 2111 o HOH E 650 -11 .912 28 .753 27 .748 1 .00 15 .52 w

ATOM 2112 o HOH E 651 -1 .841 0 .730 55 .015 1 .00 34 .19 w

ATOM 2113 o HOH E 652 27 .087 19 .363 43 .124 1 .00 35 .99 w

ATOM 2114 o HOH E 653 -5 .759 32 .720 51 .478 1 .00 42 .93 w

ATOM 2115 o HOH E 654 2 .519 -7 .426 58 .675 1 .00 44 .06

ATOM 2116 o HOH E 655 19 .199 36 .052 31 .423 1 .00 50 .09

ATOM 2117 o HOH E 656 36 .482 33 .963 37 .970 1 .00 29 .85

ATOM 2118 o HOH E 657 17 .605 38 .239 35 .191 1 .00 49 .64

ATOM 2119 o HOH E 658 -6 .132 -1 .762 40 .679 1. .00 58 .90

ATOM 2120 o HOH E 659 16 .738 -12 .983 56 .218 1 .00 26 .39 w

ATOM 2121 o HOH E 660 30 .120 2, .212 50, .795 1, .00 47, .95 w

ATOM 2122 o HOH E 661 -2 .330 32 .018 54 .211 1, .00 22, .05 w

ATOM 2123 o HOH E 662 26 .040 10, .878 43, .103 1, .00 58, .31 w

ATOM 2124 o HOH E 663 12 .297 13 .980 28 .533 1, .00 28, .23 w

ATOM 2125 o HOH E 664 29, .821 12. .619 35. .702 1. .00 36. .51

ATOM 2126 o HOH E 665 -4, .617 -1, .126 50, .876 1. .00 38. .50

ATOM 2127 o HOH E 666 24 .545 -0 .669 55, .100 1, .00 32, .21

ATOM 2128 o HOH E 667 -7. .088 31, .748 54, .539 1. .00 38. .30 w

ATOM 2129 o HOH E 668 28, .885 15, .172 42. .351 1. .00 38. .33

ATOM 2130 o HOH E 669 •10, .569 21. .693 38. .518 1. .00 38. .74 w

ATOM 2131 o HOH E 670 21. .244 5. .913 29. .116 1. ,00 61. .57

ATOM 2132 o HOH E 671 -5, .925 23. .682 38. .495 1. .00 35. .75 w

ATOM 2133 0 HOH E 672 -5. ,893 25. ,939 47. .728 1. 00 31. ,91 w

ATOM 2134 o HOH E 673 4. .714 -10. ,124 59. .049 1. ,00 47. .84 w

ATOM 2135 o HOH E 674 -7. .727 -4. ,136 55. ,451 1. ,00 24. ,28

ATOM 2136 o HOH E 675 8. .051 -12. ,031 31. ,037 1. ,00 26. .07 w

ATOM 2137 o HOH E 676 6. .482 12. ,323 23. ,254 1. ,00 41. ,15 w

ATOM 2138 o HOH E 677 28. ,692 38. ,404 43. ,002 1. 00 53. ,47

ATOM 2139 o HOH E 678 8. .274 3. .989 68. .327 1. ,00 29. ,04 w

ATOM 2140 o HOH E 679 14. ,925 -15. ,917 62. 867 1. 00 30. ,26

ATOM 2141 o HOH E 680 25. ,612 12. 902 48. 272 1. 00 68. 00 w

ATOM 2142 o HOH E 681 12. 405 4. 058 68. 632 1. 00 29. 34 w

ATOM 2143 o HOH E 682 16. 645 26. 144 28. 767 1. 00 37. 16 w

ATOM 2144 o HOH E 683 4. ,557 0. 245 60. 083 1. 00 46. 50 w

ATOM 2145 o HOH E 684 23. 005 -9. 610 47. 006 1. 00 39. 61

ATOM 2146 o HOH E 685 15. 268 27. 535 28. 052 1. 00 56. 53

ATOM 2147 o HOH E 686 -3. ,271 32. 616 30. 463 1. 00 32. 99

ATOM 2148 o HOH E 687 -1. ,210 -0. 738 58. 568 1. 00 67. 47 w

ATOM 2149 o HOH E 688 27. 788 35. 525 47. 975 1. 00 40. 99 w

ATOM 2150 o HOH E 689 2. 086 34. 462 35. 942 1. 00 27. 35 w

ATOM 2151 o HOH E 690 10. ,069 2. 633 70. 673 1. 00 49. 43 TOM 2152 o HOH E 691 21. 297 -14. 655 49. 191 1. 00 49. 35 w

ATOM 2153 o HOH E 692 19. 982 -16. 815 59. 582 1. 00 56. 16 w

ATOM 2154 o HOH E 693 20. 800 35. 579 40. 253 1. 00 48. 20 w

ATOM 2155 o HOH E 694 24. 030 6. 818 32. 263 1. 00 50. 91 w ATOM 2156 0 HOH E 695 -1.111 27.060 46.541 1.00 17.67 w

ATOM 2157 O HOH E 696 -27 .078 18 .341 26 .678 1 .00 55 .01 ATOM 2158 O HOH E 697 -10 .231 0 .457 56 .323 1 .00 33 .31 ATOM 2159 O HOH E 698 4 .275 -2 .353 63 .270 1 .00 40 .77 w ATOM 2160 O HOH E 699 28 .449 24 .425 47 .948 1 .00 32 .19 w ATOM 2161 O HOH E 700 30 .889 38 .367 39 .277 1 .00 54 .24 w ATOM 2162 O HOH E 701 6 .516 33 .704 54 .312 1 .00 24 .50 w ATOM 2163 O HOH E 702 9 .479 32 .909 53 .611 1 .00 53 .53 w ATOM 2164 O HOH E 703 9 .352 29 .832 54 .842 1 .00 34 .81 ATOM 2165 O HOH E 704 26 .759 36 .138 40 .043 1 .00 30 .98 w ATOM 2166 O HOH E 705 29 .458 -6 .695 53 .369 1 .00 47 .75 w ATOM 2167 O HOH E 706 5 .033 -10 .973 29 .828 1 .00 27 .71 w ATOM 2168 O HOH E 707 27 .793 -9 .749 35 .681 1 .00 31 .20 ATOM 2169 O HOH E 708 31 .071 -1 .537 53 .144 1 .00 32 .97 w ATOM 2170 O HOH E 709 -3 .807 22 .472 44 .590 1 .00 46 .35 w ATOM 2171 O HOH E 710 -4 .795 -7 .128 44 .799 1 .00 28 .48 w ATOM 2172 O HOH E 711 •12 .586 1 .440 45 .045 1 .00 36 .39 w ATOM 2173 O HOH E 712 -5 .260 3 .802 61 .612 1 .00 40 .65 ATOM 2174 O HOH E 713 29 .964 1 .189 35 .812 1 .00 34 .49 ATOM 2175 O HOH E 714 -2 .343 -12 .035 40 .222 1 .00 69 .00 w ATOM 2176 O HOH E 715 9 .302 23 .483 53 .331 1 .00 44 .74 ATOM 2177 0 HOH E 716 -2 .242 -2 .626 62 .126 1 .00 38 .70 ATOM 2178 0 HOH E 717 -7 .275 0 .894 52 .443 1 .00 54 .44 w ATOM 2179 o HOH E 718 -8 .110 15 .858 43 .753 1 .00 42 .70 ATOM 2180 0 HOH E 719 26, .788 -8, .036 52 .120 1, .00 40, .32 w ATOM 2181 o HOH E 720 6 .407 3, .434 64 .438 1, .00 28 .31 ATOM 2182 0 HOH E 721 -5, .768 15, .496 29 .504 1, .00 39, .40 ATOM 2183 0 HOH E 722 31. .860 30. .480 48, .051 1. .00 35, .91 ATOM 2184 o HOH E 723 -2, .018 -11, .813 46, .456 1. .00 40, .13 ATOM 2185 0 HOH E 724 ^■14. .067 13. .952 45, .904 1. .00 30, .17 ATOM 2186 o HOH E 725 11. .597 22. .036 22, .756 1. .00 43, .20 w ATOM 2187 o HOH E 726 12. .253 25. .948 27, .576 1. .00 42. .36 w ATOM 2188 0 HOH E 727 0. .693 -4. .936 60, .187 1. .00 55, .60 w ATOM 2189 0 HOH E 728 3. .595 14. ,524 25. ,741 1. ,00 30. .29 ATOM 2190 0 HOH E 729 29. .954 37. ,854 47, .035 1. .00 52. .60 ATOM 2191 0 HOH E 730 -2. .366 30. ,916 41. .868 1. .00 55. .38 ATOM 2192 0 HOH E 731 8. .713 -11. ,641 36. .683 1. .00 30. .73 ATOM 2193 0 HOH E 732 0. .761 -5. ,195 53. .384 1. ,00 38. .64 w ATOM 2194 0 HOH E 733 31. .365 26. ,739 47. .933 1. .00 31. ,61 w ATOM 2195 0 HOH E 734 7. ,345 16. 504 26. ,173 1. 00 64. ,82 w ATOM 2196 0 HOH E 735 10. ,677 0. 163 68. ,748 1. ,00 36. ,34 w ATOM 2197 o HOH E 736 27. 161 35. 880 32. 022 1. 00 33. 61 ATOM 2198 0 HOH E 737 13. 094 10. 266 30. 707 1. 00 43. 14 ATOM 2199 0 HOH E 738 10. 853 17. 032 27. 531 1. 00 38. 09 ATOM 2200 0 HOH E 739 3. 458 16. 325 42. 437 1. 00 7. 40 ATOM 2201 0 HOH E 740 1. 544 -12. 771 41. 970 1. 00 43. 59 TOM 2202 0 HOH E 741 -1. 559 2. 106 29. 784 1. 00 31. 14 ATOM 2203 0 HOH E 742 12. 165 -12. 601 53. 138 1. 00 28. 68 ATOM 2204 0 HOH E 743 -7. 457 9. 069 33. 302 1. 00 55. 50 w ATOM 2205 o HOH E 744 38. 921 31. 695 46. 548 1. 00 26. 37 ATOM 2206 0 HOH E 745 10. 857 -10. 683 32. 696 1. 00 39. 32 TOM 2207 0 HOH E 746 22. 495 18. 359 51. 539 1. 00 63. 86 TOM 2208 o HOH E 747 -2. 309 34. 601 37. 405 1. 00 44. 56 ATOM 2209 o HOH E 748 27. 912 17. 187 45. 245 1. 00 46. 22 ATOM 2210 o HOH E 749 -5. 769 11. 268 31. 499 1. 00 57. 12 w ATOM 2211 o HOH E 750 -9. 792 14. 584 34. 747 1. 00 49. 85 LΠ LΠ Φ Φ LO t to μ-¹ H LΠ σ LΠ o LΠ o LΠ o π o LΠ ^μ3 a ^μ3 to to to to to to to to to to to > to to to to to to to to l to to to to to to to to to to to to to to to to to to to to to to to to to to to to

M ta ta ^ ^ ^ H H ^ H ^ H 3 ^ ^ 3 ^ β ^ H ^μ3 ^ H 3 ^ H ^ 3 ^ 3 ^ H H3 H H H3 ^ H 3 ^ H 3 ^ ^ Ω ^μ3 H H 3 tO H tO P P P Ω P P P P Ω P P P Ω P P P P Ω P P Ω P P P P P P P P P P P P P Ω P P P P P Ω P P P P P Ω P P P ot 2 3 3 3 3 3 3 3 3 3 3 3 2 2 2 2 3 2 2 3 3 3 3 2 2 3 2 2 3 3 3 3 3 3 2 2 3 2 2 2 2 3 3 2 3 3 2 2 2 2 a to M IO IO IO IO IO IO IO U IO U K1 U IO I IO IO M IO U IO IO K1 M IO IO IO IO IO IO M IO IO IO IO IO IO IO IO IO KJ IO IO IO IO IO I IO M IO to to co co co co co co to to to io to to to to to to co to to to to co co co to to to to to to co co co co co co co co co co cn en en cn cπ cπ ιn ιπ Lπ ιπ ιπ ιπ cπ rt* rt* ιt* rt* rf_* rf* rt* ιt* lt* lt* l CO CO CO L CO C lO LO CO CO tO tO tO t C CO C C M μ-> μ-¹ to μ-> o vjo co vθ cn rf^ co co H θ vo co ι cn rt* ιo cθ H θ Vo ex> vi cn σi ι co M H o vo oo vi cn cπ rf* ιo co μ-' on Cπ rt_* t

Ω P P Ω Ω Ω Ω Ω Ω Ω Ω Ω P P P Ω Ω Ω P P P P P P Ω P P Ω Ω Ω P Ω Ω P P P P P P P P Ω P P P P P P P P P Ω

Ω a a ffi a Ω Ω P P P Ω P P P P a Ω a Ω a a a a a a a

P P P P P p P P P P P P Ω P oa pa ao aυ aυ oa ao a a a a

P o P υ a a a a a a a a a a a a a a a a w a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a to to M M to ta to to to to to to to M to to to to M ta to to M to to ta M w to to ta to to to ta to M rt_* O0 0O vl v] vI vl vI vl v] vl vl vl vl -J vJ Vl v] ^ vl vl -J vl vl vl vl vl vl vl v] v! vl l vl vl vl v] vl -vl v3 vl vl vl v] ~J v] vl ~J vl O o o » Jo β ffl » a io (o io a co ιi) i)) ii Q) Cθ co co oι _ -j θ 'j si J J i .o θ 'J m Λ Ciι oι oι m n m o> ij |j ιn ιιι ιπ oι oι lιι ιn o μ^j o vo co vi cn rt* co tθ H θ vrι co vi cn rt* ιo M H θ Lo co ι cn cπ rf* ω to H o vo oo v] m ιn ιf* co to o vo oo v! cn

co o μ u μ-> i i t μ-> to i co co μ-» co i μ-> H i co to to to cπ oo ιo cn rt* CD Co co en cn LO O vo to vo vl oo t vo vo μ^j as co vi cπ cπ co co on co σs cπ on vo rf_* co H io co o io co co co vi vo μ-' o io iπ vi M ^ o co in o vi cn ω H H to cn tn oo H co co cπ cπ H rt* VO in rt* ID co co vD CO rf* rf* on co cn co co v v] rf> ιn v] v] v] cn ιo en -J co o cπ vi co o cπ co o o rt* v] t vi cn cn LD rt* cn o o ιπ ιπ vi rf* en o -j H VD LO Cπ rt* CO CO LD vl cn to ιo to ιn cn co vo o co cn v] μJ vo vi o vo to o ιπ vo H io to cn o co rt* co rt* vi H rt* co cn o co co o -v_l co vi cπ vi cn cn vD rt* ιt*

CO co r co μ-» H to to co co to i μ-> o to vi μ-> co en o co -j io cπ o co o in rf* μ-> ω rf_* o r to i μ-> o cπ on on vo μ-¹ f* to to to oo co to I-¹ on co cπ 03 00 o rt* vr> Lo oo ιπ vi3 VO oo cθ ιt* oo v] co o ιπ co oo cn μ-' vi o rf* μ^j cπ o o rf* on co o cn cn co o ι-' Cθ vo H cn μ-> o o vo co cn cπ co rf* cπ vo o cn M oo o o tθ v] vo o co o o -j ω oo o ι-' co o rf* co μ-ι cπ v] cπ θ vi rf* cπ co rf* co cn rf* vi to μ-¹ in cπ cn co rf* !-> rf* oo co

M cn ιo e» ιo co ιt H μ-¹ cπ cn vo H (Ji o rf* μ-ι vo ιo o o co o ιπ co ιθ H io o co oo ιo vθ vi ιo rf* ιo cn to o o j-» o oo ιo co co cn θ Ui co co to ιn ιn en ιo ιn vi ιf* co cπ io co ιπ cn ιπ m ω ω co ιf* ιπ cπ ιt* c^ m o oι a H in * μ oι ιo μ μ oι u N in ιo co ιi) uι ij m * w iΛ ιt* ιo ijι -j ιo o u ιo ιo o * iD 'θ oι ιo o> -j _'j ιo ιi) _'j o u o (» co to μ^j rf* oo co to vo ιπ ιn co ιf* ιo ιo ω μ-' o vo to cn vo io ιπ rf* H μ-' to cπ vi v] CD Ui Co ιn μ^J -j ω in in o to cn co co ω vo o ∞ ω iD ιf* H in vo vo o vD rt* ω cn m ιo ιπ co en o cπ v] ω ιπ vQ v] iπ co co en cn μ^j e» vo ^■vi μ-> o co vo cn Lθ M m exi H io vi ιo on v] θ rt* co o oo H ω vo o o vo ιt* ιjι o on rt* co to rt* co ι co rt* rt* o rt* cn co ω μ-¹ μ-> H μ^j H μ-¹ H μ-¹ μ-¹ -> H H H H H H H H M μ-^, μ^j μ-' μ-^, μ-^, μ-> H μ-' H H H H H o O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O o O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

^ ω ω u ij ω ω * W ιt. ιn iΛ ^ ω u ιt. ιjι to ^ u * ιt> u ιo u M μ w ιo ιo μ * ** U) Ui ιt> (* ιt» *. oι iJ ιt> ι* u ιn ιt. ιo uι u *_* iD fl] ^ (Λ σι c uι rf* co o\ ιo ιo o ^ ιjι o vo u ^ ui ^ιθ >j M .J co o μ iD μ M ^ ^ . σι o o ^ ιo θ σi (jι ιo (D Ui u ^ co cn H <n en cn o co en oo co on on vi co vi rf* co e» rf* o cn co o LD Co on Lo tθ v- co cπ cπ ι--' μ-' o co vD cn Lo vD vo vi cn o oo o o co in μ to μ cπ co on vo vo en co j cn oo o o vo en cn to io cn v] o io o io rf* H VD H O o in LD cn M Lo Lo en rt* cn co io cn cn

S Sl -S SI S S Sj Sl Sj Sj Si Sj S SJ S Sj SI S S ≤ S Sj SJ S S S ≤ ≤ ^ S Si S Sj Sj a Sj Sj ≤ S Sj Sj Si Si ≤ S Sj Ej Si S Si

Table 2 - Interactions between the α2 I-domain surface and the triple-helical peptide .

The table shows the co-ordinates of both the receptor and ligand surfaces, defined by identifiable interactions between the two. The interacting residue is indicated as (A) or (M) , according to Table 1, representing I-domain or metal ion, respectively, or as (D) or (C) , according to Table 1, representing middle or trailing strand, respectively, of the triple-helical peptide. Interacting atoms within the amino acid residue are identified according to Table 1. Hydrophobic interactions, more diffuse in nature are identified by residue number and chain only, not be co-ordinates.

Residues E318 (A) and D292 (A) become more exposed upon ligand binding.

Residues L286 (A) and Co²⁺ (M) become exposed and contact ligand.

Claims

Claims

1. A method of identifying a potential inhibitor of an I- domain-containing polypeptide, the method comprising the step of employing a three-dimensional structure of the Integrin .2 I-domain as shown in Table 1 to design or select a potential inhibitor.

2. A method of identifying a potential inhibitor according to claim 1, wherein the potential inhibitor is designed or selected to inhibit conformational changes to the C-helix and/or Helix 7 of the Integrin 2 I-domain.

3. A method of identifying a potential inhibitor of an I- domain-containing polypeptide, the method comprising the step of designing or selecting a potential inhibitor that interacts with one or more points in the I-domain crystal structure shown for the I-domain in Table 2.

4. A method of identifying a potential inhibitor of an I- domain-containing polypeptide, the method comprising the step of designing or selecting a potential inhibitor that mimics one or more points in the peptide structure shown for the peptide structure in Table 2.

5. A method of identifying a potential inhibitor according to any one of claims 1 to 4 , the method comprising the further steps of : synthesizing or providing said potential inhibitor; and testing said potential inhibitor for ability to interact with an I-domain-containing polypeptide.

6. A method of identifying a potential inhibitor according to claim 5, wherein the testing step includes bringing said potential inhibitor into contact with an I-domain-containing polypeptide to determine the ability of said potential inhibitor to inhibit (i) the ability of the I-domain to interact with collagen or a collagen peptide or other ligand which binds the I-domain, and/or (ii) I-domain or I-domain- containing polypeptide function.

7. A method of identifying a potential inhibitor according to claim 5, wherein testing step includes the sub-steps of:

(i) forming a complex of the I-domain-containing polypeptide and said potential inhibitor ; and

(ii) analysing said complex by X-ray crystallography or MR spectroscopy to determine the ability of said potential inhibitor to interact with the I-domain-containing polypeptide.

8. A method of identifying a potential inhibitor according to any one of claims 1 to 7 , wherein the I-domain-containing, polypeptide is an integrin.

9. A method of obtaining a potential inhibitor of an integrin, the method comprising the steps of:

(a) providing a peptide fragment of integrin 2 I-domain, which peptide fragment contains the E318 residue, the D292 residue, or the residues 284-288;

(b) bringing the peptide fragment into contact with a test substance ; and

(c) determining the ability of the peptide fragment to bind with the test substance.

10. A method of obtaining a potential inhibitor according to claim 9, wherein the test substance is an antibody molecule.

11. A method of analysing an I-domain-containing polypeptide complex comprising employing (i) X-ray crystallographic diffraction data from the I-domain-containing polypeptide complex and (ii) atomic coordinate data according to Table 1 to generate a difference Fourier electron density map of the complex.

12. A crystal of 2 I-domain complex having a space group P2₁2₁2₁, and unit cell dimensions of a = 42.0 A, b = 48.4 A, and c = 114.5 A.

13. A crystal of α2 I-domain complex having the three dimensional atomic coordinates of Table 1.

14. A computer system, intended to generate structures and/or perform rational drug design for I-domain-containing polypeptides or I-domain-containing polypeptide complexes, the system containing atomic coordinate data according to Table 1 or Table 2.

15. Computer readable media for use in the computer system of claim 14, having atomic coordinate data according to Table 1 or Table 2 recorded thereon.

16. An inhibitor of an I-domain-containing polypeptide which is identified or obtained by any one of methods 1 to 10.

17. The inhibitor of claim 16 for treatment of a disorder or disease.

18. Use of the inhibitor of claim 16 in the manufacture of a pharmaceutical composition for the treatment of a disorder or disease.

19. A method of making a pharmaceutical composition comprising admixing the inhibitor of claim 16 with a pharmaceutically acceptable excipient, vehicle or carrier.

20. A method of treating a disease or disorder in which an I- domain-containing polypeptide has a role, comprising administering an effective amount of an inhibitor of the I- domain-containing polypeptide to an individual, the inhibitor being identified or obtained by any one of methods 1 to 10.