PATENT ABSTRACT
The invention relates to the three-dimensional structure of a crystal of an EphB4 receptor complexed with a ligand. The three-dimensional structure of a Receptor-Ligand Complex is disclosed. The receptor-ligand crystal structure, wherein the ligand is an inhibitor molecule, is useful for providing structural information that may be integrated into drug screening and drug design processes. Thus, the invention also relates to methods for utilizing the crystal structure of the Receptor-Ligand Complex for identifying, designing, selecting, or testing inhibitors of the EphB4 receptor protein, such inhibitors being useful as therapeutics for the treatment or modulation of i) diseases; ii) disease symptoms; or iii) the effect of other physiological events mediated by the receptor.

PATENT DESCRIPTION
CROSS-REFERENCE TO RELATED APPLICATIONS  
       [0001]     This application claims priority to U.S. Provisional Application 60/759,167 filed Jan. 12, 2006 which is hereby incorporated by reference in its entirety. 
     
    
     STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT  
       [0002]     Not Applicable.  
       INCORPORATION-BY-REFERENCE OF SEQUENCE LISTING  
       [0003]     The Sequence Listing, which is a part of the present disclosure, is a written sequence listing comprising nucleotide and amino acid sequences of the present invention. The subject matter of the Sequence Listing is incorporated herein by reference in its entirety.  
       FIELD  
       [0004]     The present invention relates to a three-dimensional structure of a receptor tyrosine kinase from the erythropoietin-producing hepatocellular carcinoma family of receptor tyrosine kinases (“Eph”), particularly an EphB complexed with an ephrin ligand (“Receptor-Ligand Complex”), for example an EphB4 or similar polypeptide complexed with an ephrin-B2 or analog, three-dimensional coordinates of a Receptor-Ligand Complex, models thereof, and uses of such structures and models.  
       INTRODUCTION  
       [0005]     The Eph receptor tyrosine kinases and their ligands, the ephrins, regulate numerous biological processes in developing and adult tissues and have been implicated in cancer progression and in pathological forms of angiogenesis. For example, the Eph receptors and their ligands, the ephrins, play critical roles in angiogenesis during embryonic development as well as in adult tissues (Brantley-Sieders and Chen, 2004; Cheng et al., 2002; Gale and Yancopoulos, 1999; Kullander and Klein, 2002). The Eph family of receptor tyrosine kinases also regulates many other biological processes, including tissue patterning, axonal guidance, and as more recently discovered, tumorigenesis (Carmeliet and Collen, 1999; Ferrara, 1999; Pasquale, 2005; Wilkinson, 2000). Both the Eph receptor and the ephrin are membrane bound, and therefore require cell-cell contact to signal a cellular response. The interaction between Eph receptors and ephrins on adjacent cell surfaces results in multimerization and clustering of the Eph-ephrin complexes, leading to forward signaling in the Eph-expressing cell and reverse signaling in the ephrin-expressing cell. EphB4 belongs to the Eph (erythropoietin-producing hepatocellular carcinoma) family of receptor tyrosine kinases, which is divided into two subclasses, A and B, based on binding preferences and sequence conservation (Gale et al., 1996). In general, EphA receptors (EphA1-EphA10) bind to glycosyl phosphatidyl in ositol-(GPI) anchored ephrin-A ligands (ephrin-A1-ephrin-A6), while EphB receptors (EphB1-EphB6) interact with transmembrane ephrin-B ligands (ephrin-B1-ephrin-B3) (Eph Nomenclature Committee, 1997). While interactions between the Eph receptors and ephrin ligands of the same subclass are quite promiscuous, interactions between subclasses are rare. A few cross-subclass exceptions include the EphA4-ephrin-B2/B3 interactions (Takemoto et al., 2002), and the EphB2-ephrinA5 interaction, which has been characterized structurally (Himanen et al., 2004). EphB4 is unique within the Eph family in that it selectively binds ephrin-B2, while demonstrating only weak binding for both ephrin-B1 and ephrin-B3.  
         [0006]     Eph receptors have a modular structure, consisting of an N-terminal ephrin binding domain adjacent to a cysteine-rich domain and two fibronectin type III repeats in the extracellular region. The intracellular region consists of a juxtamembrane domain, a conserved tyrosine kinase domain, a C-terminal sterile α-domain (SAM), and a PDZ binding motif. The N-terminal 180 amino acid globular domain is sufficient for high-affinity ligand binding (Himanen et al., 2001).  
         [0007]     Several 12-amino-acid peptides that selectively bind to individual Eph receptors were recently identified by phage display (Koolpe et al., 2005; Koolpe et al., 2002; Murai et al., 2003). A number of EphB4-binding peptides could be aligned with each other and the 15 amino acid segment corresponding to the ephrin-B2 G-H loop (Koolpe et al., 2005). The TNYL EphB4-binding peptide was modified based on this alignment to include a carboxy-terminal RAW sequence. The resulting TNYL-RAW (TNYLFSPNGPIARAW; SEQ ID NO: 1) peptide is a potent antagonist of ephrin-B2 binding to EphB4, with an IC 50  value of ˜15 nM for the murine receptor, which is comparable to the IC 50  of ˜10 nM measured for ephrin-B2 (Table 1A). Interestingly, the TNYL peptide (which lacks the carboxy-terminal RAW sequence) is 10,000-fold less potent than TNYL-RAW (IC 50  of ˜150 μM).  
         [0008]     Despite attempts to model the structural changes of EphB4 upon ligand binding, a detailed view of conformational arrangements of an EphB4 receptor in complex with a highly-selective ligand has remained elusive. Thus, the development of useful reagents for treatment or diagnosis of disease was hindered by lack of structural information of such a Receptor-Ligand Complex. Therefore, there is a need in the art to elucidate the three-dimensional structure and models of Receptor-Ligand Complexes, and to use such structures and models in therapeutic strategies, such as drug design.  
       SUMMARY  
       [0009]     The present teachings include a method for designing a drug which interferes with an activity of an EphB4 receptor, the method comprising providing on a digital computer a three-dimensional structure of a receptor-ligand complex comprising the EphB4 receptor and at least one ligand of the EphB4 receptor, and using software comprised by the digital computer to design a chemical compound which is predicted to bind to the EphB4 receptor. The method can further comprise synthesizing the chemical compound, and evaluating the chemical compound for an ability to interfere with an activity of the EphB4 receptor.  
         [0010]     In accordance with a further aspect, the chemical compound of the method is designed by computational interaction with reference to a three-dimensional site of the structure of the receptor-ligand complex. The three-dimensional site can include EphB4 D-E and J-K loops. The three-dimensional site can also include Leu-48, Cys-61, Leu-95, Ser-99Leu-100, Pro-101, Thr-147, Lys-149, Ala-155, and Cys-184 of human EphB4 (SEQ ID NO:26). In another aspect, the EphB4 receptor is a human EphB4 receptor.  
         [0011]     The present teachings also include a method for determining a three-dimensional structure of a target EphB receptor-ligand complex structure comprising providing an amino acid sequence of a target EphB structure, wherein the three-dimensional structure of the target EphB structure is not known, predicting a pattern of folding of the amino acid sequence in a three-dimensional conformation using a fold recognition algorithm, and comparing the pattern of folding of the target structure amino acid sequence with the three-dimensional structure of a known EphB4 receptor-ligand complex. In certain aspects, the EphB4 receptor comprises a truncated EphB4 receptor, such as EphB4 (17-196) as set forth in SEQ ID NO: 2, and other homologs and analogs such as EphB4 (17-198) as set forth in SEQ ID NO: 3. In certain aspects, the EphB4 receptor consists essentially of an amino acid sequence as set forth in SEQ ID NO: 2 and other homologs and analogs such asEphB4 (17-198) as set forth in SEQ ID NO: 3. In certain aspects, the known receptor-ligand complex comprises a three-dimensional structure described by atomic coordinates that substantially conform to atomic coordinates set forth in Table 1. In additional aspects, the EphB4 receptor is a human EphB4 receptor.  
         [0012]     In accordance with yet another aspect, a method is provided for generating a model of a three-dimensional structure of an EphB-ligand complex, the method comprising providing an amino acid sequence of a reference EphB4 polypeptide and an amino acid sequence of a target EphB comprised by the EphB-ligand complex, identifying structurally conserved regions shared between the reference EphB4 amino acid sequence and the target EphB amino acid sequence, and assigning atomic coordinates from the conserved regions to the target EphB-ligand complex. In certain aspects, the EphB4 polypeptide comprises a truncated EphB4 receptor, such as EphB4 (17-196) as set forth in SEQ ID NO:2, and other homologs and analogs such as EphB4 (17-198) as set forth in SEQ ID NO: 3. In certain aspects, the EphB4 polypeptide consists essentially of an amino acid sequence asset forth in SEQ ID NO: 2, and other homologs and analogs such as EphB4 (17-198) as set forth in SEQ ID NO: 3. In certain aspects, the target EphB-ligand complex comprises a three-dimensional structure described by atomic coordinates that substantially conform to atomic coordinates set forth in Table 1. In certain aspects, the reference EphB4-ligand complex comprises a three-dimensional structure described by atomic coordinates that substantially conform to atomic coordinates set forth in Table 1. In additional aspects, the EphB4 polypeptide is a human EphB4 polypeptide.  
         [0013]     In accordance with another aspect, a method is provided for generating a model of a three-dimensional structure of an EphB receptor-ligand complex, the method comprising providing an amino acid sequence of a known EphB4 receptor in complex with at least one known ligand of the EphB4 receptor, providing an amino acid sequence of a target EphB receptor in complex with at least one target ligand of the EphB receptor, identifying structurally conserved regions shared between the known receptor-ligand complex amino acid sequence and the target receptor-ligand complex amino acid sequence, and assigning atomic coordinates of the conserved regions to the target receptor-ligand complex. In certain aspects, the EphB4 receptor comprises a truncated EphB4 receptor, such as EphB4(17-196) as set forth in SEQ ID NO: 2, and other homologs and analogs such as EphB4 (17-198) as set forth in SEQ ID NO: 3. In certain aspects, the EphB4 receptor consists essentially of an amino acid sequence as set forth in SEQ ID NO: 2 and other homologs and analogs such as EphB4 (17-198) as set forth in SEQ ID NO: 3. In certain aspects, the EphB4 receptor is a human EphB4 receptor. In additional aspects, the known receptor-ligand complex comprises a three-dimensional structure described by atomic coordinates that substantially conform to Table 1.  
         [0014]     According to another aspect, a crystal is provided consisting essentially of an EphB4 ligand binding domain and a ligand. In certain aspects, the EphB4 ligand binding domain is a truncated EphB4 polypeptide having the sequence of SEQ ID NO: 2 and other homologs and analogs such as EphB4 (17-198) as set forth in SEQ ID NO: 3. In certain aspects, the EphB4 ligand binding domain consists essentially of EphB4 D-E and J-K loops. In certain aspects, the EphB4 ligand binding domain consists essentially of Leu-48, Cys-61, Leu-95, Ser-99 Leu-100, Pro-101, Thr-147, Lys-149, Ala-155, and Cys-184 of human EphB4(SEQ ID NO: 27). In certain aspects, the EphB4 ligand binding domain is a human EphB4 ligand binding domain. In additional aspects, the ligand is ephrin-B2. In certain aspects, the ligand comprises Phe-120, Pro-122, Leu-124, Trp-125, and Leu-127 of human ephrin-B2 (SEQ ID NO: 29). In certain aspects, the ligand comprises sequence motif NxWxL, wherein x is any amino acid. In certain aspects, the ligand is TNYL-RAW, a polypeptide having SEQ ID NO: 1. In other aspects, the ligand is a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: 4 through SEQ ID NO: 26. In certain aspects, the ligand is a polypeptide having at least 50% sequence identity to a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: 1 and SEQ ID NO: 4 through SEQ ID NO: 26. In certain aspects, the ligand is a polypeptide having at least 75% sequence identity to a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: land SEQ ID NO: 4 through SEQ ID NO: 26. In certain other aspects, the ligand is a polypeptide having at least 90% sequence identity to a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: 1 and SEQ ID NO: 4 through SEQ ID NO: 26. In additional aspects, the crystal comprises space group P41212 so as to form a unit cell of dimensions a=60.97 Å, b=60.97 Å, and c=151.7 Å.  
         [0015]     In yet another aspect, a crystal is provided comprising a polypeptide having SEQ ID NO: 2 or 3 complexed with a ligand, wherein the crystal is sufficiently pure to determine atomic coordinates of the complex by X-ray diffraction to a resolution of about 1.65 Å. In certain aspects, the ligand comprises Phe-120, Pro-122, Leu-124, Trp-125, and Leu-127 of ephrin-B2. In certain aspects, the ligand comprises sequence motif NxWxL, wherein x is any amino acid. In certain aspects, the ligand is a polypeptide having SEQ ID NO: 1. In certain aspects, the ligand is a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: 4 through SEQ ID NO: 26. In certain aspects, the ligand is a polypeptide having at least 50% sequence identity to a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: 1 and SEQ ID NO: 4 through SEQ ID NO: 26. In certain aspects, the ligand is a polypeptide having at least 75% sequence identity to a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: 1 and SEQ ID NO: 4 through SEQ ID NO: 26. In certain aspects, the ligand is a polypeptide having at least 90% sequence identity to a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: 1 and SEQ ID NO: 4 through SEQ ID NO: 26.  
         [0016]     In yet another aspect, a polypeptide is provided having SEQ ID NO: 2 or 3 in complex with a ligand. In certain aspects, the ligand is an ephrin. In certain aspects, the ephrin is ephrin-B2. In certain aspects, the ligand comprises Phe-120, Pro-122, Leu-124, Trp-125, and Leu-127 of ephrin-B2. In certain aspects, the ligand comprises sequence motif NxWxL, wherein x is any amino acid. In certain aspects, the ligand is a polypeptide having SEQ ID NO: 1. In certain aspects, the ligand is a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: 4 through SEQ ID NO: 26. In certain aspects, the ligand is a polypeptide having at least 50% sequence identity to a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: 1 and SEQ ID NO: 4 through SEQ ID NO: 26. In certain aspects, the ligand is a polypeptide having at least 75%sequence identity to a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: 1 and SEQ ID NO: 4 through SEQ ID NO: 26. In certain aspects, the ligand is a polypeptide having at least 90% sequence identity to a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: 1 and SEQ ID NO: 4 through SEQ ID NO: 26.  
         [0017]     In other aspects, a therapeutic compound is provided that inhibits an activity of an EphB4 receptor, wherein the compound is selected by performing a structure based drug design using a three-dimensional structure determined for a crystal comprising an EphB4 receptor and a ligand, contacting a sample comprising the EphB4 receptor with the compound, and detecting inhibition of at least one activity of the EphB4 receptor. In certain aspects, the EphB4 is a polypeptide having SEQ ID NO: 2 or 3. In certain aspects, the EphB4 receptor is a human EphB4 receptor. In certain aspects, the ligand is a polypeptide having SEQ ID NO: 1. In certain aspects, the ligand is a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: 4 through SEQ ID NO: 26. In certain aspects, the ligand is a polypeptide having at least 50% sequence identity to a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: 1 and SEQ ID NO: 4 through SEQ ID NO: 26. In certain aspects, the ligand is a polypeptide having at least 75% sequence identity to a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: 1 and SEQ ID NO: 4 through SEQ ID NO: 26. In certain aspects, the ligand is a polypeptide having at least 90% sequence identity to a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: 1 and SEQ ID NO: 4 through SEQ ID NO: 26.  
         [0018]     In yet another aspect, a three-dimensional computer image of the three-dimensional structure of an EphB4-ligand complex is provided wherein the structure substantially conforms to the three-dimensional coordinates listed in Table 1.  
         [0019]     In yet another aspect, a computer-readable medium encoded with a set of three-dimensional coordinates set forth in Table 1 is provided wherein, using a graphical display software program, the three-dimensional coordinates of Table 1 create an electronic file that can be visualized on a computer capable of representing said electronic file as a three-dimensional image.  
         [0020]     In yet another aspect, a computer-readable medium encoded with a set of three-dimensional coordinates of a three-dimensional structure which substantially conforms to the three-dimensional coordinates represented in Table 1 is provided wherein, using a graphical display software program, the set of three-dimensional coordinates create an electronic file that can be visualized on a computer capable of representing said electronic file as a three-dimensional image.  
         [0021]     In yet another aspect, a method is provided for assaying EphB4 receptor binding to a compound, the method comprising providing an EphB4 receptor bound with a polypeptide having SEQ ID NO: 1, contacting the ligand-bound EphB4 receptor with a compound, and detecting the release of the polypeptide having SEQ ID NO: 1 from the EphB4 receptor, wherein the release of the polypeptide having SEQ ID NO: 1 is indicative of the compound binding to the EphB4 receptor. In certain aspects, the EphB4 receptor is a polypeptide having SEQ ID NO: 2 or 3. In certain aspects, the EphB4 receptor consists essentially of EphB4 D-E and J-K loops. In certain aspects, the EphB4 receptor consists essentially of Leu-48, Cys-61, Leu-95, Ser-99 Leu-100, Pro-101, Thr-147, Lys-149, Ala-155, and Cys-184 of SEQ ID NO: 27. In certain aspects, the EphB4 receptor is a human EphB4 receptor.  
         [0022]     In another aspect, a method is provided for crystallizing an EphB4 receptor, the method comprising providing an EphB4 receptor in contact with a first polypeptide having SEQ ID NO: 1, and contacting the EphB4 receptor in contact with the first polypeptide with a second polypeptide having at least 50% sequence identity to SEQ ID NO: 1, but not identical to SEQ ID NO: 1, wherein the EphB4 receptor in contact with the first and second polypeptides forms an EphB4 receptor crystal. In certain aspects, the second polypeptide comprises at least 75% sequence identity to SEQ ID NO: 1. In certain aspects, the second polypeptide comprises at least 90% sequence identity to SEQ ID NO: 1.  
         [0023]     In yet another aspect, a method is provided for crystallizing an EphB4 receptor, the method comprising providing an EphB4 receptor in contact with a polypeptide having SEQ ID NO: 1, and contacting the EphB4 receptor in contact with the polypeptide with a compound provided above, wherein the EphB4 receptor in contact with the polypeptide and the compound forms an EphB4 receptor crystal.  
         [0024]     In another aspect, a composition is provided comprising EphB4 receptor, a ligand, and a compound provided above. In certain aspects, the EphB4 receptor is a polypeptide having SEQ ID NO: 2 or 3. In certain aspects, the EphB4 receptor consists essentially of EphB4 D-E and J-K loops. In certain aspects, the EphB4 receptor consists essentially of Leu-48, Cys-61, Leu-95, Ser-99 Leu-100, Pro-101, Thr-147, Lys-149, Ala-155, and Cys-184 of SEQ ID NO: 27. In certain aspects, the EphB4 receptor is a human EphB4 receptor. In certain aspects, the ligand is a polypeptide having SEQ ID NO: 1. In certain aspects, the ligand is a polypeptide selected from the group consisting of polypeptide shaving SEQ ID NO: 4 through SEQ ID NO: 26. In certain aspects, the ligand is a polypeptide having at least 50% sequence identity to a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: 1 and SEQ ID NO: 4 through SEQ ID NO: 26. In certain aspects, the ligand is a polypeptide having at least 75% sequence identity to a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: 1 and SEQ ID NO: 4 through SEQ ID NO: 26. In additional aspects, the ligand is a polypeptide having at least 90% sequence identity to a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: 1 and SEQ ID NO: 4 through SEQ ID NO: 26.  
         [0025]     These and other features, aspects and advantages of the present teachings will become better understood with reference to the following description, examples and appended claims. 
     
    
     DRAWINGS  
       [0026]     Those of skill in the art will understand that the drawings, described below, are for illustrative purposes only. The drawings are not intended to limit the scope of the present teachings in any way.  
         [0027]      FIG. 1 . The ephrin binding domain of the EphB4 receptor in complex with an antagonistic peptide, TNYL-RAW. Upper left panel, composite image of complex; upper right panel, β-sheets and peptide; lower left panel, loops; lower right panel, α-helices. The ephrin binding domain consists of a jellyroll folding topology with 13 anti-parallel B-sheets connected by loops of varying lengths. Peptide binding orders the D-E and J-K loops, which cannot be visualized in the apo structure of the related EphB2 receptor.  
         [0028]      FIG. 2 . Superposition of the EphB4 receptor on the EphB2 receptor from the EphB2-ephrin-B2 structure (Himanen et al., 2001; Protein Data Base Accession No. 1KGY, incorporated herein by reference in its entirety). The structures are superimposed with an overall r.m.s.d. of 1.08 Å between equivalent Cα positions. The J-K loop is displaced by as much as 20 Å in EphB4 compared to EphB2.  
         [0029]      FIG. 3 . Model of the EphB4-ephrin-B2 complex. The EphB4 receptor is predicted to form interactions similar to those previously described in the EphB2-ephrin-B2 complex. Although several interactions are likely absent in the EphB4-ephrin-B2 complex compared to the EphB2-ephrin-B2 complex, the tetramer is likely to form at high EphB4 and ephrin-B2 concentrations.  
         [0030]      FIG. 4 . Stereoview of sigma-A weighted 2|F obs |-|F calc | electron density at 1.65 Å resolution, contoured at 1 a for the antagonistic TNYL-RAW peptide (SEQ ID NO: 1). The peptide was placed into the density after an initial round of structure refinement. The N-terminal threonine lacks clear electron density and is therefore absent from the structure.  
         [0031]      FIG. 5 . Close-up of the binding interface of a model of the EphB4-ephrinB2 (SEQ ID NO: 27, and SEQ ID NO: 29 respectively) complex. Position of the peptide is distinct from the ephrinB2 G-H loop. Both peptide and ephrin G-H loop reside within the hydrophobic binding cleft of the EphB4 receptor.  
         [0032]      FIG. 6 . EphB4-TNYL interactions. Non-covalent interactions are indicated by dashed lines.  
         [0033]      FIG. 7 . Superposition of the TNYL-RAW peptide (SEQ ID NO: 1) on the EphB4 (surface)-ephrin-B2 model. The ligand G-H loop extends into the hydrophobic binding cleft of the EphB4 receptor such that the TNYL-RAW peptide (SEQ ID NO: 1) and the ephrin-B2 G-H loop compete for the same binding site. The peptide binds distinctly within the binding cleft, inhibiting ephrin-B2 (SEQ ID NO: 29) binding at both high affinity dimerization interfaces. 
     
    
     DETAILED DESCRIPTION  
       [0034]     The present invention relates to the discovery of the three-dimensional structure of a Receptor-Ligand Complex, models of such three-dimensional structures, a method of structure-based drug design using such structures, the compounds identified by such methods and the use of such compounds in therapeutic compositions. In particular, the present invention involves the crystal structure of the EphB4 receptor in complex with a highly specific antagonistic peptide at a resolution of 1.65 Å. The peptide is situated in a hydrophobic cleft of EphB4 corresponding to the cleft in EphB2 occupied by the ephrin-B2G-H loop. The crystal reveals structural features of EphB4 that, when in complex a ligand, provides a basis for antagonist design and modeling.  
         [0035]     In particular, the structural and thermodynamic characterization of the EphB4 receptor in complex with a polypeptide having SEQ ID NO: 1 is described. The polypeptide is situated in the same hydrophobic cleft occupied by the ephrinB2 G-H loop, assuming a position distinct from this loop and preventing ligand binding interactions at two high-affinity dimerization interfaces. Although the peptide binds independently from the ephrin ligand, the interactions within the binding cleft are remarkably similar to previous complex structures, providing a stable network of interactions for binding. Further, structural analysis reveals the molecular determinants for the directed specificity of this antagonist for the EphB4 receptor, allowing the first insights into modulating pathways resulting in tumorigenesis and angiogenesis that rely on EphB4-ephrinB2 signaling.  
         [0036]     One aspect of the present invention includes a model of a Receptor-Ligand Complex in which the model represents a three-dimensional structure of a Receptor-Ligand Complex. Another aspect of the present invention includes the three-dimensional structure of a Receptor-Ligand Complex. A three-dimensional structure of a Receptor-Ligand Complex substantially conforms with the atomic coordinates represented in Table 1. According to the present invention, the use of the term “substantially conforms” refers to at least a portion of a three-dimensional structure of a Receptor-Ligand Complex which is sufficiently spatially similar to at least a portion of a specified three-dimensional configuration of a particular set of atomic coordinates (e.g., those represented by Table 1) to allow the three-dimensional structure of a Receptor-Ligand Complex to be modeled or calculated using the particular set of atomic coordinates as a basis for determining the atomic coordinates defining the three-dimensional configuration of a Receptor-Ligand Complex.  
         [0037]     More particularly, a structure that substantially conforms to a given set of atomic coordinates is a structure wherein at least about 50% of such structure has an average root-mean-square deviation (RMSD) of less than about 1.8 Å for the backbone atoms in secondary structure elements in each domain, and in various aspects, less than about 1.25 Å for the backbone atoms in secondary structure elements in each domain, and, in various aspects less than about 1.0 Å, in other aspects less than about 0.75 Å, less than about 0.5 Å, and, less than about 0.25 Å for the backbone atoms in secondary structure elements in each domain. In one aspect of the present invention, a structure that substantially conforms to a given set of atomic coordinates is a structure wherein at least about 75% of such structure has the recited average RMSD value, and in some aspects, at least about 90% of such structure has the recited average RMSD value, and in some aspects, about 100% of such structure has the recited average RMSD value. In particular, the above definition of “substantially conforms” can be extended to include atoms of amino acid side chains. As used herein, the phrase “common amino acid side chains” refers to amino acid side chains that are common to both the structure which substantially conforms to a given set of atomic coordinates and the structure that is actually represented by such atomic coordinates.  
         [0038]     In another aspect of the present invention, a three-dimensional structure that substantially conforms to a given set of atomic coordinates is a structure wherein at least about 50% of the common amino acid side chains have an average RMSD of less than about 1.8 Å, and in various aspects, less than about 1.25 Å, and, in other aspects, less than about 1.0 Å, less than about 0.75 Å, less than about 0.5 Å, and less than about 0.25 Å. Inane aspect of the present invention, a structure that substantially conforms to a given set of atomic coordinates is a structure wherein at least about 75% of the common amino acid side chains have the recited average RMSD value, and in some aspects, at least about 90% of the common amino acid side chains have the recited average RMSD value, and in some aspects, about 100% of the common amino acid side chains have the recited average RMSD value.  
         [0039]     A three-dimensional structure of a Receptor-Ligand Complex which substantially conforms to a specified set of atomic coordinates can be modeled by a suitable modeling computer program such as MODELER (A. Sali and T. L. Blundell, J. Mol. Biol., vol. 234:779-815, 1993 as implemented in the Insight II software package Insight II, available from Accelerys (San Diego, Calif.)) and those software packages listed in the Examples, using information, for example, derived from the following data: (1) the amino acid sequence of the Receptor-Ligand Complex; (2) the amino acid sequence of the related portion(s) of the protein represented by the specified set of atomic coordinates having a three-dimensional configuration; and, (3) the atomic coordinates of the specified three-dimensional configuration. A three-dimensional structure of a Receptor-Ligand Complex which substantially conforms to a specified set of atomic coordinates can also be calculated by a method such as molecular replacement, which is described in detail below.  
         [0040]     A suitable three-dimensional structure of the Receptor-Ligand Complex for use in modeling or calculating the three-dimensional structure of another Receptor-Ligand Complex comprises the set of atomic coordinates represented in Table 1. The set of three-dimensional coordinates set forth in Table 1 is represented in standard Protein Data Bank format. The atomic coordinates have been deposited in the Protein Data Bank, having Accession No. 2BBA. According to the present invention, a Receptor-Ligand Complex has a three-dimensional structure which substantially conforms to the set of atomic coordinates represented by Table 1. As used herein, a three-dimensional structure can also be a most probable, or significant, fit with a set of atomic coordinates. According to the present invention, a most probable or significant fit refers to the fit that a particular Receptor-Ligand Complex has with a set of atomic coordinates derived from that particular Receptor-Ligand Complex. Such atomic coordinates can be derived, for example, from the crystal structure of the protein such as the coordinates determined for the Receptor-Ligand Complex structure provided herein, or from a model of the structure of the protein. For example, the three-dimensional structure of a dimeric protein, including a naturally occurring or recombinantly produced EphB4 receptor protein, substantially conforms to and is a most probable fit, or significant fit, with the atomic coordinates of Table 1. The three-dimensional crystal structure of the Receptor-Ligand Complex may comprise the atomic coordinates of Table 1. Also as an example, the three-dimensional structure of another Receptor-Ligand Complex would be understood by one of skill in the art to substantially conform to the atomic coordinates of Table 1. This definition can be applied to the other EphB4 receptor proteins in a similar manner.  
         [0041]     For example, the structure of the EphB4 receptor establishes the general architecture of the EphB receptor family. Accordingly, in some configurations, EphB4 receptor protein sequence homology across eukaryotes can be used as a basis to predict the structure of such receptors, in particular the structure for such receptor-ligand binding sites and other conserved regions.  
         [0042]     In various aspects of the present invention, a structure of a Receptor-Ligand Complex substantially conforms to the atomic coordinates represented in Table 1. Such values as listed in Table 1 can be interpreted by one of skill in the art. In other aspects, at three-dimensional structure of a Receptor-Ligand Complex substantially conforms to the three-dimensional coordinates represented in Table 1. In other aspects, a three-dimensional structure of a Receptor-Ligand Complex is a most probable fit with the three-dimensional coordinates represented in Table 1. Methods to determine a substantially conforming and probable fit are within the expertise of skill in the art and are described herein in the Examples section.  
         [0043]     A Receptor-Ligand Complex that has a three-dimensional structure which substantially conforms to the atomic coordinates represented by Table 1 includes an EphB4 receptor protein having an amino acid sequence that is at least about 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to an amino acid sequence of a human EphB4 receptor protein, in particular an amino acid sequence having SEQ ID NO:27, across the full-length of the EphB4 receptor sequence. A sequence alignment program such as BLAST (available from the National Institutes of Health Internet web site http://www.ncbi.nlm.nih.gov/BLAST) may be used by one of skill in the art to compare sequences of an EphB receptor to the EphB4 receptor.  
         [0044]     A three-dimensional structure of any Receptor-Ligand Complex can be modeled using methods generally known in the art based on information obtained from analysis of a Receptor-Ligand Complex crystal, and from other Receptor-Ligand Complex structures which are derived from a Receptor-Ligand Complex crystal. The Examples section below discloses the production of a Receptor-Ligand Complex crystal, in particular a truncated EphB4 receptor having SEQ ID NO: 2 or 3 complexed with a polypeptide having SEQ ID NO: 1, and a model of a Receptor-Ligand Complex, in particular a truncated EphB4 receptor having SEQ ID NO: 2 or 3 complexed with a polypeptide having SEQ ID NO: 1, using methods generally known in the art based on the information obtained from analysis of a Receptor-Ligand Complex crystal.  
         [0045]     An aspect of the present invention comprises using the three-dimensional structure of a crystalline Receptor-Ligand Complex to derive the three-dimensional structure of another Receptor-Ligand Complex. Therefore, the crystalline EphB4 receptor complexed with a ligand, particularly a ligand having a sequence of SEQ ID NO: 1 or SEQ ID NOs: 4 through 26, and the three-dimensional structure of EphB4 complexed with such ligands permits one of ordinary skill in the art to now derive the three-dimensional structure, and models thereof, of any Receptor-Ligand Complex. The derivation of the structure of any Receptor-Ligand Complex can now be achieved even in the absence of having crystal I structure data for such other Receptor-Ligand Complexes, and when the crystal structure of another Receptor-Ligand Complex is available, the modeling of the three-dimensional structure of the new Receptor-Ligand Complex can be refined using the knowledge already gained from the Receptor-Ligand Complex structure.  
         [0046]     In some configurations of the present teachings, the absence of crystal structure data for other Receptor-Ligand Complexes, the three-dimensional structures of other Receptor-Ligand Complexes can be modeled, taking into account differences in the amino acid sequence of the other Receptor-Ligand Complex. Moreover, the present invention allows for structure-based drug design of compounds which affect the activity of virtually any EphB receptor, and particularly, of EphB4.  
         [0047]     One aspect of the present invention includes a three-dimensional structure of a Receptor-Ligand Complex, in which the atomic coordinates of the Receptor-Ligand Complex are generated by the method comprising: (a) providing an EphB receptor complexed with a ligand in crystalline form; (b) generating an electron-density map of the crystalline EphB receptor complexed with the ligand; and (c) analyzing the electron-density map to produce the atomic coordinates. For example, the structure of human EphB4 receptor in complex with a polypeptide ligand having SEQ ID NO: 1 is provided herein.  
         [0048]     Structural Topology of the EphB4 Receptor  
         [0049]     The crystal structure of the human EphB4 ligand binding domain (LBD) in complex with the antagonistic TNYL-RAW peptide (SEQ ID NO: 1) was refined to a 1.65 Å resolution. The structure of the EphB4 receptor is similar to the EphB2 receptor (Himanen et al., 1998), consisting of a jellyroll folding topology composed of 13 anti-parallel β-sheets( FIG. 1 ) arranged as a compact β-sandwich, with the concave sheet comprised of strands C, F, F′, L, H, and I, and the convex sheet comprised of strands D, E, A, M, G, K, and J (nomenclature according to Himanen et al. (Himanen et al., 1998)). Loops with a varying number of amino acids link each of these β-sheets. The corresponding loops in EphB2 have been shown to play essential roles in receptor-ligand dimerization (D-E, E-F, G-H, J-K) and tetramerization (H-I). Two conserved disulfide bridges that are strictly conserved across Eph receptor subclasses stabilize the G-H loop and the E-F/L-M loops at the top of the β-sandwich. The structure of the globular domain of EphB4 is similar to the apo, ephrin-B2-and ephrin-A5-bound EphB2 structures determined previously ( FIG. 2 ), with root mean square deviations (RMSD) of 1.05, 1.08, and 0.94 Å over equivalent Cα positions (Himanenet al., 2004; Himanen et al., 1998; Himanen et al., 2001).  
         [0050]     The ephrin-binding domain of human EphB4 (SEQ ID NO: 27) shares 45% sequence identity with that of human EphB2. Like the EphB2 crystals, the crystals of EphB4 in complex with the TNYL-RAW peptide (SEQ ID NO: 1) contain one molecule in the asymmetric unit. Unlike the apo EphB2 structure, however, the D-E and J-K loops are well ordered in EphB4 and form the peptide binding channel. These loops adopt novel conformations compared to the corresponding loops of the previously described EphB2-ephrin complex structures. Most notably, the J-K loop is significantly shifted in order to avoid steric interference with the peptide ( FIG. 2 ). In fact, this loop is displaced by over 20 Å and17 Å from the furthest Cα positions in the structure of EphB2 in complex with ephrin-B2 orephrin-A5, respectively. The D-E loop is also shifted due to the presence of the antagonist peptide, deviating 2.3 Å and 3.2 Å from the structures of EphB2 in complex with ephrin-B2 and ephrin-A5, respectively. Less significant changes occur at adjacent loops involved in dimerization, due to the new position of the J-K loop, including the disulfide-stabilized G-H loop and the C-D loop, which contains a unique two amino acid insert not found in any other Eph receptors. This insert does not appear to play a role in peptide or ephrin binding and, therefore, presumably does not contribute to the ligand selectivity of EphB4.  
         [0051]     EphB4-ephrin-B2 Interaction  
         [0052]     Using the overall topology of the EphB4 binding cleft for comparison, the EphB4-ephrin-B2 interaction was modeled using the EphB2-ephrin-B2 structure as a starting model ( FIG. 3 ). The ephrin-B2 G-H loop forms contacts similar to those described in the structure of the EphB2-ephrin-B2 complex. This high affinity binding interface is highly hydrophobic, and includes residues Phe-120, Pro-122, Leu-124, Trp-125, and Leu-127 of ephrin-B2. The G-H loop of ephrin-B2 is buttressed by the G-H and J-K loops of EphB4, and forms similar main chain hydrogen bonds and numerous van der Waals interactions with EphB4 as previously described in the complex with EphB2 (Himanen et al., 2004; Himanenet al., 2001). In addition, the conserved Cys-61-Cys-184 disulfide bridge of EphB4 is stabilized by Pro-122 from the conserved FSPN segment of the ephrin-B2 G-H loop. As predicted by the Pro-122 positioning in the EphB4 G-H loop, this residue assumes a position similar to that described in the complex with EphB2. The J-K loop of EphB4 shifts towards ephrin-B2 in order to maximize the binding potential between receptor and ligand, as observed in the EphB2-ephrin crystal structures. Indeed, the Eph receptor J-K loop displays remarkable flexibility and is present in a different conformation in EphB2 bound to ephrin-B2or to ephrin-A5. In addition, the J-K loop in the apo structure of EphB2 could not be visualized probably because it is disordered in the absence of a bound ligand (Himanen et al., 2004; Himanen et al., 1998; Himanen et al., 2001).  
         [0053]     A second, lower affinity binding interface between EphB2 and ephrin-B2 has been structurally characterized ( FIG. 3 ). This interface, which has been implicated in tetramerization, is absent in the EphB2-ephrinA5 complex, suggesting that it confers subclass binding specificity (Himanen et al., 2004; Himanen et al., 2001). The interface is framed by the H-I subclass-specificity loop. In EphB4, this loop is similar to the EphB2 H-I loop, with a maximum displacement of 2.5 Å at conserved residue Thr-39 of EphB4. Like the EphB2-ephrin-B2 low affinity interface, the EphB4-ephrin-B2 interface is dominated by hydrophobic interactions and few weak polar contacts between the receptor H-I loop and the A-A′ β strands of the ephrin. Hydrophobic interactions similar to those observed in the EphB2-ephrin-B2 complex can also be modeled between the F-G and K-L loops of EphB4and the C-D loop of ephrin-B2.  
         [0054]     Accordingly, the present invention provides a three-dimensional structure of the EphB4 receptor protein complexed with a ligand, particularly a polypeptide having SEQ ID NO: 1, can be used to derive a model of the three-dimensional structure of another Receptor-Ligand Complex (i.e., a structure to be modeled). As used herein, a “structure” of a protein refers to the components and the manner of arrangement of the components to constitute the protein. As used herein, the term “model” refers to a representation in a tangible medium of the three-dimensional structure of a protein, polypeptide or peptide. For example, a model can be a representation of the three-dimensional structure in an electronic file, on a computer screen, on a piece of paper (i.e., on a two dimensional medium), and/or as a ball-and-stick figure. Physical three-dimensional models are tangible and include, but are not limited to, stick models and space-filling models. The phrase “imaging the model on a computer screen” refers to the ability to express (or represent) and manipulate the model on a computer screen using appropriate computer hardware and software technology known to those skilled in the art. Such technology is available from a variety of sources including, for example, Accelrys, Inc. (San Diego, Calif.). The phrase “providing a picture of the model” refers to the ability to generate a “hard copy” of the model. Hard copies include both motion and still pictures. Computer screen images and pictures of the model can be visualized in a number of formats including space-filling representations, a-carbon traces, ribbon diagrams and electron density maps.  
         [0055]     Suitable target Receptor-Ligand Complex structures to model using a method of the present invention include any EphB receptor protein, polypeptide or peptide that is substantially structurally related to an EphB4 receptor protein complexed with a ligand. In various embodiments, a target Receptor-Ligand Complex structure that is substantially structurally related to an EphB4 receptor protein includes a target Receptor-Ligand Complex structure having an amino acid sequence that is at least about 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to an amino acid sequence of a human EphB4 receptor protein, in particular an amino acid sequence having SEQ ID NO: 27, across the full-length of the EphB4 receptor sequence when using, for example, a sequence alignment program such as BLAST (supra). In various aspects of the present invention, target Receptor-Ligand Complex structures to model include proteins comprising amino acid sequences that are at least about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to amino acid sequence of a truncated EphB4 receptor, EphB4(17-196), having SEQ ID NO: 2 or EphB4 17-198, having SEQ ID NO: 3, when comparing suitable regions of the sequence, such as the amino acid sequence for an ephrin binding site of any one of the amino acid sequences, when using an alignment program such as BLAST (supra) to align the amino acid sequences.  
         [0056]     According to the present invention, a structure can be modeled using techniques generally described by, for example, Sali, Current Opinions in Biotechnology, vol. 6, pp. 437-451, 1995, and algorithms can be implemented in program packages such as Insight II, available from Accelerys (San Diego, Calif.). Use of Insight II HOMOLOGY requires an alignment of an amino acid sequence of a known structure having a known three-dimensional structure with an amino acid sequence of a target structure to be modeled. The alignment can be a pairwise alignment or a multiple sequence alignment including other related sequences (for example, using the method generally described by Rost, Meth. Enzymol., vol. 266, pp. 525-539, 1996) to improve accuracy. Structurally conserved regions can be identified by comparing related structural features, or by examining the degree of sequence homology between the known structure and the target structure. Certain coordinates for the target structure are assigned using known structures from the known structure. Coordinates for other regions of the target structure can be generated from fragments obtained from known structures such as those found in the Protein Data Bank. Conformation of side chains of the target structure can be assigned with reference to what is sterically allowable and using a library of rotamers and their frequency of occurrence (as generally described in Ponder and Richards, J. Mol. Biol., vol. 193, pp. 775-791, 1987). The resulting model of the target structure, can be refined by molecular mechanics to ensure that the model is chemically and conformationally reasonable.  
         [0057]     Accordingly, one embodiment of the present invention is a method to derive a model of the three-dimensional structure of a target Receptor-Ligand Complex structure the method comprising the steps of: (a) providing an amino acid sequence of a Receptor-Ligand Complex and an amino acid sequence of a target ligand-complexed EphB receptor ;(b) identifying structurally conserved regions shared between the Receptor-Ligand Complex amino acid sequence and the target ligand-complexed EphB4 receptor amino acid sequence; (c) determining atomic coordinates for the target ligand-complexed EphB4 receptor by assigning said structurally conserved regions of the target ligand-complexed EphB4 receptor to a three-dimensional structure using a three-dimensional structure of a Receptor-Ligand Complex based on atomic coordinates that substantially conform to the atomic coordinates represented in Table 1, to derive a model of the three-dimensional structure of the target ligand-complexed EphB4 receptor amino acid sequence. A model according to the present invention has been previously described herein. In one aspect, the model comprises a computer model. The method can further comprise the step of electronically simulating the structural assignments to derive a computer model of the three-dimensional structure of the target ligand-complexed EphB4 receptor amino acid sequence.  
         [0058]     Another embodiment of the present invention is a method to derive a computer model of the three-dimensional structure of a target ligand-complexed EphB4 receptor structure for which a crystal has been produced (referred to herein as a “crystallized target structure”). A suitable method to produce such a model includes the method comprising molecular replacement. Methods of molecular replacement are generally known by those of skill in the art and are performed in a software program including, for example, XPLOR available from Accelerys (San Diego, Calif.). In various aspects, a crystallized target ligand-complexed EphB receptor structure useful in a method of molecular replacement according to the present invention has an amino acid sequence that is at least about 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the search structure (e.g., human EphB4), when the two amino acid sequences are compared using an alignment program such as BLAST (supra). A suitable search structure of the present invention includes a Receptor-Ligand Complex having a three-dimensional structure that substantially conforms with the atomic coordinates listed in Table 1.  
         [0059]     Another aspect of the present invention is a method to determine a three-dimensional structure of a target Receptor-Ligand Complex structure, in which the three-dimensional structure of the target Receptor-Ligand Complex structure is not known. Such a method is useful for identifying structures that are related to the three-dimensional structure of a Receptor-Ligand Complex based only on the three-dimensional structure of the target structure. For example, the present method enables identification of structures that do not have high amino acid identity with an EphB4 receptor protein but which share three-dimensional structure similarities of a ligand-complexed EphB4 receptor. In various aspects of the present invention, a method to determine a three-dimensional structure of a target Receptor-Ligand Complex structure comprises: (a) providing an amino acid sequence of a target structure, wherein the three-dimensional structure of the target structure is not known; (b) analyzing the pattern of folding of the amino acid sequence in a three-dimensional conformation by fold recognition; and (c) comparing the pattern of folding of the target structure amino acid sequence with the three-dimensional structure of a Receptor-Ligand Complex to determine the three-dimensional structure of the target structure, wherein the three-dimensional structure of the Receptor-Ligand Complex substantially conforms to the atomic coordinates represented in Table 1. For example, methods of fold recognition can include the methods generally described in Jones, Curr. Opinion Struc. Biol., vol. 7, pp. 377-387, 1997. Such folding can be analyzed based on hydrophobic and/or hydrophilic properties of a target structure.  
         [0060]     One aspect of the present invention includes a three-dimensional computer image of the three-dimensional structure of a Receptor-Ligand Complex. In one aspect, a computer image is created to a structure which substantially conforms with the three-dimensional coordinates listed in Table 1. A computer image of the present invention can be produced using any suitable software program, including, but not limited to, Pymol available from DeLano Scientific, LLC (South San Francisco, Calif.). Suitable computer hardware useful for producing an image of the present invention is known to those of skill in the art.  
         [0061]     Another aspect of the present invention relates to a computer-readable medium encoded with a set of three-dimensional coordinates represented in Table 1, wherein, using a graphical display software program, the three-dimensional coordinates create an electronic file that can be visualized on a computer capable of representing said electronic file as a three-dimensional image. Yet another aspect of the present invention relates to a computer-readable medium encoded with a set of three-dimensional coordinates of a three-dimensional structure which substantially conforms to the three-dimensional coordinates represented in Table 1, wherein, using a graphical display software program, the set of three-dimensional coordinates create an electronic file that can be visualized on a computer capable of representing said electronic file as a three-dimensional image. The present invention also includes a three-dimensional model of the three-dimensional structure of a target structure, such a three-dimensional model being produced by the method comprising: (a) providing an amino acid sequences of an EphB4 receptor comprised by a Receptor-Ligand Complex and an amino acid sequence of a target Receptor-Ligand Complex structure; (b) identifying structurally conserved regions shared between the EphB4 receptor amino acid sequence and the amino acid sequence comprised by the target Receptor-Ligand Complex structure; (c) determining atomic coordinates for the target Receptor-Ligand Complex by assigning the structurally conserved regions of the target Receptor-Ligand Complex to a three-dimensional structure using a three-dimensional structure of the EphB4 receptor comprised by a Receptor-Ligand Complex based on atomic coordinates that substantially conform to the atomic coordinates represented in Table 1 to derive a model of the three-dimensional structure of the target Receptor-Ligand Complex. In one aspect, the model comprises a computer model.  
         [0062]     Any isolated EphB receptor protein can be used with the methods of the present invention. An isolated EphB receptor protein can be isolated from its natural milieu or produced using recombinant DNA technology (e.g., polymerase chain reaction (PCR) amplification, cloning) or chemical synthesis. To produce recombinant EphB receptor protein, a nucleic acid molecule encoding EphB receptor protein (e.g., SEQ ID NO: 28) can be inserted into any vector capable of delivering the nucleic acid molecule into a host cell. A nucleic acid molecule of the present invention can encode any portion of an EphB receptor protein, in various aspects a full-length EphB receptor protein, and in various aspects a soluble or truncated form of EphB4 receptor protein (i.e., a form of EphB4 receptor protein capable of being secreted by a cell that produces such protein). A suitable nucleic acid molecule to include in a recombinant vector, and particularly in a recombinant molecule, includes a nucleic acid molecule encoding a protein having the amino acid sequence represented by SEQ ID NOs: 2 or 3 and SEQ ID NO: 27.  
         [0063]     A recombinant vector can be either RNA or DNA, either prokaryotic or eukaryotic, and typically is a virus or a plasmid. In various aspects, a nucleic acid molecule encoding an EphB4 receptor protein is inserted into a vector comprising an expression vector to form a recombinant molecule. As used herein, an expression vector is a DNA or RNA vector that is capable of transforming a host cell and of affecting expression of a specified nucleic acid molecule. Expression vectors of the present invention include any vectors that function (i.e., direct gene expression) in recombinant cells of the present invention, including in bacterial, fungal, endo parasite, insect, other animal, and plant cells.  
         [0064]     An expression vector can be transformed into any suitable host cell to form a recombinant cell. A suitable host cell includes any cell capable of expressing a nucleic acid molecule inserted into the expression vector. For example, a prokaryotic expression vector can be transformed into a bacterial host cell. One method to isolate EphB4 receptor protein useful for producing ligand-complexed EphB4 receptor crystals includes recovery of recombinant proteins from cell cultures of recombinant cells expressing such EphB4 receptor protein.  
         [0065]     EphB4 receptor proteins of the present invention can be purified using a variety of standard protein purification techniques, such as, but not limited to, affinity chromatography, ion exchange chromatography, filtration, electrophoresis, hydrophobic interaction chromatography, gel filtration chromatography, reverse phase chromatography, chromatofocusing and differential solubilization. In various aspects of the present invention, an EphB4 receptor protein is purified in such a manner that the protein is purified sufficiently for formation of crystals useful for obtaining information related to the three-dimensional structure of a Receptor-Ligand Complex. In some aspects, a composition of EphB4 receptor protein is about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% pure.  
         [0066]     Another embodiment of the present invention includes a composition comprising a Receptor-Ligand Complex in a crystalline form (i.e., Receptor-Ligand Complex crystals). As used herein, the terms “crystalline Receptor-Ligand Complex” and “Receptor-Ligand Complex crystal” both refer to crystallized a Receptor-Ligand Complex and are intended to be used interchangeably. In various aspects of the present invention, a crystalline Receptor-Ligand Complex is produced using the crystal formation method described in the Examples.  
         [0067]     In particular, the present invention includes a composition comprising EphB4 receptor complexed with a ligand in a crystalline form (i.e., ligand-complexed EphB4 crystals). As used herein, the terms “crystalline ligand-complexed EphB4” and “ligand complexed EphB4 crystal” both refer to crystallized EphB4 receptor complexed with a ligand and are intended to be used interchangeably. In various aspects of the present invention, a crystal ligand-complexed EphB4 is produced using the crystal formation method described in the Examples. In some aspects, a composition of the present invention includes ligand-complexed EphB4 molecules arranged in a crystalline manner in a space group P41212 so as to form a unit cell of dimensions a=60.97 Å, b=60.97 Å, and c=151.7 Å. A suitable crystal of the present invention provides X-ray diffraction data for determination of atomic coordinates of the ligand-complexed EphB4 to a resolution of about 1.6 Å, and in some aspects about 1.0 Å, and in other aspects at about 0.8 Å.  
         [0068]     According to an aspect of the present invention, crystalline Receptor-Ligand Complex can be used to determine the ability of a compound of the present invention to bind to an EphB4 receptor in a manner predicted by a structure based drug design method of the present invention. In various aspects of the present invention, a Receptor-Ligand Complex crystal is soaked in a solution containing a chemical compound of the present invention. Binding of the chemical compound to the crystal is then determined by methods standard in the art.  
         [0069]     One aspect of the present invention is a therapeutic composition. A therapeutic composition of the present invention comprises one or more therapeutic compounds. In one aspect, a therapeutic composition is provided that is capable of antagonizing the EphB4 receptor. For example, a therapeutic composition of the present invention can inhibit (i.e., prevent, block) binding of an EphB4 receptor on a cell having anEphB4 receptor (e.g., human cells) to a, e.g., ephrin-B2 or ephrin-B2 analog by interfering with the ligand binding domain of an EphB4 receptor. As used herein, the term “ligand binding domain” refers to the region of a molecule to which another molecule specifically binds.  
         [0070]     Suitable inhibitory compounds of the present invention are compounds that interact directly with an EphB receptor protein, and in various aspects an EphB4 receptor protein or truncated EphB4 receptor protein (e.g., SEQ ID NOs: 2 or 3), thereby inhibiting the binding of an EphB4 receptor ligand, e.g., ephrin-B2, to an EphB4 receptor, by blocking the ligand binding domain of an EphB4 receptor (referred to herein as substrate analogs). An EphB4 receptor substrate analog refers to a compound that interacts with (e.g., binds to, associates with, modifies) the ligand binding domain of an EphB4 receptor. An EphB4 receptor substrate analog can, for example, comprise a chemical compound that mimics a polypeptide having SEQ ID NO: 1 or one of SEQ ID NOs: 4 through 26, or that binds specifically to the ephrin binding globular domain of an EphB4 receptor. Further examples of EphB4 receptor substrates upon which an EphB4 ligand analog can be derived are found in U.S. Patent Application No. 20040180823, incorporated herein by reference in its entirety. In various aspects, an EphB4 receptor substrate analog useful in the present invention has an amino acid sequence that is at least about 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1 or one of SEQ ID NOs: 4 through 26.  
         [0071]     According to the present invention, suitable therapeutic compounds of the present invention include peptides or other organic molecules, and inorganic molecules. Suitable organic molecules include small organic molecules. In various aspects, a therapeutic compound of the present invention is not harmful (e.g., toxic) to an animal when such compound is administered to an animal. Peptides refer to a class of compounds that is small in molecular weight and yields two or more amino acids upon hydrolysis. A polypeptide is comprised of two or more peptides. As used herein, a protein is comprised of one or more polypeptides. Suitable therapeutic compounds to design include peptides composed of “L” and/or “D” amino acids that are configured as normal or retro inversopeptides, peptidomimetic compounds, small organic molecules, or homo- or hetero-polymers thereof, in linear or branched configurations.  
         [0072]     Therapeutic compounds of the present invention can be designed using structure based drug design. Structure based drug design refers to the use of computer simulation to predict a conformation of a peptide, polypeptide, protein, or conformational interaction between a peptide or polypeptide, and a therapeutic compound. In the present teachings, knowledge of the three-dimensional structure of the EphB4 ligand binding domain of an EphB4 receptor provide one of skill in the art the ability to design a therapeutic compound that binds to EphB4 receptors, is stable and results in inhibition of a biological response, such as tumorigenesis. For example, knowledge of the three-dimensional structure of the EphB4 ligand binding domain of an EphB4 receptor provides to a skilled artisan the ability to design a ligand or an analog of a ligand which can function as a substrate or ligand of an EphB4 receptor.  
         [0073]     Suitable structures and models useful for structure-based drug design are disclosed herein. Models of target structures to use in a method of structure-based drug design include models produced by any modeling method disclosed herein, such as, for example, molecular replacement and fold recognition related methods. In some aspects of the present invention, structure based drug design can be applied to a structure of EphB4 in complex with a ligand, particularly a polypeptide having SEQ ID NO: 1, and to a model of a target EphB receptor structure.  
         [0074]     One embodiment of the present invention is a method for designing a drug which interferes with an activity of an EphB4 receptor. In various configurations, the method comprises providing a three-dimensional structure of a Receptor-Ligand Complex comprising the EphB4 receptor and at least one ligand of the receptor; and designing a chemical compound which is predicted to bind to the EphB4 receptor. The designing can comprise using physical models, such as, for example, ball-and-stick representations of atoms and bonds, or on a digital computer equipped with molecular modeling software. In some configurations, these methods can further include synthesizing the chemical compound, and evaluating the chemical compound for ability to interfere with an activity of the EphB4 receptor.  
         [0075]     Suitable three-dimensional structures of a Receptor-Ligand Complex and models to use with the present method are disclosed herein. According to the present invention, designing a compound can include creating a new chemical compound or searching databases of libraries of known compounds (e.g., a compound listed in a computational screening database containing three-dimensional structures of known compounds). Designing can also include simulating chemical compounds having substitute moieties at certain structural features. In some configurations, designing can include selecting a chemical compound based on a known function of the compound. In some configurations designing can comprise computational screening of one or more databases of compounds in which three-dimensional structures of the compounds are known. In these configurations, a candidate compound can be interacted virtually (e.g., docked, aligned, matched, interfaced) with the three-dimensional structure of a Receptor-Ligand Complex by computer equipped with software such as, for example, the AutoDock software package, (The Scripps Research Institute, La Jolla, Calif.) or described by Humblet and Dunbar, Animal Reports in Medicinal Chemistry, vol. 28, pp. 275-283, 1993, M Venuti, ed., Academic Press. Methods for synthesizing candidate chemical compounds are known to those of skill in the art.  
         [0076]     Various other methods of structure-based drug design are disclosed in references such as Maulik et al., 1997, Molecular Biotechnology: Therapeutic Applications and Strategies, Wiley-Liss, Inc., which is incorporated herein by reference in its entirety. Maulik et al. disclose, for example, methods of directed design, in which the user directs the process of creating novel molecules from a fragment library of appropriately selected fragments; random design, in which the user uses a genetic or other algorithm to randomly mutate fragments and their combinations while simultaneously applying a selection criterion to evaluate the fitness of candidate ligands; and a grid-based approach in which the user calculates the interaction energy between three-dimensional structures and small fragment probes, followed by linking together of favorable probe sites.  
         [0077]     In one aspect, a chemical compound of the present invention that binds to the ligand binding domain of a Receptor-Ligand Complex can be a chemical compound having chemical and/or stereochemical complementarity with an EphB receptor, e.g., an EphB4 receptor or ligand such as, for example, a polypeptide having SEQ ID NO: 1. in some configurations, a chemical compound that binds to the ligand binding domain an EphB4 receptor can associate with an affinity of at least about 10-6 M, at least about 10-7 M, or at least about 10-8 M.  
         [0078]     Several sites of an EphB4 receptor can be targeted for structure based drug design. These sites include, in non-limiting example residues which contact ephrin-B2 or a polypeptide having SEQ ID NO: 1, e.g., EphB4 D-E and J-K loops; Leu-48, Cys-61, Leu-95, Ser-99 Leu-100, Pro-101, Thr-147, Lys-149, Ala-155, and Cys-184 of SEQ ID NO: 27. Conversely, the structure based drug design can be based upon the sites of the ligand which bind to the EphB receptor, e.g., Phe-120, Pro-122, Leu-124, Trp-125, and Leu-127 of ephrin-B2; and a ligand comprising a sequence motif NxWxL, wherein x is any amino acid.  
         [0079]     TNYL-RAW Peptide Binding  
         [0080]     The TNYL-RAW peptide (SEQ ID NO: 1) was modeled into the electron density after initial rounds of refinement using unbiased electron density from simulated annealing omit maps and |Fobs|−|Fcalc|, φcalc maps ( FIG. 4 ). The peptide was inserted into the same cleft occupied by ephrin-B2, along the hydrophobic upper convex portion of the EphB4 receptor, which is situated on top of a β-sheet “floor” formed by β-strands D and E. In addition, loops D-E, E-F, G-H and J-K effectively buttress the peptide in the cavity, forming numerous van der Waals interactions and main chain hydrogen bonds that stabilize binding. Although the TNYL-RAW peptide (SEQ ID NO: 1) shares the FSPN sequence motif with the G-H loop of ephrin-B2 (Koolpe et al., 2005), surprisingly it assumes a distinct conformation as compared with the ephrin-B2 G-H loop bound to EphB2 (Himanen et al., 2001) ( FIG. 5 ). The peptide has little secondary structure at the N terminus, but forms a pseudo-helix at its C-terminal end. A glycine-proline motif in the middle of the peptide induces a sharp 90° turn that angles the peptide into the upper edge of the binding cleft adjacent to the EphB4 G-H loop, where the high affinity-conferring RAW sequence binds.  
         [0081]     The N-terminal residue of the peptide, Thr-P1, could not be modeled into the electron density map, and therefore is not depicted in the final model of the complex. The adjacent Asn-P2 is located along the plane of β-strand D of EphB4, in between the D-E and J-K loops, and forms few interactions with the receptor ( FIG. 1 ). The position of Asn-P2 suggests that the N-terminal Thr-P1 may be disordered because it does not bind to EphB4, likely explaining its absence in the electron density map. Tyr-P3 is positioned on top of β-sheet D, forming a pseudo-sandwich between the D-E loop of the EphB4 receptor and the N-terminal end of the peptide. The hydroxyl group of the tyrosine forms a hydrogen bond with the EphB4 main chain oxygen of Ser-39 and stacking interactions with neighboring β-sheet residues ( FIG. 6 ). Similar interactions are observed between Trp-125 of ephrin-B2 and the EphB2 D-E loop. These interactions likely play a key role in ordering this region of the bound ephrin (Himanen et al., 2004; Himanen et al., 2001).  
         [0082]     The G-H loop of ephrin-B2 contains a conserved FSPN sequence, which plays an essential role in receptor binding and is the only sequence within the G-H loop that is also present in the TNYL-RAW peptide (SEQ ID NO: 1). Substantial hydrophobic interactions between this sequence and the G-H loop of the EphB2 receptor essentially lockephrin-B2 into the binding cleft of the receptor (Himanen et al., 2001). In the structure of the peptide in complex with EphB4, the corresponding Phe-P5 of the peptide is completely buried by the J-K loop of the receptor and by residues of the peptide, including lie-P11 and Trp-P15. This residue is situated more than 8 Å away from the equivalent phenylalanine residue in the ephrin-B2 G-H loop, and the N- to C-terminal orientation of the FSPN sequence in the ephrin and the peptide are pointed in opposite directions. Furthermore, unlike the SPN sequence of ephrin-B2 in complex with EphB2, the SPN sequence of the peptide is not buried by the hydrophobic G-H loop of EphB4, but instead is positioned along the solvent exposed surface of the receptor. The side chain of Ser-P6 forms a hydrogen bond with the main chain nitrogen of Asn-P8, which together with the intervening Pro-P7contributes to a sharp turn in the middle of the peptide. This turn positions Ile-P11 to interact with the conserved disulfide bridge in the E-F and L-M loops of EphB4 (Cys-61-Cys-184). Ile-P11 resides in the equivalent position as the conserved Pro-122 in ephrin-B2 (Pro-125 in ephrin-A5), which interacts with the corresponding disulfide bridge (Cys-60-Cys-192) in EphB2. The side chain of Ile-P11 forms a frame similar to the ephrin-B2 Pro-122 CD, CG, and CB positions, thus providing a hydrophobic backbone that stabilizes the position of the functionally important disulfide bridge in EphB4.  
         [0083]     Alignment of a number of the EphB4-binding peptides that were identified by phage display (e.g., SEQ ID NOs: 4 through 26) revealed a conserved glycine-proline motif corresponding to a tryptophan located at the tip of the ephrin-B2 G-H loop. Although praline and tryptophan are not structurally similar, the G-P residues in the peptides were predicted to mimic the turn of the middle of the ephrin G-H loop (Koolpe et al., 2005). Surprisingly, the bend induced by the G-P motif is instead most similar to the turn present at the beginning of the ephrin-B2 G-H loop and formed by residues Phe-117, Gln-118 and Glu-119, which angle the ephrin G-H loop into the hydrophobic cleft of the Eph receptor. The G-P turn in the TNYL-RAW peptide (SEQ ID NO: 1) positions the RAW sequence into the upper edge of the EphB4 binding cleft, where Trp-P15 is effectively stabilized between the J-K and G-H loops of the receptor. Trp-P15 forms a main chain hydrogen bond with Ser-93 and hydrophobic interactions with Leu-88, Leu-93, Pro-94, Lys-142, and Phe-P5. These interactions are similar to those formed by Phe-120 in the ephrin-B2 FSPN motif. Unlike Phe-120 of ephrin-B2, however, Trp-P15 is buried within the hydrophobic binding cleft maximizing its interactions with the receptor. Arg-P13, which is also part of the peptide sequence important for high affinity binding, forms a hydrogen bond with the sidechain of Glu-43 of the receptor, and also aids in structuring the C-terminal end of the peptide by forming a side-chain to main-chain hydrogen bond with the solvent exposed Asn-P8. Together, Arg-P13 and Trp-P15 could disrupt several hydrogen bonds in the high affinity dimerization interface between EphB4 and the ephrin-B2 ligand, consistent with the antagonistic properties of the TNYLRAW peptide (SEQ ID NO: 1). Overall, the network of interactions between EphB4 and the high affinity-conferring RAW sequence is highly stable and similar to the interactions of the conserved FSPN sequence of ephrin-B2. Taken together, these data suggest that the TNYL-RAW peptide (SEQ ID NO: 1) can inhibit ephrin binding to the high affinity dimerization interface of the EphB4 ephrin-binding domain ( FIG. 6 ).  
         [0084]     A second region of the dimerization interface has been characterized adjacent to the high affinity dimerization interface that provides significant structural integrity for complex formation ( FIG. 7 ), with numerous hydrogen bonds formed between receptor and ephrin from backbone-backbone, backbone-sidechain, and sidechain-sidechain contacts (Himanen et al., 2001). Several of these contacts can also be mapped onto a model of the EphB4-ephrin-B2 complex, including interactions between Asp-110 (L) and Thr-38 (R), Leu-101 (L) and Ser-47 (R) and Lys-112 (L) and Ser55 (R). The residues in this second interface of EphB4 would remain accessible to ephrin-B2 in the presence of the bound TNYL-RAW peptide (SEQ ID NO: 1). However, the protruding Arg-P13 and Asn-P8 of the peptide would sterically interfere with the positioning of β-strand G of ephrin-B2. Arg-P13 in particular extends away from the body of the peptide into the space that would be occupied by β-strand G of ephrin-B2. Therefore, the presence of the bound peptide would likely reposition the ephrin such that weak hydrogen bonds would dominate this affinity interface, making the interaction much weaker. In addition, the FSPN residues of the peptide would sterically clash with several residues at the tip of the low affinity EphB4-ephrin-B2 interface, including residues Lys-116, Phe-117, and Gln-118 of the ephrin ligand.  
         [0085]     Thermodynamic Characterization  
         [0086]     The molecular determinants were experimentally verified for the high affinity binding of the peptide predicted based on the crystal structure, a thermodynamic characterization of TNYL-RAW and truncated forms of this peptide using isothermal titration calorimetry (ITC). The binding of TNYL-RAW (SEQ ID NO: 1) to the human EphB4 ephrin-binding domain (amino acids 17-196; SEQ ID NO: 2) at 25° C. yields a Kd of 70 nM and a ΔHo of −14.7 kcal mol-1 (Table 1 B). As an internal control, the interaction between EphB4 (17-196) and the Eph-binding domain of human ephrin-B2 yielded a Kd of 40 nM and a βHo of +3.3 kcal mol-1. This is slightly lower than the affinity reported for the interaction between the entire mouse EphB4 extracellular domain and mouse or human ephrin-B2 (Table 1A). The existence of a third low affinity Eph-ephrin interface located outside the ephrin-binding domain provides for the difference (Smith et al., 2004).  
         [0087]     The structural information suggests that two contact areas between EphB4 and the peptide are particularly critical for their interaction. One involves the N-terminal Tyr-P3 (TNYL) and the other the C-terminal Arg-P13 and Trp-P15 (RAW). The importance of these residues was verified by determining the Kd values for binding of peptides with N- and C-terminal truncations to human EphB4 (17-196) as measured in ITC experiments (Table 1B). Deletion of the N-terminal Thr-P1 and Asn-P2 of the peptide produced negligible changes in Kd (65-80 nM) and ΔHo. However, deletion of Tyr-P3 caused a 40-fold reduction in affinity (Kd=3.5 μM), indicating that the tyrosine is the first residue from the N-terminus of the peptide that is required for high affinity binding. The RAW sequence is predicted to play an essential role in peptide binding due to its extensive interactions with EphB4 residues in the EphB4-peptide complex structure. Truncation of this sequence indeed resulted in very weak binding (Kd&gt;140 μM), in agreement with previous results (Koople et al., 2005), indicating that this region of the peptide provides critical binding determinants. Trp-P15 in particular is highly stabilized by both polar and hydrophobic interactions with the same region of EphB4 that is modeled to interact with the conserved FSPN sequence of ephrin-B2.  
         [0088]     Competition studies measuring the ability of truncated forms of the TNYL-RAW peptide (SEQ ID NO: 1) to antagonize murine ephrin-B2 binding to murine EphB4 are also provided in addition to the ITC results with the human proteins. Thr-P1 and Asn-P2 do not affect the ability of TNYL-RAW to inhibit ephrin-B2 binding to EphB4 (Table 1A). In contrast, Tyr-P3 was required for efficient antagonistic properties. The IC50 for inhibition of ephrin-B2 binding to the TNYL-RAW and YL-RAW (NYLFSPNGPIARAW; SEQ IN NO: 30) peptide is approximately 40 nM and that for L-RAW (YLFSPNGPIARAW; SEQ ID NO: 31) is approximately 15 μM (Table 1A).  
         [0089]     EphB4 is the sole member of the Eph receptor family that interacts preferentially with only one ephrin ligand, ephrin-B2, whereas it is only weakly activated by ephrin-B1 and ephrin-B3, the other two ephrins of the B subclass. EphB2, on the other hand, is activated by multiple ephrins, including one from the A subclass (Himanen et al., 2004). The overall structure of the EphB4 ephrin-binding domain is similar to that previously reported for EphB2 (Himanen et al., 2004; Himanen et al., 1998; Himanen et al., 2001). Furthermore, the overall topology of the high affinity dimerization interface is remarkably similar between the EphB2 and EphB4 structures, considering that only 42% of the residues in the EphB4 binding cleft are identical to the corresponding residues of EphB2 (Koolpe et al., 2005). However, there are important differences that could explain the higher ligands electivity of EphB4.  
         [0090]     Several amino acid residues that make important contacts with the ephrin G-H loop in the high affinity dimerization interface of EphB2 are not conserved in EphB4. For example, Ser-194 of EphB2 is conserved in other EphB receptors but not in EphB4, where an alanine is present at the corresponding position. Therefore, EphB4 cannot form the polar interaction observed between the side chain of Ser-194 of EphB2 and the ephrin-B2 main chain oxygen of Glu-128. Furthermore, all EphB receptors have an aromatic residue at the position corresponding to Tyr-57 of EphB2. In EphB4 this position is occupied by Leu (residue 48), which cannot form a hydrogen bond with the main chain oxygen of Pro-150 of ephrin-B2 or an aromatic-aromatic interaction with Phe-113 of ephrin-B2, as observed for Tyr-57 of EphB2. Rather, Leu-48 forms only weak hydrophobic interactions with ephrin-B2. Leu-95 is present in EphB4 at the corresponding Arg-103 position of EphB2, resulting in the absence of another salt bridge that is present in the dimerization interface of EphB2 with both ephrin-B2 and ephrin-A5 (Himanen et al., 2004; Himanen et al., 2001). The presence of a leucine is unique to EphB4, because an arginine is conserved at this position in all other Eph receptors across subclasses.  
         [0091]     Some of the differences between EphB4 and the other EphB receptors also explain the ability of the TNYL-RAW peptide (SEQ ID NO: 1) to selectively bind only to EphB4. In particular, two non-conserved amino acids of EphB4 make critical contacts with the high affinity-conferring RAW motif in the peptide. Leu-95 of EphB4 forms van der Waals interactions with both Phe-P3 and Trp-P15 of the peptide, aiding in the overall positioning of the peptide. The arginine present in the corresponding position of all other Eph receptors (Arg-103 in EphB2, see above) would result in steric clashes with both Trp-P15 and Phe-P5in the EphB4-TNYL-RAW structure. Furthermore, Thr-147 of EphB4 forms hydrophobic interactions with several residues of the peptide and aids in the overall positioning of Phe-P5from the peptide. The phenylalanine present in the corresponding position of other Eph receptors (Phe-155 in EphB2) would instead result in a steric clash with Phe-P5 of the peptide. The non-conserved Leu-48 of EphB4 also contributes to peptide binding by forming a van der Waals interaction with the tyrosine in the TNYL-RAW peptide (SEQ ID NO: 1).  
         [0092]     Additional differences in the lower affinity tetramer interface of EphB4 and other EphB receptors may further contribute to the selectivity of EphB4 for ephrin-B2. For example, EphB4 lacks several residues involved in interactions that provide stability in the EphB2-ephrin-B2 tetrameric complex. Of particular interest is the absence of the stacking interaction between Phe-128 (EphB2) and Tyr-37 (ephrin-B2), due to the presence of an alanine (Ala-120) at the equivalent position in EphB4. An alanine at this position should result in a substantial loss of stability at the tetramer interface due not only to the absence of the stacking interaction with the ephrin aromatic residue, but also to the absence of interactions with residues Ser-139, Gly-141, and Asn-142 of ephrin-B2. Interestingly, ephrin-B1 contains a serine at the position corresponding to Tyr-37 in ephrin-B2, which is also predicted to destabilize the tetramer interface (Nikolov et al., 2005). In association with the missing aromatic in EphB4 (Phe-128) at the tetramer interface, formation of an EphB4-ephrin-B1 tetramer is highly unfavorable, providing one explanation for the weak interaction between this receptor and ligand. In addition, the presence in EphB4 of Thr-127 instead of Phe-135 of EphB2 results in the absence of the hydrophobic interaction with Glu-134 of ephrin-B2, which is not replaced by other interactions with the ephrin. Despite the weaker contacts at the tetramer interface, we have found that the EphB4 receptor can form a heterotetramer with the ephrin-B2 ligand (data not shown).  
         [0093]     An interesting feature of the Eph receptors is the flexibility of their D-E and J-K loops, which line the high affinity ephrin binding cleft (Himanen et al., 2004; Himanen et al., 2001). These loops are disordered in the apo structure of EphB2, suggesting that a ligand is required to promote their stability. EphB2 can accommodate ephrins of both the A and B subclasses by shifting the position of the J-K loop by more than 10 Å. Furthermore in the structures of EphB2 in complex with ephrin-B2 or ephrin-A5, the J-K loop is positioned adjacent to the D-E loop, forming weak hydrophobic interactions that likely aid in the ordering of these loops. In the presence of bound TNYL-RAW peptide (SEQ ID NO: 1), the J-K loop of EphB4 is shifted by as much as 20 Å compared to the J-K loop of apo EphB2, suggesting that this region can undergo marked movements in order to accommodate a ligand. Supporting the idea that a ligand stabilizes the conformation of the Eph receptor ephrin-binding domain, EphB4 readily formed well-diffracting crystals in the presence of the TNYL-RAW peptide (SEQ ID NO: 1), whereas the apo form of the receptor did not crystallize.  
         [0094]     The topology of the high affinity binding cleft in the complex with the TNYL-RAW peptide (SEQ ID NO: 1) can also accommodate the modeled ephrin-B2 G-H loop. Thus, despite marked differences in the primary and secondary structures of the peptide and the ephrin G-H loop, the two ligands both similarly fit in the EphB4 binding cleft. It will be interesting to model the many other EphB4-specific peptides that were identified by phage display (Koolpe et al., 2005) in order to gain information on the range of residues that can be accommodated at each position, as well as additional ligand structures that can be accommodated by the ephrin binding cleft of EphB4. Two of the peptides identified by phage display are unrelated in sequence to TNYL-RAW, but share with ephrin-B2 the sequence motif NxWxL (where x is any amino acid). Several other peptides with different sequences also appear to target the ephrin binding cleft of EphB4.  
         [0095]     Although the precise roles of Eph receptor-ephrin bi-directional signaling in angiogenesis are incompletely understood, it is clear that the EphB4 receptor has a critical function because it is required for normal vascular development in the embryo (Gerety et al., 1999). The ability to modulate EphB4-ephrin-B2 binding will be critical to dissect the roles of these molecules in tumorigenesis and angiogenesis. Furthermore, antagonizing EphB4-ephrin-B2 binding will undoubtedly be of high therapeutic value. High affinity selective antagonists of this interaction could be used to inhibit tumor angiogenesis (Martiny-Baron et al., 2004; Noren et al., 2004) and pathological forms of angiogenesis, including inflammatory angiogenesis and the excessive retinal neovascularization that plays an important role in retinopathy of prematurity, macular degeneration, and diabetic retinopathy (Yuan et al., 2004; Zamora et al., 2005). The high resolution structure of the ephrin-binding domain of EphB4 in complex with a highly selective and potent peptide antagonist, which we report here, will allow the design of novel compounds that recapitulate the critical contacts of the peptide with EphB4 while having good pharmacokinetic properties.  
         [0096]     Drug design strategies as specifically described above with regard to residues and regions of the ligand-complexed EphB4 receptor crystal can be similarly applied to the other EphB structures, including other EphB receptors disclosed herein. One of ordinary skill in the art, using the art recognized modeling programs and drug design methods, many of which are described herein, can modify the EphB4 design strategy according to differences in amino acid sequence. For example, this strategy can be used to design compounds which regulate a function of the EphB4 receptor in EphB receptors. In addition, one of skill in the art can use lead compound structures derived from one Eph-B receptor, such as the EphB4 receptor, and take into account differences in amino acid residues in other EphB4 receptors.  
         [0097]     In the present method of structure-based drug design, it is not necessary to align a candidate chemical compound (i.e., a chemical compound being analyzed in, for example, a computational screening method of the present invention) to each residue in a target site. Suitable candidate chemical compounds can align to a subset of residues described for a target site. In some configurations of the present invention, a candidate chemical compound can comprise a conformation that promotes the formation of covalent or non-covalent crosslinking between the target site and the candidate chemical compound. In certain aspects, a candidate chemical compound can bind to a surface adjacent to a target site to provide an additional site of interaction in a complex. For example, when designing an antagonist (i.e., a chemical compound that inhibits the binding of a ligand to an EphB4 receptor by blocking a ligand binding domain or interface), the antagonist can be designed to bind with sufficient affinity to the binding site or to substantially prohibit a ligand from binding to a target area. It will be appreciated by one of skill in the art that it is not necessary that the complementarity between a candidate chemical compound and a target site extend overall residues specified here.  
         [0098]     In various aspects, the design of a chemical compound possessing stereochemical complementarity can be accomplished by means of techniques that optimize, chemically or geometrically, the “fit” between a chemical compound and a target site. Such techniques are disclosed by, for example, Sheridan and Venkataraghavan, Acc. Chem Res., vol. 20, p. 322, 1987: Goodford, J. Med. Chem., vol. 27, p. 557, 1984; Beddell, Chem. Soc. Reviews, vol. 279, 1985; Hol, Angew. Chem., vol. 25, p. 767, 1986; and Verlinde and Hol, Structure, vol. 2, p. 577, 1994, each of which are incorporated by this reference herein in their entirety.  
         [0099]     Some embodiments of the present invention for structure-based drug design comprise methods of identifying a chemical compound that complements the shape of an EphB4 receptor, particularly one that substantially conforms to the atomic coordinates of Table 1, or a structure that is related to an EphB4 receptor. Such method is referred to herein as a “geometric approach”. In a geometric approach of the present invention, the number of internal degrees of freedom (and the corresponding local minima in the molecular conformation space) can be reduced by considering only the geometric (hard-sphere) interactions of two rigid bodies, where one body (the active site) contains “pockets” or “grooves” that form binding sites for the second body (the complementing molecule, such as a ligand).  
         [0100]     The geometric approach is described by Kuntz et al., J. Mol. Biol., vol. 161, p. 269, 1982, which is incorporated by this reference herein in its entirety. The algorithm for chemical compound design can be implemented using a software program such as AutoDock, available from The Scripps Research Institute (La Jolla, Calif.). One or more extant databases of crystallographic data (e.g., the Cambridge Structural Database System maintained by University Chemical Laboratory, Cambridge University, Lensfield Road, Cambridge CB2 IEW, U.K. or the Protein Data Bank maintained by Rutgers University) can then be searched for chemical compounds that approximate the shape thus defined. Chemical compounds identified by the geometric approach can be modified to satisfy criteria associated with chemical complementarity, such as hydrogen bonding, ionic interactions or Van der Waals interactions.  
         [0101]     In some embodiments, a therapeutic composition of the present invention can comprise one or more therapeutic compounds. A therapeutic composition can further comprise other compounds capable of inhibiting an EphB4 receptor. A therapeutic composition of the present invention can be used to treat disease in an animal such as, for example, a human in need of treatment by administering such composition to the human. Non-limiting examples of animals to treat include mammals, reptiles and birds, companion animals, food animals, zoo animals and other economically relevant animals (e.g., racehorses and animals valued for their coats, such as minks). Additional animals to treat include dogs, cats, horses, cattle, sheep, swine, chickens, turkeys. Accordingly, in some aspects, animals to treat include humans.  
         [0102]     A therapeutic composition of the present invention can also include an excipient, an adjuvant and/or carrier. Suitable excipients include compounds that the animal to be treated can tolerate. Examples of such excipients include water, saline, Ringer&#39;s solution, dextrose solution, Hank&#39;s solution, and other aqueous physiologically balanced salt solutions. Nonaqueous vehicles, such as fixed oils, sesame oil, ethyl oleate, or triglycerides may also be used. Other useful formulations include suspensions containing viscosity enhancing agents, such as sodium carboxymethylcellulose, sorbitol, or dextran. Excipients can also contain minor amounts of additives, such as substances that enhance isotonicity and chemical stability. Examples of buffers include phosphate buffer, bicarbonate buffer and Tris buffer, while examples of preservatives include thimerosal, o-cresol, formalin and benzyl alcohol. Standard formulations can either be liquid injectables or solids which can be taken up in a suitable liquid as a suspension or solution for injection. Thus, in a non-liquid formulation, the excipient can comprise dextrose, human serum albumin, preservatives, etc., to which sterile water or saline can be added prior to administration.  
         [0103]     In one embodiment of the present invention, a therapeutic composition can include a carrier. Carriers include compounds that increase the half-life of a therapeutic composition in the treated animal. Suitable carriers include, but are not limited to, polymeric controlled release vehicles, biodegradable implants, liposomes, bacteria, viruses, other cells, oils, esters, and glycols.  
         [0104]     Acceptable protocols to administer therapeutic compositions of the present invention in an effective manner include individual dose size, number of doses, frequency of dose administration, and mode of administration. Determination of such protocols can be accomplished by those skilled in the art. Modes of administration can include, but are not limited to, subcutaneous, intradermal, intravenous, intranasal, oral, transdermal, intraocular and intramuscular routes.  
         [0105]     In yet another embodiment, a method is provided for assaying EphB4 receptor binding to a compound. The method can comprise providing an EphB4 receptor bound with a polypeptide, e.g., having SEQ ID NO: 1, followed by contacting the ligand bound EphB4 receptor with a compound. The release can be detected indicating that the compound binds to the EphB4 receptor. The EphB4 receptor can be a polypeptide having SEQ ID NO: 2 or 3. In certain embodiments, the EphB4 receptor can consist essentially of EphB4 D-E and J-K loops. The EphB4 receptor can also consist essentially of Leu-48, Cys-61, Leu-95, Ser-99 Leu-100, Pro-101, Thr-147, Lys-149, Ala-155, and Cys-184 of EphB4 (SEQ ID NO: 27). The EphB4 receptor can be a human EphB4 receptor.  
         [0106]     In another embodiment, a method is provided for crystallizing an EphB4 receptor which includes providing an EphB4 receptor in contact with a first polypeptide having SEQ ID NO: 1, followed by contacting the EphB4 receptor in contact with the first polypeptide with a second polypeptide having at least 50% sequence identity to SEQ ID NO:1, but not identical to SEQ ID NO: 1, wherein the EphB4 receptor in contact with the first and second polypeptides forms an EphB4 receptor crystal. The second polypeptide can comprise at least 75% sequence identity to SEQ ID NO: 1, and in certain embodiments, at least 90% sequence identity to SEQ ID NO: 1.  
         [0107]     In yet another embodiment, a method is provided for crystallizing an EphB4 receptor which includes providing an EphB4 receptor in contact with a polypeptide having SEQ ID NO: 1, followed by contacting the EphB4 receptor in contact with the polypeptide with a therapeutic compound as provided above, wherein the EphB4 receptor in contact with the polypeptide and the compound forms an EphB4 receptor crystal.  
         [0108]     In another embodiment, a composition is provided comprising EphB4 receptor, a ligand, and a therapeutic compound as provided above. The EphB4 receptor can be a polypeptide having SEQ ID NO: 2 or 3. The EphB4 receptor can also consist essentially of EphB4 D-E and J-K loops or Leu-48, Cys-61, Leu-95, Ser-99 Leu-100, Pro-101, Thr-147, Lys-149, Ala-155, and Cys-184 of SEQ ID NO: 27. In certain embodiments, the EphB4 receptor can be a human EphB4 receptor.  
         [0109]     In certain embodiments, the ligand can be a polypeptide having SEQ ID NO: 1 or polypeptides having SEQ ID NO: 4 through SEQ ID NO: 26. In other embodiments, the ligand can be a polypeptide having at least 50%, 75% or 90% sequence identity to a polypeptide selected from the group consisting of polypeptides having SEQ ID NO: 1 and SEQ ID NO: 4 through SEQ ID NO: 26.  
                                                                       TABLE 1                       Protein Databank Coordinates       of Eph4 Receptor-Complexed TNYL-RAW                                HEADER ----- XX-XXX-XX xxxx       COMPND ---       REMARK 3       REMARK 3 REFINEMENT.       REMARK 3 PROGRAM: REFMAC 5.2.0005       REMARK 3 AUTHORS: MURSHUDOV, VAGIN, DODSON       REMARK 3       REMARK 3 REFINEMENT TARGET: MAXIMUM LIKELIHOOD       REMARK 3       REMARK 3 DATA USED IN REFINEMENT.       REMARK 3 RESOLUTION RANGE HIGH (ANGSTROMS): 1.65       REMARK 3 RESOLUTION RANGE LOW (ANGSTROMS): 56.61       REMARK 3 DATA CUTOFF (SIGMA(F)): NONE       REMARK 3 COMPLETENESS FOR RANGE (%): 99.92       REMARK 3 NUMBER OF REFLECTIONS: 31786       REMARK 3       REMARK 3 FIT TO DATA USED IN REFINEMENT.       REMARK 3 CROSS-VALIDATION METHOD: THROUGHOUT       REMARK 3 FREE R VALUE TEST SET SELECTION: RANDOM       REMARK 3 R VALUE (WORKING + TEST SET): 0.16824       REMARK 3 R VALUE (WORKING SET): 0.16622       REMARK 3 FREE R VALUE: 0.18595       REMARK 3 FREE R VALUE TEST SET SIZE (%): 10.0       REMARK 3 FREE R VALUE TEST SET COUNT: 3533       REMARK 3       REMARK 3 FIT IN THE HIGHEST RESOLUTION BIN.       REMARK 3 TOTAL NUMBER OF BINS USED: 20       REMARK 3 BIN RESOLUTION RANGE HIGH: 1.650       REMARK 3 BIN RESOLUTION RANGE LOW: 1.693       REMARK 3 REFLECTION IN BIN (WORKING SET): 2286       REMARK 3 BIN COMPLETENESS (WORKING + TEST) (%): 98.94       REMARK 3 BIN R VALUE (WORKING SET): 0.156       REMARK 3 BIN FREE R VALUE SET COUNT: 243       REMARK 3 BIN FREE R VALUE: 0.195       REMARK 3       REMARK 3 NUMBER OF NON-HYDROGEN ATOMS USED IN       REFINEMENT.       REMARK 3 ALL ATOMS: 1843       REMARK 3       REMARK 3 B VALUES.       REMARK 3 FROM WILSON PLOT (A**2): NULL       REMARK 3 MEAN B VALUE (OVERALL, A**2): 11.757       REMARK 3 OVERALL ANISOTROPIC B VALUE.       REMARK 3 B11 (A**2): 0.21       REMARK 3 B22 (A**2): 0.21       REMARK 3 B33 (A**2): −0.42       REMARK 3 B12 (A**2): 0.00       REMARK 3 B13 (A**2): 0.00       REMARK 3 B23 (A**2): 0.00       REMARK 3       REMARK 3 ESTIMATED OVERALL COORDINATE ERROR.       REMARK 3 ESU BASED ON R VALUE (A): 0.078       REMARK 3 ESU BASED ON FREE R VALUE (A): 0.077       REMARK 3 ESU BASED ON MAXIMUM LIKELIHOOD (A): 0.041       REMARK 3 ESU FOR B VALUES BASED ON MAXIMUM LIKELIHOOD       (A**2): 2.276       REMARK 3       REMARK 3 CORRELATION COEFFICIENTS.       REMARK 3 CORRELATION COEFFICIENTS FO-FC: 0.958       REMARK 3 CORRELATION COEFFICIENTS FO-FC FREE: 0.952       REMARK 3       REMARK 3 RMS DEVIATIONS FROM IDEAL VALUES COUNT RMS       WEIGHT       REMARK 3 BOND LENGTHS REFINED ATOMS (A): 1667; 0.017;       0.021       REMARK 3 BOND LENGTHS OTHERS (A): 1438; 0.002; 0.020       REMARK 3 BOND ANGLES REFINED ATOMS (DEGREES): 2282;       1.801; 1.959       REMARK 3 BOND ANGLES OTHERS (DEGREES): 3327; 0.894;       3.000       REMARK 3 TORSION ANGLES, PERIOD 1 (DEGREES): 201;       7.448; 5.000       REMARK 3 TORSION ANGLES, PERIOD 2 (DEGREES): 72;       31.759; 23.056       REMARK 3 TORSION ANGLES, PERIOD 3 (DEGREES): 242;       10.377; 15.000       REMARK 3 TORSION ANGLES, PERIOD 4 (DEGREES): 9; 16.603;       15.000       REMARK 3 CHIRAL-CENTER RESTRAINTS (A**3): 246; 0.117;       0.200       REMARK 3 GENERAL PLANES REFINED ATOMS (A): 1823;       0.010; 0.020       REMARK 3 GENERAL PLANES OTHERS (A): 348; 0.001;       0.020       REMARK 3 NON-BONDED CONTACTS REFINED ATOMS (A): 244;       0.277; 0.200       REMARK 3 NON-BONDED CONTACTS OTHERS (A): 1343; 0.212;       0.200       REMARK 3 NON-BONDED TORSION REFINED ATOMS (A): 744;       0.182; 0.200       REMARK 3 NON-BONDED TORSION OTHERS (A): 881; 0.88;       0.200       REMARK 3 H-BOND (X . . . Y) REFINED ATOMS (A): 144; 0.156;       0.200       REMARK 3 H-BOND (X . . . Y) OTHERS (A): 1; 0.026; 0.200       REMARK 3 SYMMETRY VDW REFINED ATOMS (A): 23; 0.705;       0.200       REMARK 3 SYMMETRY VDW OTHERS (A): 86; 0.356; 0.200       REMARK 3 SYMMETRY H-BOND REFINED ATOMS (A): 16; 0.630;       0.200       REMARK 3       REMARK 3 ISOTROPIC THERMAL FACTOR RESTRAINTS. COUNT       RMS WEIGHT       REMARK 3 MAIN-CHAIN BOND REFINED ATOMS (A**2): 1080;       1.274; 1.500       REMARK 3 MAIN-CHAIN BOND OTHER ATOMS (A**2): 407;       0.336; 1.500       REMARK 3 MAIN-CHAIN ANGLE REFINED ATOMS (A**2): 1609;       1.704; 2.000       REMARK 3 SIDE-CHAIN BOND REFINED ATOMS (A**2): 750;       2.842; 3.000       REMARK 3 SIDE-CHAIN ANGLE REFINED ATOMS (A**2): 672;       4.040; 4.500;       REMARK 3       REMARK 3 NCS RESTRAINTS STATISTICS       REMARK 3 NUMBER OF NCS GROUPS: NULL       REMARK 3       REMARK 3       REMARK 3 TLS DETAILS       REMARK 3 NUMBER OF TLS GROUPS: 2       REMARK 3 ATOM RECORD CONTAINS RESIDUAL B FACTORS ONLY       REMARK 3       REMARK 3 TLS GROUP: 1       REMARK 3 NUMBER OF COMPONENTS GROUP: 1       REMARK 3 COMPONENTS C SSSEQI TO C SSSEQI       REMARK 3 RESIDUE RANGE: A 12 A 196       REMARK 3 ORIGIN FOR THE GROUP (A): 24.6062 11.8279       51.1982       REMARK 3 T TENSOR       REMARK 3 T11: −0.0492 T22: −0.0141       REMARK 3 T33: −0.0334 T12: −0.0003       REMARK 3 T13: 0.0030 T23: −0.0021       REMARK 3 L TENSOR       REMARK 3 L11: 1.2428 L22: 0.2699       REMARK 3 L33: 0.4593 L12: −0.0754       REMARK 3 L13: −0.3122 L23: 0.0783       REMARK 3 S TENSOR       REMARK 3 S11: 0.0019 S12: 0.0337 S13: −0.0331       REMARK 3 S21: −0.0179 S22: −0.0002 S23: −0.0058       REMARK 3 S31: −0.0101 S32: −0.325 S33: −0.0018       REMARK 3       REMARK 3 TLS GROUP: 2       REMARK 3 NUMBER OF COMPONENTS GROUP: 1       REMARK 3 COMPONENTS C SSSEQI TO C SSSEQI       REMARK 3 RESIDUE RANGE: P 251 P 264       REMARK 3 ORIGIN FOR THE GROUP (A): 31.4082 0.9166       39.8199       REMARK 3 T TENSOR       REMARK 3 T11: −0.439 T22: −0.0267       REMARK 3 T33: −0.0328 T12: 0.0096       REMARK 3 T13: 0.0511 T23: −0.0513       REMARK 3 L TENSOR       REMARK 3 L11: 5.1441 L22: 2.1674       REMARK 3 L33: 7.0541 L12: 1.1502       REMARK 3 L13: 3.4336 L23: −0.5897       REMARK 3 S TENSOR       REMARK 3 S11: −0.1929 S12: 0.1435 S13: −0.2481       REMARK 3 S21: −0.1624 S22: 0.0877 S23: −0.1382       REMARK 3 S31: 0.2811 S32: 0.1920 S33: 0.1053       REMARK 3       REMARK 3       REMARK 3 BULK SOLVENT MODELLING.       REMARK 3 METHOD USED: MASK       REMARK 3 PARAMETERS FOR MASK CALCUALTION       REMARK 3 VDW PROBE RADIUS: 1.20       REMARK 3 ION PROBE RADIUS: 0.80       REMARK 3 SHRINKAGE RADIUS: 0.80       REMARK 3       REMARK 3 OTHER REFINEMENT REMARKS:       REMARK 3 HYDROGENS HAVE BEEN ADDED IN THE RIDING       POSITIONS       REMARK 3       SSBOND 1 CYS A 61 CYS A 184       SSBOND 2 CYS A 97 CYS A 107       CISPEP 1 PHE A 35 PRO A 36 0.00       CISPEP 2 THR A 127 PRO A 128 0.00       CISPEP 3 ASN A 133 PRO A 134 0.00       CISPEP 4 GLY A 167 PRO A 168 0.00       CRYST1 60.972 60.972 151.681 90.00 90.00 90.00 P 41 21       2       SCALE1 0.016401 0.000000 0.000000 0.00000       SCALE2 0.000000 0.016401 0.000000 0.00000       SCALE3 0.000000 0.000000 0.006593 0.00000            ATOM   1   N   HIS   A   12   33.704   21.776   75.467   1.00   23.03   N       ATOM   2   CA   HIS   A   12   34.487   22.989   75.312   1.00   20.91   C       ATOM   4   CB   HIS   A   12   33.719   24.090   74.745   1.00   20.12   C       ATOM   7   CG   HIS   A   12   34.117   24.583   73.396   1.00   2.00   C       ATOM   8   ND1   HIS   A   12   33.142   24.401   72.432   1.00   18.31   N       ATOM   10   CE1   HIS   A   12   33.487   25.097   71.361   1.00   22.05   C       ATOM   12   NE2   HIS   A   12   34.473   25.876   71.733   1.00   17.59   N       ATOM   14   CD2   HIS   A   12   34.710   25.639   73.059   1.00   2.00   C       ATOM   16   C   HIS   A   12   34.821   23.565   76.638   1.00   23.03   C       ATOM   17   O   HIS   A   12   35.059   24.763   76.648   1.00   26.11   O       ATOM   21   N   HIS   A   13   34.796   22.824   77.760   1.00   24.22   N       ATOM   22   CA   HIS   A   13   35.792   23.137   78.752   1.00   21.79   C       ATOM   24   CB   HIS   A   13   35.635   22.485   80.143   1.00   24.26   C       ATOM   27   CG   HIS   A   13   36.377   21.203   80.304   1.00   27.78   C       ATOM   28   ND1   HIS   A   13   35.792   19.975   80.068   1.00   33.44   N       ATOM   30   CE1   HIS   A   13   36.686   19.023   80.270   1.00   32.20   C       ATOM   32   NE2   HIS   A   13   37.833   19.593   80.595   1.00   31.56   N       ATOM   34   CD2   HIS   A   13   37.666   20.956   80.618   1.00   28.51   C       ATOM   36   C   HIS   A   13   37.116   22.806   78.029   1.00   19.23   C       ATOM   37   O   HIS   A   13   38.060   23.526   78.235   1.00   18.18   O       ATOM   39   N   HIS   A   14   37.153   21.811   77.114   1.00   16.79   N       ATOM   40   CA   HIS   A   14   38.201   21.799   76.068   1.00   16.44   C       ATOM   42   CB   HIS   A   14   39.054   20.546   76.115   1.00   16.82   C       ATOM   45   CG   HIS   A   14   39.769   20.380   77.409   1.00   18.04   C       ATOM   46   ND1   HIS   A   14   39.709   19.220   78.150   1.00   22.52   N       ATOM   48   CE1   HIS   A   14   40.403   19.384   79.261   1.00   20.48   C       ATOM   50   NE2   HIS   A   14   40.900   20.609   79.272   1.00   22.11   N       ATOM   52   CD2   HIS   A   14   40.530   21.245   78.113   1.00   19.51   C       ATOM   54   C   HIS   A   14   37.569   21.900   74.708   1.00   13.95   C       ATOM   55   O   HIS   A   14   36.698   21.131   74.396   1.00   13.43   O       ATOM   57   N   HIS   A   15   38.008   22.870   73.924   1.00   11.83   N       ATOM   58   CA   HIS   A   15   37.403   23.182   72.623   1.00   11.43   C       ATOM   60   CB   HIS   A   15   37.811   24.582   72.208   1.00   12.51   C       ATOM   63   CG   HIS   A   15   37.613   25.585   73.298   1.00   15.38   C       ATOM   64   ND1   HIS   A   15   36.373   26.065   73.622   1.00   18.20   N       ATOM   66   CE1   HIS   A   15   36.475   26.923   74.627   1.00   15.56   C       ATOM   68   NE2   HIS   A   15   37.744   26.993   74.977   1.00   16.84   N       ATOM   70   CD2   HIS   A   15   38.471   26.148   74.173   1.00   14.49   C       ATOM   72   C   HIS   A   15   37.823   22.178   71.572   1.00   10.00   C       ATOM   73   O   HIS   A   15   39.029   21.913   71.367   1.00   9.89   O       ATOM   75   N   HIS   A   16   36.829   21.605   70.889   1.00   9.16   N       ATOM   76   CA   HIS   A   16   37.126   20.594   69.895   1.00   8.66   C       ATOM   78   CB   HIS   A   16   37.485   19.278   70.572   1.00   9.36   C       ATOM   81   CG   HIS   A   16   36.378   18.666   71.384   1.00   12.06   C       ATOM   82   ND1   HIS   A   16   36.052   19.115   72.645   1.00   13.77   N       ATOM   84   CE1   HIS   A   16   35.077   18.366   73.134   1.00   16.21   C       ATOM   86   NE2   HIS   A   16   34.785   17.427   72.245   1.00   14.78   N       ATOM   88   CD2   HIS   A   16   35.606   17.579   71.155   1.00   13.75   C       ATOM   90   C   HIS   A   16   35.957   20.379   68.944   1.00   8.83   C       ATOM   91   O   HIS   A   16   34.834   20.813   69.251   1.00   9.76   O       ATOM   93   N   GLU   A   17   36.189   19.627   67.866   1.00   7.24   N       ATOM   94   CA   GLU   A   17   35.066   19.171   67.022   1.00   7.03   C       ATOM   96   CB   GLU   A   17   35.446   19.014   65.549   1.00   7.82   C       ATOM   99   CG   GLU   A   17   35.649   20.369   64.832   1.00   6.61   C       ATOM   102   CD   GLU   A   17   36.201   20.232   63.446   1.00   8.29   C       ATOM   103   OE1   GLU   A   17   36.658   19.131   63.080   1.00   8.96   O       ATOM   104   OE2   GLU   A   17   36.147   21.259   62.691   1.00   8.78   O       ATOM   105   C   GLU   A   17   34.638   17.804   67.554   1.00   7.32   C       ATOM   106   O   GLU   A   17   35.474   16.991   67.936   1.00   8.43   O       ATOM   108   N   GLU   A   18   33.330   17.584   67.549   1.00   7.30   N       ATOM   109   CA   GLU   A   18   32.706   16.372   68.110   1.00   9.43   C       ATOM   111   CB   GLU   A   18   31.807   16.800   69.239   1.00   11.29   C       ATOM   114   CG   GLU   A   18   31.129   15.663   69.960   1.00   13.90   C       ATOM   117   CD   GLU   A   18   32.079   14.901   70.885   1.00   22.21   C       ATOM   118   OE1   GLU   A   18   33.301   15.167   70.928   1.00   22.48   O       ATOM   119   OE2   GLU   A   18   31.574   13.976   71.533   1.00   24.63   O       ATOM   120   C   GLU   A   18   31.873   15.714   66.996   1.00   8.52   C       ATOM   121   O   GLU   A   18   31.031   16.361   66.335   1.00   7.95   O       ATOM   123   N   THR   A   19   32.122   14.426   66.790   1.00   7.26   N       ATOM   124   CA   THR   A   19   31.423   13.651   65.774   1.00   8.12   C       ATOM   126   CB   THR   A   19   32.216   12.399   65.428   1.00   7.71   C       ATOM   128   OG1   THR   A   19   33.491   12.739   64.803   1.00   8.16   O       ATOM   130   CG2   THR   A   19   31.450   11.491   64.534   1.00   7.98   C       ATOM   134   C   THR   A   19   29.990   13.249   66.195   1.00   6.76   C       ATOM   135   O   THR   A   19   29.800   12.787   67.352   1.00   8.39   O       ATOM   137   N   LEU   A   20   29.037   13.430   65.273   1.00   7.50   N       ATOM   138   CA   LEU   A   20   27.680   12.910   65.412   1.00   8.69   C       ATOM   140   CB   LEU   A   20   26.663   13.989   65.076   1.00   7.93   C       ATOM   143   CG   LEU   A   20   26.630   15.185   66.010   1.00   8.84   C       ATOM   145   CD1   LEU   A   20   25.765   16.318   65.438   1.00   11.10   C       ATOM   149   CD2   LEU   A   20   26.188   14.811   67.481   1.00   9.30   C       ATOM   153   C   LEU   A   20   27.444   11.629   64.566   1.00   9.13   C       ATOM   154   O   LEU   A   20   26.607   10.792   64.953   1.00   10.80   O       ATOM   156   N   LEU   A   21   28.130   11.502   63.445   1.00   8.78   N       ATOM   157   CA   LEU   A   21   28.000   10.372   62.568   1.00   8.95   C       ATOM   159   CB   LEU   A   21   26.719   10.483   61.749   1.00   8.65   C       ATOM   162   CG   LEU   A   21   26.479   9.488   60.622   1.00   11.72   C       ATOM   164   CD1   LEU   A   21   26.560   8.089   61.045   1.00   18.08   C       ATOM   168   CD2   LEU   A   21   25.080   9.799   60.008   1.00   14.08   C       ATOM   172   C   LEU   A   21   29.220   10.319   61.680   1.00   8.86   C       ATOM   173   O   LEU   A   21   29.599   11.317   61.146   1.00   9.99   O       ATOM   175   N   ASN   A   22   29.816   9.139   61.512   1.00   8.68   N       ATOM   176   CA   ASN   A   22   30.886   8.943   60.530   1.00   7.18   C       ATOM   178   CB   ASN   A   22   32.262   9.048   61.208   1.00   7.76   C       ATOM   181   CG   ASN   A   22   33.411   8.909   60.207   1.00   7.95   C       ATOM   182   OD1   ASN   A   22   33.209   8.470   59.053   1.00   9.79   O       ATOM   183   ND2   ASN   A   22   34.620   9.287   60.638   1.00   11.49   N       ATOM   186   C   ASN   A   22   30.694   7.591   59.869   1.00   8.44   C       ATOM   187   O   ASN   A   22   30.911   6.555   60.494   1.00   8.66   O       ATOM   189   N   THR   A   23   30.196   7.619   58.647   1.00   8.29   N       ATOM   190   CA   THR   A   23   29.883   6.375   57.972   1.00   8.29   C       ATOM   192   CB   THR   A   23   29.277   6.589   56.556   1.00   9.39   C       ATOM   194   OG1   THR   A   23   30.222   7.277   55.734   1.00   9.28   O       ATOM   196   CG2   THR   A   23   27.976   7.304   56.639   1.00   9.26   C       ATOM   200   C   THR   A   23   31.078   5.392   57.853   1.00   8.69   C       ATOM   201   O   THR   A   23   30.879   4.188   57.814   1.00   9.41   O       ATOM   203   N   LYS   A   24   32.300   5.912   57.767   1.00   8.61   N       ATOM   204   CA   LYS   A   24   33.504   5.081   57.613   1.00   9.10   C       ATOM   206   CB   LYS   A   24   34.728   5.936   57.267   1.00   8.84   C       ATOM   209   CG   LYS   A   24   34.635   6.631   55.911   1.00   10.31   C       ATOM   212   CD   LYS   A   24   35.793   7.539   55.642   1.00   12.72   C       ATOM   215   CE   LYS   A   24   35.586   8.923   56.230   1.00   19.96   C       ATOM   218   NZ   LYS   A   24   36.870   9.639   56.390   1.00   21.45   N       ATOM   222   C   LYS   A   24   33.767   4.202   58.849   1.00   9.30   C       ATOM   223   O   LYS   A   24   34.583   3.279   58.791   1.00   10.78   O       ATOM   225   N   LEU   A   25   33.118   4.548   59.973   1.00   7.98   N       ATOM   226   CA   LEU   A   25   33.261   3.773   61.196   1.00   9.56   C       ATOM   228   CB   LEU   A   25   33.431   4.698   62.394   1.00   8.59   C       ATOM   231   CG   LEU   A   25   34.666   5.591   62.340   1.00   11.50   C       ATOM   233   CD1   LEU   A   25   34.608   6.552   63.511   1.00   11.62   C       ATOM   237   CD2   LEU   A   25   35.915   4.801   62.362   1.00   14.34   C       ATOM   241   C   LEU   A   25   32.158   2.717   61.406   1.00   9.15   C       ATOM   242   O   LEU   A   25   32.218   1.955   62.379   1.00   12.15   O       ATOM   244   N   GLU   A   26   31.167   2.664   60.531   1.00   8.87   N       ATOM   245   CA   GLU   A   26   30.142   1.641   60.585   1.00   10.20   C       ATOM   247   CB   GLU   A   26   29.022   1.940   59.577   1.00   10.65   C       ATOM   250   CG   GLU   A   26   27.963   0.852   59.519   1.00   11.96   C       ATOM   253   CD   GLU   A   26   27.288   0.604   60.839   1.00   17.08   C       ATOM   254   OE1   GLU   A   26   26.798   1.600   61.451   1.00   20.71   O       ATOM   255   OE2   GLU   A   26   27.230   −0.595   61.279   1.00   16.36   O       ATOM   256   C   GLU   A   26   30.749   0.284   60.259   1.00   11.21   C       ATOM   257   O   GLU   A   26   31.342   0.123   59.217   1.00   13.21   O       ATOM   259   N   THR   A   27   30.579   −0.679   61.156   1.00   14.03   N       ATOM   260   CA   THR   A   27   31.199   −1.991   60.979   1.00   16.39   C       ATOM   262   CB   THR   A   27   31.779   −2.520   62.316   1.00   17.17   C       ATOM   264   OG1   THR   A   27   30.725   −2.729   63.251   1.00   18.71   O       ATOM   266   CG2   THR   A   27   32.793   −1.537   62.898   1.00   18.99   C       ATOM   270   C   THR   A   27   30.254   −3.045   60.378   1.00   17.58   C       ATOM   271   O   THR   A   27   30.728   −4.107   59.928   1.00   21.24   O       ATOM   273   N   ALA   A   28   28.960   −2.766   60.383   1.00   15.57   N       ATOM   274   CA   ALA   A   28   27.977   −3.671   59.830   1.00   16.89   C       ATOM   276   CB   ALA   A   28   26.981   −4.129   60.889   1.00   16.73   C       ATOM   280   C   ALA   A   28   27.369   −2.859   58.721   1.00   17.49   C       ATOM   281   O   ALA   A   28   28.145   −2.160   58.022   1.00   20.58   O       ATOM   283   N   ASP   A   29   26.063   −2.917   58.523   1.00   15.97   N       ATOM   284   CA   ASP   A   29   25.446   −2.197   57.420   1.00   17.34   C       ATOM   286   CB   ASP   A   29   24.522   −3.136   56.640   1.00   19.00   C       ATOM   289   CG   ASP   A   29   25.301   −4.257   55.860   1.00   22.70   C       ATOM   290   OD1   ASP   A   29   26.556   −4.303   55.845   1.00   25.94   O       ATOM   291   OD2   ASP   A   29   24.626   −5.102   55.234   1.00   33.57   O       ATOM   292   C   ASP   A   29   24.739   −0.927   57.917   1.00   15.71   C       ATOM   293   O   ASP   A   29   24.199   −0.841   59.071   1.00   16.45   O       ATOM   295   N   LEU   A   30   24.729   0.099   57.067   1.00   13.49   N       ATOM   296   CA   LEU   A   30   24.132   1.369   57.449   1.00   13.28   C       ATOM   298   CB   LEU   A   30   24.507   2.446   56.436   1.00   12.20   C       ATOM   301   CG   LEU   A   30   25.968   2.938   56.482   1.00   11.60   C       ATOM   303   CD1   LEU   A   30   26.311   3.826   55.253   1.00   10.66   C       ATOM   307   CD2   LEU   A   30   26.230   3.709   57.775   1.00   13.79   C       ATOM   311   C   LEU   A   30   22.606   1.398   57.639   1.00   15.47   C       ATOM   312   O   LEU   A   30   22.095   2.178   58.420   1.00   19.16   O       ATOM   314   N   LYS   A   31   21.916   0.608   56.880   1.00   16.56   N       ATOM   315   CA   LYS   A   31   20.435   0.542   57.010   1.00   16.90   C       ATOM   317   CB   LYS   A   31   19.967   0.052   58.412   1.00   17.83   C       ATOM   324   C   LYS   A   31   19.707   1.845   56.679   1.00   16.92   C       ATOM   325   O   LYS   A   31   18.606   2.161   57.233   1.00   18.10   O       ATOM   327   N   TRP   A   32   20.280   2.654   55.794   1.00   14.03   N       ATOM   328   CA   TRP   A   32   19.619   3.894   55.463   1.00   12.43   C       ATOM   330   CB   TRP   A   32   20.553   4.837   54.691   1.00   11.17   C       ATOM   333   CG   TRP   A   32   21.612   5.473   55.539   1.00   10.85   C       ATOM   334   CD1   TRP   A   32   21.845   5.269   56.865   1.00   11.79   C       ATOM   336   NE1   TRP   A   32   22.923   6.044   57.280   1.00   12.05   N       ATOM   338   CE2   TRP   A   32   23.415   6.724   56.214   1.00   11.63   C       ATOM   339   CD2   TRP   A   32   22.618   6.389   55.092   1.00   10.21   C       ATOM   340   CE3   TRP   A   32   22.904   6.982   53.869   1.00   10.29   C       ATOM   342   CZ3   TRP   A   32   23.969   7.858   53.782   1.00   12.53   C       ATOM   344   CH2   TRP   A   32   24.726   8.154   54.907   1.00   11.69   C       ATOM   346   CZ2   TRP   A   32   24.448   7.626   56.126   1.00   10.84   C       ATOM   348   C   TRP   A   32   18.371   3.523   54.650   1.00   11.50   C       ATOM   349   O   TRP   A   32   18.311   2.522   53.944   1.00   12.52   O       ATOM   351   N   VAL   A   33   17.375   4.377   54.719   1.00   11.31   N       ATOM   352   CA   VAL   A   33   16.065   4.099   54.102   1.00   10.50   C       ATOM   354   CB   VAL   A   33   14.960   4.610   55.034   1.00   10.68   C       ATOM   356   CG1   VAL   A   33   13.594   4.610   54.343   1.00   10.00   C       ATOM   360   CG2   VAL   A   33   14.951   3.783   56.320   1.00   11.80   C       ATOM   364   C   VAL   A   33   16.043   4.779   52.728   1.00   10.58   C       ATOM   365   O   VAL   A   33   16.485   5.929   52.557   1.00   11.61   O       ATOM   367   N   THR   A   34   15.540   4.048   51.738   1.00   9.11   N       ATOM   368   CA   THR   A   34   15.419   4.579   50.386   1.00   9.33   C       ATOM   370   CB   THR   A   34   16.195   3.711   49.392   1.00   10.58   C       ATOM   372   OG1   THR   A   34   15.703   2.367   49.443   1.00   12.23   O       ATOM   374   CG2   THR   A   34   17.684   3.722   49.746   1.00   11.70   C       ATOM   378   C   THR   A   34   13.937   4.638   49.958   1.00   9.28   C       ATOM   379   O   THR   A   34   13.072   3.984   50.540   1.00   10.10   O       ATOM   381   N   PHE   A   35   13.676   5.457   48.934   1.00   8.75   N       ATOM   382   CA   PHE   A   35   12.338   5.626   48.370   1.00   8.92   C       ATOM   384   CB   PHE   A   35   11.574   6.664   49.204   1.00   9.31   C       ATOM   387   CG   PHE   A   35   10.237   7.021   48.650   1.00   10.11   C       ATOM   388   CD1   PHE   A   35   9.107   6.312   49.017   1.00   10.65   C       ATOM   390   CE1   PHE   A   35   7.868   6.655   48.510   1.00   12.03   C       ATOM   392   CZ   PHE   A   35   7.761   7.700   47.584   1.00   10.81   C       ATOM   394   CE2   PHE   A   35   8.859   8.421   47.249   1.00   11.68   C       ATOM   396   CD2   PHE   A   35   10.098   8.088   47.764   1.00   10.45   C       ATOM   398   C   PHE   A   35   12.483   6.122   46.940   1.00   9.83   C       ATOM   399   O   PHE   A   35   13.330   6.968   46.666   1.00   10.00   O       ATOM   401   N   PRO   A   36   11.600   5.685   46.025   1.00   9.75   N       ATOM   402   CA   PRO   A   36   10.481   4.741   46.162   1.00   10.89   C       ATOM   404   CB   PRO   A   36   9.557   5.200   45.048   1.00   10.66   C       ATOM   407   CG   PRO   A   36   10.437   5.623   44.008   1.00   10.68   C       ATOM   410   CD   PRO   A   36   11.597   6.320   44.697   1.00   10.68   C       ATOM   413   C   PRO   A   36   10.812   3.244   45.986   1.00   10.85   C       ATOM   414   O   PRO   A   36   9.860   2.383   45.907   1.00   12.56   O       ATOM   415   N   GLN   A   37   12.093   2.887   45.961   1.00   11.74   N       ATOM   416   CA   GLN   A   37   12.490   1.460   45.869   1.00   12.44   C       ATOM   418   CB   GLN   A   37   12.088   0.679   47.099   1.00   12.50   C       ATOM   421   CG   GLN   A   37   12.730   1.215   48.358   1.00   14.22   C       ATOM   424   CD   GLN   A   37   12.498   0.370   49.582   1.00   16.16   C       ATOM   425   OE1   GLN   A   37   11.862   −0.674   49.520   1.00   21.49   O       ATOM   426   NE2   GLN   A   37   12.953   0.843   50.710   1.00   22.36   N       ATOM   429   C   GLN   A   37   12.015   0.793   44.586   1.00   11.98   C       ATOM   430   O   GLN   A   37   11.424   −0.304   44.594   1.00   15.13   O       ATOM   432   N   VAL   A   38   12.253   1.474   43.488   1.00   12.06   N       ATOM   433   CA   VAL   A   38   11.939   0.961   42.159   1.00   12.33   C       ATOM   435   CB   VAL   A   38   11.084   1.982   41.362   1.00   12.47   C       ATOM   437   CG1   VAL   A   38   9.796   2.290   42.117   1.00   13.77   C       ATOM   441   CG2   VAL   A   38   11.830   3.262   41.037   1.00   13.76   C       ATOM   445   C   VAL   A   38   13.248   0.578   41.452   1.00   13.01   C       ATOM   446   O   VAL   A   38   14.332   0.723   42.011   1.00   12.39   O       ATOM   448   N   ASP   A   39   13.131   0.043   40.242   1.00   13.10   N       ATOM   449   CA   ASP   A   39   14.318   −0.237   39.441   1.00   14.56   C       ATOM   451   CB   ASP   A   39   13.911   −0.652   38.020   1.00   15.71   C       ATOM   454   CG   ASP   A   39   13.239   −2.028   37.949   1.00   20.14   C       ATOM   455   OD1   ASP   A   39   13.261   −2.810   38.933   1.00   27.15   O       ATOM   456   OD2   ASP   A   39   12.740   −2.346   36.852   1.00   25.39   O       ATOM   457   C   ASP   A   39   15.199   0.996   39.390   1.00   12.97   C       ATOM   458   O   ASP   A   39   14.705   2.129   39.202   1.00   13.90   O       ATOM   460   N   GLY   A   40   16.503   0.789   39.588   1.00   12.14   N       ATOM   461   CA   GLY   A   40   17.447   1.873   39.553   1.00   11.59   C       ATOM   464   C   GLY   A   40   17.750   2.479   40.907   1.00   10.89   C       ATOM   465   O   GLY   A   40   18.521   3.419   41.007   1.00   11.12   O       ATOM   467   N   GLN   A   41   17.097   1.967   41.946   1.00   11.44   N       ATOM   468   CA   GLN   A   41   17.245   2.470   43.296   1.00   10.98   C       ATOM   470   CB   GLN   A   41   16.397   1.644   44.282   1.00   12.13   C       ATOM   473   CG   GLN   A   41   16.743   0.139   44.297   1.00   12.95   C       ATOM   476   CD   GLN   A   41   15.707   −0.648   45.075   1.00   15.14   C       ATOM   477   OE1   GLN   A   41   15.550   −0.435   46.256   1.00   18.59   O       ATOM   478   NE2   GLN   A   41   15.003   −1.543   44.411   1.00   22.18   N       ATOM   481   C   GLN   A   41   18.683   2.545   43.803   1.00   10.18   C       ATOM   482   O   GLN   A   41   19.559   1.787   43.358   1.00   10.73   O       ATOM   484   N   TRP   A   42   18.913   3.449   44.758   1.00   9.29   N       ATOM   485   CA   TRP   A   42   20.175   3.475   45.500   1.00   8.62   C       ATOM   487   CB   TRP   A   42   20.067   4.399   46.695   1.00   9.35   C       ATOM   490   CG   TRP   A   42   20.068   5.871   46.455   1.00   8.24   C       ATOM   491   CD1   TRP   A   42   18.985   6.677   46.392   1.00   9.84   C       ATOM   493   NE1   TRP   A   42   19.362   7.987   46.236   1.00   9.90   N       ATOM   495   CE2   TRP   A   42   20.736   8.048   46.247   1.00   8.26   C       ATOM   496   CD2   TRP   A   42   21.209   6.727   46.362   1.00   8.34   C       ATOM   497   CE3   TRP   A   42   22.600   6.506   46.347   1.00   9.51   C       ATOM   499   CZ3   TRP   A   42   23.436   7.588   46.260   1.00   9.12   C       ATOM   501   CH2   TRP   A   42   22.956   8.883   46.090   1.00   11.10   C       ATOM   503   CZ2   TRP   A   42   21.601   9.144   46.088   1.00   9.47   C       ATOM   505   C   TRP   A   42   20.501   2.061   46.079   1.00   9.65   C       ATOM   506   O   TRP   A   42   16.585   1.348   46.537   1.00   11.45   O       ATOM   508   N   GLU   A   43   21.772   1.681   46.012   1.00   9.40   N       ATOM   509   CA   GLU   A   43   22.284   0.387   46.512   1.00   10.45   C       ATOM   511   CB   AGLU   A   43   22.746   −0.490   45.364   0.50   10.06   C       ATOM   512   CB   BGLU   A   43   22.784   −0.537   45.338   0.50   10.16   C       ATOM   517   CG   AGLU   A   43   21.634   −0.910   44.427   0.50   12.10   C       ATOM   518   CG   BGLU   A   43   23.036   −2.043   45.750   0.50   10.29   C       ATOM   523   CD   AGLU   A   43   22.142   −1.894   43.380   0.50   14.51   C       ATOM   524   CD   BGLU   A   43   23.688   −3.052   44.695   0.50   13.19   C       ATOM   525   OE1   AGLU   A   43   23.302   −2.357   43.490   0.50   20.44   O       ATOM   526   OE1   BGLU   A   43   23.946   −2.788   43.499   0.50   12.08   O       ATOM   527   OE2   AGLU   A   43   21.367   −2.226   42.455   0.50   22.84   O       ATOM   528   OE2   BGLU   A   43   23.962   −4.202   45.106   0.50   15.03   O       ATOM   529   C   GLU   A   43   23.411   0.602   47.474   1.00   9.78   C       ATOM   530   O   GLU   A   43   24.319   1.419   47.216   1.00   9.79   O       ATOM   532   N   GLU   A   44   23.423   −0.158   48.567   1.00   8.15   N       ATOM   533   CA   GLU   A   44   24.572   −0.124   49.511   1.00   9.00   C       ATOM   535   CB   GLU   A   44   24.095   −0.475   50.912   1.00   10.13   C       ATOM   538   CG   GLU   A   44   25.149   −0.187   51.988   1.00   10.06   C       ATOM   541   CD   GLU   A   44   24.692   −0.489   53.391   1.00   11.49   C       ATOM   542   OE1   GLU   A   44   23.500   −0.851   53.554   1.00   12.88   O       ATOM   543   OE2   GLU   A   44   25.529   −0.343   54.332   1.00   12.69   O       ATOM   544   C   GLU   A   44   25.636   −1.122   49.065   1.00   9.85   C       ATOM   545   O   GLU   A   44   25.290   −2.321   48.823   1.00   10.25   O       ATOM   547   N   LEU   A   45   26.879   −0.659   48.967   1.00   10.70   N       ATOM   548   CA   LEU   A   45   28.020   −1.454   48.498   1.00   12.02   C       ATOM   550   CB   LEU   A   45   28.459   −0.992   47.102   1.00   12.79   C       ATOM   553   CG   LEU   A   45   27.360   −1.452   46.135   1.00   15.99   C       ATOM   555   CD1   LEU   A   45   26.815   −0.440   45.202   1.00   20.04   C       ATOM   559   CD2   LEU   A   45   27.663   −2.822   45.541   1.00   15.67   C       ATOM   563   C   LEU   A   45   29.217   −1.302   49.411   1.00   12.37   C       ATOM   564   O   LEU   A   45   29.462   −0.213   49.957   1.00   12.81   O       ATOM   566   N   ASER   A   46   29.991   −2.366   49.589   0.50   13.04   N       ATOM   567   N   BSER   A   46   29.981   −2.386   49.551   0.50   12.82   N       ATOM   568   CA   ASER   A   46   31.244   −2.192   50.328   0.50   13.68   C       ATOM   569   CA   BSER   A   46   31.300   −2.357   50.215   0.50   13.35   C       ATOM   572   CB   ASER   A   46   31.713   −3.484   50.957   0.50   14.34   C       ATOM   573   CB   BSER   A   46   31.770   −3.818   50.405   0.50   13.78   C       ATOM   578   OG   ASER   A   46   32.852   −3.193   51.749   0.50   17.56   O       ATOM   579   OG   BSER   A   46   32.829   −3.971   51.338   0.50   16.91   O       ATOM   582   C   ASER   A   46   32.362   −1.625   49.451   0.50   13.16   C       ATOM   583   C   BSER   A   46   32.319   −1.559   49.362   0.50   12.99   C       ATOM   584   O   ASER   A   46   32.724   −2.219   48.426   0.50   14.44   O       ATOM   585   O   BSER   A   46   32.524   −1.885   48.203   0.50   14.64   O       ATOM   588   N   GLY   A   47   32.931   −0.516   49.911   1.00   12.98   N       ATOM   589   CA   GLY   A   47   34.067   0.174   49.264   1.00   12.65   C       ATOM   592   C   GLY   A   47   35.295   0.132   50.139   1.00   12.62   C       ATOM   593   O   GLY   A   47   35.322   −0.585   51.123   1.00   11.81   O       ATOM   595   N   LEU   A   48   36.324   0.859   49.719   1.00   12.18   N       ATOM   596   CA   LEU   A   48   37.609   0.936   50.440   1.00   13.20   C       ATOM   598   CB   LEU   A   48   38.703   0.319   49.567   1.00   14.06   C       ATOM   601   CG   LEU   A   48   38.539   −1.139   49.254   1.00   16.14   C       ATOM   603   CD1   LEU   A   48   39.564   −1.533   48.222   1.00   17.56   C       ATOM   607   CD2   LEU   A   48   38.722   −1.970   50.503   1.00   15.62   C       ATOM   611   C   LEU   A   48   37.989   2.347   50.759   1.00   14.96   C       ATOM   612   O   LEU   A   48   37.853   3.224   49.886   1.00   17.67   O       ATOM   614   N   ASP   A   49   38.457   2.587   51.982   1.00   14.25   N       ATOM   615   CA   ASP   A   49   38.898   3.925   52.362   1.00   15.81   C       ATOM   617   CB   ASP   A   49   38.508   4.250   53.792   1.00   15.75   C       ATOM   620   CG   ASP   A   49   39.232   3.414   54.842   1.00   16.73   C       ATOM   621   OD1   ASP   A   49   40.250   2.750   54.552   1.00   16.95   O       ATOM   622   OD2   ASP   A   49   38.742   3.421   56.007   1.00   23.27   O       ATOM   623   C   ASP   A   49   40.407   4.086   52.098   1.00   15.71   C       ATOM   624   O   ASP   A   49   40.991   3.232   51.452   1.00   15.44   O       ATOM   626   N   GLU   A   50   40.984   5.201   52.574   1.00   16.80   N       ATOM   627   CA   GLU   A   50   42.447   5.505   52.380   1.00   16.83   C       ATOM   629   CB   GLU   A   50   42.754   6.946   52.825   1.00   16.31   C       ATOM   632   CG   GLU   A   50   42.096   7.950   52.002   1.00   17.42   C       ATOM   635   CD   GLU   A   50   42.520   9.388   52.332   1.00   15.16   C       ATOM   636   OE1   GLU   A   50   43.455   9.619   53.192   1.00   14.33   O       ATOM   637   OE2   GLU   A   50   41.849   10.255   51.735   1.00   15.53   O       ATOM   638   C   GLU   A   50   43.427   4.558   53.046   1.00   19.00   C       ATOM   639   O   GLU   A   50   44.650   4.553   52.703   1.00   19.95   O       ATOM   641   N   GLU   A   51   42.934   3.766   53.982   1.00   19.32   N       ATOM   642   CA   GLU   A   51   43.741   2.769   54.672   1.00   20.38   C       ATOM   644   CB   GLU   A   51   43.417   2.808   56.159   1.00   21.41   C       ATOM   647   CG   GLU   A   51   43.711   4.160   56.784   1.00   23.95   C       ATOM   650   CD   GLU   A   51   43.500   4.152   58.257   1.00   24.68   C       ATOM   651   OE1   GLU   A   51   44.373   3.593   58.950   1.00   30.31   O       ATOM   652   OE2   GLU   A   51   42.488   4.733   58.706   1.00   32.21   O       ATOM   653   C   GLU   A   51   43.466   1.384   54.124   1.00   19.92   C       ATOM   654   O   GLU   A   51   43.931   0.378   54.697   1.00   19.56   O       ATOM   656   N   GLN   A   52   42.717   1.327   53.020   1.00   18.89   N       ATOM   657   CA   GLN   A   52   42.328   0.054   52.400   1.00   18.69   C       ATOM   659   CB   GLN   A   52   43.549   −0.779   52.000   1.00   19.90   C       ATOM   666   C   GLN   A   52   41.423   −0.789   53.285   1.00   18.80   C       ATOM   667   O   GLN   A   52   41.434   −2.040   53.172   1.00   19.32   O       ATOM   669   N   HIS   A   53   40.663   −0.138   54.166   1.00   17.19   N       ATOM   670   CA   HIS   A   53   39.715   −0.828   55.003   1.00   15.92   C       ATOM   672   CB   HIS   A   53   39.600   −0.162   56.376   1.00   17.51   C       ATOM   675   CG   HIS   A   53   40.864   −0.204   57.199   1.00   20.93   C       ATOM   676   ND1   HIS   A   53   41.949   −0.994   56.884   1.00   27.78   N       ATOM   678   CE1   HIS   A   53   42.906   −0.804   57.780   1.00   26.65   C       ATOM   680   NE2   HIS   A   53   42.474   0.073   58.669   1.00   27.47   N       ATOM   682   CD2   HIS   A   53   41.199   0.457   58.334   1.00   27.24   C       ATOM   684   C   HIS   A   53   38.357   −0.770   54.326   1.00   14.19   C       ATOM   685   O   HIS   A   53   38.030   0.211   53.651   1.00   13.34   O       ATOM   687   N   SER   A   54   37.560   −1.810   54.539   1.00   13.06   N       ATOM   688   CA   ASER   A   54   36.206   −1.870   53.974   0.50   12.48   C       ATOM   689   CA   BSER   A   54   36.210   −1.865   53.965   0.50   12.34   C       ATOM   692   CB   ASER   A   54   35.624   −3.262   54.156   0.50   12.71   C       ATOM   693   CB   BSER   A   54   35.628   −3.265   54.097   0.50   12.50   C       ATOM   698   OG   ASER   A   54   34.435   −3.423   53.403   0.50   14.69   O       ATOM   699   OG   BSER   A   54   36.326   −4.201   53.280   0.50   13.56   O       ATOM   702   C   SER   A   54   35.297   −0.859   54.655   1.00   12.10   C       ATOM   703   O   SER   A   54   35.269   −0.787   55.896   1.00   13.90   O       ATOM   705   N   VAL   A   55   34.535   −0.100   53.854   1.00   11.09   N       ATOM   706   CA   VAL   A   55   33.566   0.891   54.371   1.00   10.54   C       ATOM   708   CB   VAL   A   55   34.114   2.330   54.277   1.00   10.19   C       ATOM   710   CG1   VAL   A   55   35.310   2.461   55.167   1.00   13.09   C       ATOM   714   CG2   VAL   A   55   34.460   2.665   52.856   1.00   11.17   C       ATOM   718   C   VAL   A   55   32.238   0.771   53.602   1.00   10.18   C       ATOM   719   O   VAL   A   55   32.214   0.333   52.462   1.00   11.24   O       ATOM   721   N   ARG   A   56   31.135   1.140   54.233   1.00   9.01   N       ATOM   722   CA   ARG   A   56   29.826   1.113   53.595   1.00   9.91   C       ATOM   724   CB   ARG   A   56   28.716   1.048   54.615   1.00   10.97   C       ATOM   727   CG   ARG   A   56   28.801   −0.147   55.563   1.00   11.58   C       ATOM   730   CD   ARG   A   56   29.104   −1.447   54.865   1.00   15.21   C       ATOM   733   NE   ARG   A   56   28.040   −1.854   53.969   1.00   17.47   N       ATOM   735   CZ   ARG   A   56   28.133   −2.887   53.129   1.00   20.77   C       ATOM   736   NH1   ARG   A   56   27.092   −3.224   52.358   1.00   22.08   N       ATOM   739   NH2   ARG   A   56   29.247   −3.592   53.071   1.00   21.45   N       ATOM   742   C   ARG   A   56   29.663   2.399   52.762   1.00   8.97   C       ATOM   743   O   ARG   A   56   29.967   3.514   53.222   1.00   9.94   O       ATOM   745   N   THR   A   57   29.169   2.213   51.535   1.00   9.12   N       ATOM   746   CA   THR   A   57   28.921   3.316   50.591   1.00   8.61   C       ATOM   748   CB   THR   A   57   29.972   3.361   49.481   1.00   9.01   C       ATOM   750   OG1   THR   A   57   29.798   2.254   48.563   1.00   9.10   O       ATOM   752   CG2   THR   A   57   31.412   3.330   50.074   1.00   9.29   C       ATOM   756   C   THR   A   57   27.549   3.129   49.941   1.00   9.15   C       ATOM   757   O   THR   A   57   26.953   2.050   50.011   1.00   8.65   O       ATOM   759   N   TYR   A   58   27.067   4.170   49.276   1.00   8.82   N       ATOM   760   CA   TYR   A   58   25.812   4.073   48.489   1.00   9.14   C       ATOM   762   CB   TYR   A   58   24.694   4.925   49.121   1.00   10.04   C       ATOM   765   CG   TYR   A   58   24.006   4.219   50.253   1.00   9.55   C       ATOM   766   CD1   TYR   A   58   23.002   3.253   50.008   1.00   9.24   C       ATOM   768   CE1   TYR   A   58   22.357   2.622   51.048   1.00   9.04   C       ATOM   770   CZ   TYR   A   58   22.793   2.824   52.344   1.00   10.33   C       ATOM   771   OH   TYR   A   58   22.181   2.115   53.417   1.00   13.23   O       ATOM   773   CE2   TYR   A   58   23.759   3.767   52.620   1.00   9.75   C       ATOM   775   CD2   TYR   A   58   24.382   4.456   51.562   1.00   10.04   C       ATOM   777   C   TYR   A   58   26.066   4.544   47.058   1.00   9.09   C       ATOM   778   O   TYR   A   58   26.751   5.552   46.857   1.00   9.85   O       ATOM   780   N   GLU   A   59   25.509   3.823   46.085   1.00   7.72   N       ATOM   781   CA   GLU   A   59   25.622   4.186   44.660   1.00   8.04   C       ATOM   783   CB   GLU   A   59   26.491   3.177   43.912   1.00   9.06   C       ATOM   786   CG   GLU   A   59   27.910   3.032   44.412   1.00   8.60   C       ATOM   789   CD   GLU   A   59   28.738   2.070   43.535   1.00   9.81   C       ATOM   790   OE1   GLU   A   59   28.170   1.590   42.538   1.00   9.82   O       ATOM   791   OE2   GLU   A   59   29.925   1.884   43.849   1.00   12.02   O       ATOM   792   C   GLU   A   59   24.248   4.212   44.000   1.00   9.20   C       ATOM   793   O   GLU   A   59   23.337   3.488   44.368   1.00   8.68   O       ATOM   795   N   VAL   A   60   24.140   5.064   42.988   1.00   8.44   N       ATOM   796   CA   VAL   A   60   22.956   5.146   42.127   1.00   7.85   C       ATOM   798   CB   VAL   A   60   21.914   6.133   42.665   1.00   8.42   C       ATOM   800   CG1   VAL   A   60   22.382   7.596   42.623   1.00   8.14   C       ATOM   804   CG2   VAL   A   60   20.563   5.969   41.977   1.00   10.07   C       ATOM   808   C   VAL   A   60   23.429   5.545   40.724   1.00   8.37   C       ATOM   809   O   VAL   A   60   24.353   6.371   40.582   1.00   8.58   O       ATOM   811   N   CYS   A   61   22.861   4.928   39.697   1.00   8.88   N       ATOM   812   CA   CYS   A   61   23.260   5.245   38.330   1.00   9.45   C       ATOM   814   CB   CYS   A   61   24.553   4.536   37.981   1.00   9.31   C       ATOM   817   SG   CYS   A   61   25.313   5.075   36.382   1.00   9.25   S       ATOM   819   C   CYS   A   61   22.136   4.912   37.310   1.00   10.12   C       ATOM   820   O   CYS   A   61   22.342   4.133   36.386   1.00   10.79   O       ATOM   822   N   ASP   A   62   20.988   5.558   37.497   1.00   9.85   N       ATOM   823   CA   ASP   A   62   19.793   5.376   36.660   1.00   9.28   C       ATOM   825   CB   ASP   A   62   18.546   5.341   37.553   1.00   10.45   C       ATOM   828   CG   ASP   A   62   17.292   5.094   36.806   1.00   10.86   C       ATOM   829   OD1   ASP   A   62   17.381   4.800   35.577   1.00   12.22   O       ATOM   830   OD2   ASP   A   62   16.194   5.144   37.448   1.00   11.23   O       ATOM   831   C   ASP   A   62   19.788   6.503   35.646   1.00   11.31   C       ATOM   832   O   ASP   A   62   19.204   7.568   35.876   1.00   12.18   O       ATOM   834   N   VAL   A   63   20.458   6.261   34.514   1.00   11.89   N       ATOM   835   CA   VAL   A   63   20.638   7.279   33.478   1.00   13.16   C       ATOM   837   CB   VAL   A   63   22.122   7.642   33.304   1.00   13.22   C       ATOM   839   CG1   VAL   A   63   22.649   8.312   34.536   1.00   12.96   C       ATOM   843   CG2   VAL   A   63   22.963   6.406   32.886   1.00   14.83   C       ATOM   847   C   VAL   A   63   20.081   6.837   32.138   1.00   14.23   C       ATOM   848   O   VAL   A   63   19.822   7.649   31.266   1.00   16.46   O       ATOM   850   N   GLN   A   64   19.887   5.542   31.985   1.00   15.84   N       ATOM   851   CA   GLN   A   64   19.426   4.983   30.720   1.00   18.13   C       ATOM   853   CB   GLN   A   64   20.275   3.754   30.377   1.00   18.23   C       ATOM   860   C   GLN   A   64   17.948   4.668   30.812   1.00   19.94   C       ATOM   861   O   GLN   A   64   17.161   5.116   29.956   1.00   22.90   O       ATOM   863   N   ARG   A   65   17.549   3.933   31.849   1.00   20.14   N       ATOM   864   CA   ARG   A   65   16.182   3.488   32.024   1.00   19.89   C       ATOM   866   CB   ARG   A   65   16.116   2.460   33.151   1.00   21.74   C       ATOM   875   C   ARG   A   65   15.242   4.657   32.342   1.00   19.41   C       ATOM   876   O   ARG   A   65   14.266   4.904   31.598   1.00   18.18   O       ATOM   878   N   ALA   A   66   15.523   5.374   33.434   1.00   17.78   N       ATOM   879   CA   ALA   A   66   14.647   6.477   33.834   1.00   15.90   C       ATOM   881   CB   ALA   A   66   13.568   6.005   34.787   1.00   17.23   C       ATOM   885   C   ALA   A   66   15.425   7.631   34.441   1.00   14.82   C       ATOM   886   O   ALA   A   66   15.431   7.807   35.652   1.00   12.98   O       ATOM   888   N   PRO   A   67   16.086   8.439   33.602   1.00   13.82   N       ATOM   889   CA   PRO   A   67   16.815   9.560   34.155   1.00   14.16   C       ATOM   891   CB   PRO   A   67   17.626   10.096   32.966   1.00   13.92   C       ATOM   894   CG   PRO   A   67   16.887   9.608   31.762   1.00   13.64   C       ATOM   897   CD   PRO   A   67   16.213   8.342   32.130   1.00   13.56   C       ATOM   900   C   PRO   A   67   15.933   10.643   34.787   1.00   13.32   C       ATOM   901   O   PRO   A   67   16.461   11.477   35.529   1.00   14.01   O       ATOM   902   N   GLY   A   68   14.608   10.628   34.558   1.00   12.54   N       ATOM   903   CA   GLY   A   68   13.755   11.553   35.252   1.00   12.21   C       ATOM   906   C   GLY   A   68   13.158   10.971   36.523   1.00   11.44   C       ATOM   907   O   GLY   A   68   12.387   11.656   37.202   1.00   12.78   O       ATOM   909   N   GLN   A   69   13.483   9.724   36.869   1.00   10.14   N       ATOM   910   CA   GLN   A   69   12.998   9.159   38.153   1.00   10.41   C       ATOM   912   CB   GLN   A   69   13.012   7.621   38.111   1.00   10.00   C       ATOM   915   CG   GLN   A   69   12.675   6.939   39.427   1.00   9.92   C       ATOM   918   CD   GLN   A   69   11.232   7.122   39.827   1.00   10.80   C       ATOM   919   OE1   GLN   A   69   10.307   6.749   39.064   1.00   13.37   O       ATOM   920   NE2   GLN   A   69   11.030   7.676   41.007   1.00   9.15   N       ATOM   923   C   GLN   A   69   13.846   9.645   39.331   1.00   10.33   C       ATOM   924   O   GLN   A   69   15.071   9.470   39.355   1.00   9.39   O       ATOM   926   N   ALA   A   70   13.228   10.239   40.332   1.00   9.62   N       ATOM   927   CA   ALA   A   70   13.970   10.585   41.559   1.00   9.05   C       ATOM   929   CB   ALA   A   70   13.269   11.657   42.362   1.00   10.32   C       ATOM   933   C   ALA   A   70   14.159   9.350   42.419   1.00   9.58   C       ATOM   934   O   ALA   A   70   13.252   8.543   42.597   1.00   11.06   O       ATOM   936   N   HIS   A   71   15.345   9.286   43.028   1.00   7.99   N       ATOM   937   CA   HIS   A   71   15.731   8.234   43.969   1.00   9.09   C       ATOM   939   CB   HIS   A   71   16.817   7.328   43.364   1.00   9.38   C       ATOM   942   CG   HIS   A   71   16.411   6.620   42.113   1.00   9.04   C       ATOM   943   ND1   HIS   A   71   15.569   5.527   42.122   1.00   10.50   N       ATOM   945   CE1   HIS   A   71   15.444   5.073   40.884   1.00   9.85   C       ATOM   947   NE2   HIS   A   71   16.158   5.834   40.073   1.00   8.23   N       ATOM   949   CD2   HIS   A   71   16.779   6.806   40.817   1.00   10.81   C       ATOM   951   C   HIS   A   71   16.249   8.919   45.224   1.00   8.98   C       ATOM   952   O   HIS   A   71   17.191   9.718   45.170   1.00   9.27   O       ATOM   954   N   TRP   A   72   15.621   8.599   46.357   1.00   8.10   N       ATOM   955   CA   TRP   A   72   15.913   9.199   47.655   1.00   8.30   C       ATOM   957   CB   TRP   A   72   14.601   9.697   48.329   1.00   8.49   C       ATOM   960   CG   TRP   A   72   13.929   10.870   47.685   1.00   8.08   C       ATOM   961   CD1   TRP   A   72   13.113   10.859   46.603   1.00   9.35   C       ATOM   963   NE1   TRP   A   72   12.671   12.153   46.316   1.00   10.16   N       ATOM   965   CE2   TRP   A   72   13.200   13.002   47.244   1.00   10.46   C       ATOM   966   CD2   TRP   A   72   14.006   12.234   48.118   1.00   8.67   C       ATOM   967   CE3   TRP   A   72   14.663   12.862   49.162   1.00   10.76   C       ATOM   969   CZ3   TRP   A   72   14.533   14.248   49.299   1.00   9.32   C       ATOM   971   CH2   TRP   A   72   13.704   14.953   48.451   1.00   8.41   C       ATOM   973   CZ2   TRP   A   72   13.057   14.361   47.395   1.00   10.47   C       ATOM   975   C   TRP   A   72   16.587   8.259   48.621   1.00   8.56   C       ATOM   976   O   TRP   A   72   16.277   7.069   48.685   1.00   8.28   O       ATOM   978   N   LEU   A   73   17.454   8.841   49.457   1.00   8.33   N       ATOM   979   CA   LEU   A   73   18.276   8.127   50.455   1.00   8.49   C       ATOM   981   CB   LEU   A   73   19.702   8.013   49.922   1.00   8.82   C       ATOM   984   CG   LEU   A   73   20.739   7.348   50.793   1.00   8.48   C       ATOM   986   CD1   LEU   A   73   20.455   5.895   51.007   1.00   9.79   C       ATOM   990   CD2   LEU   A   73   22.131   7.516   50.167   1.00   9.77   C       ATOM   994   C   LEU   A   73   18.274   8.950   51.732   1.00   8.70   C       ATOM   995   O   LEU   A   73   18.618   10.119   51.712   1.00   9.55   O       ATOM   997   N   ARG   A   74   17.906   8.347   52.844   1.00   8.25   N       ATOM   998   CA   ARG   A   74   17.804   9.028   54.143   1.00   8.92   C       ATOM   1000   CB   ARG   A   74   16.337   9.019   54.599   1.00   8.19   C       ATOM   1003   CG   ARG   A   74   16.044   9.851   55.867   1.00   9.06   C       ATOM   1006   CD   ARG   A   74   14.587   9.693   56.300   1.00   8.70   C       ATOM   1009   NE   ARG   A   74   14.322   8.348   56.834   1.00   9.15   N       ATOM   1011   CZ   ARG   A   74   13.146   7.711   56.777   1.00   10.02   C       ATOM   1012   NH1   ARG   A   74   12.107   8.206   56.136   1.00   8.19   N       ATOM   1015   NH2   ARG   A   74   13.043   6.513   57.364   1.00   10.25   N       ATOM   1018   C   ARG   A   74   18.640   8.368   55.231   1.00   8.94   C       ATOM   1019   O   ARG   A   74   18.580   7.140   55.431   1.00   8.17   O       ATOM   1021   N   THR   A   75   19.362   9.187   55.991   1.00   8.60   N       ATOM   1022   CA   THR   A   75   20.146   8.679   57.112   1.00   8.62   C       ATOM   1024   CB   THR   A   75   21.096   9.767   57.658   1.00   8.78   C       ATOM   1026   OG1   THR   A   75   20.367   10.829   58.287   1.00   8.90   O       ATOM   1028   CG2   THR   A   75   21.959   10.364   56.585   1.00   10.28   C       ATOM   1032   C   THR   A   75   19.244   8.253   58.264   1.00   8.43   C       ATOM   1033   O   THR   A   75   18.035   8.532   58.278   1.00   8.19   O       ATOM   1035   N   GLY   A   76   19.817   7.593   59.259   1.00   9.46   N       ATOM   1036   CA   GLY   A   76   19.152   7.453   60.520   1.00   8.62   C       ATOM   1039   C   GLY   A   76   18.957   8.781   61.212   1.00   8.90   C       ATOM   1040   O   GLY   A   76   19.496   9.813   60.773   1.00   8.59   O       ATOM   1042   N   TRP   A   77   18.196   8.750   62.312   1.00   9.17   N       ATOM   1043   CA   TRP   A   77   17.969   9.943   63.121   1.00   8.14   C       ATOM   1045   CB   TRP   A   77   16.779   9.726   64.058   1.00   8.44   C       ATOM   1048   CG   TRP   A   77   16.293   10.907   64.819   1.00   7.96   C       ATOM   1049   CD1   TRP   A   77   15.678   12.024   64.318   1.00   9.29   C       ATOM   1051   NE1   TRP   A   77   15.356   12.889   65.323   1.00   8.84   N       ATOM   1053   CE2   TRP   A   77   15.705   12.319   66.525   1.00   11.12   C       ATOM   1054   CD2   TRP   A   77   16.302   11.073   66.245   1.00   9.62   C       ATOM   1055   CE3   TRP   A   77   16.786   10.300   67.306   1.00   10.69   C       ATOM   1057   CZ3   TRP   A   77   16.600   10.783   68.622   1.00   10.71   C       ATOM   1059   CH2   TRP   A   77   15.994   12.028   68.843   1.00   9.85   C       ATOM   1061   CZ2   TRP   A   77   15.526   12.791   67.825   1.00   10.22   C       ATOM   1063   C   TRP   A   77   19.232   10.253   63.938   1.00   9.50   C       ATOM   1064   O   TRP   A   77   19.766   9.410   64.641   1.00   10.66   O       ATOM   1066   N   VAL   A   78   19.701   11.502   63.839   1.00   7.99   N       ATOM   1067   CA   VAL   A   78   20.933   11.956   64.510   1.00   8.77   C       ATOM   1069   CB   VAL   A   78   21.868   12.650   63.480   1.00   8.76   C       ATOM   1071   CG1   VAL   A   78   23.149   13.128   64.160   1.00   9.73   C       ATOM   1075   CG2   VAL   A   78   22.140   11.723   62.286   1.00   10.01   C       ATOM   1079   C   VAL   A   78   20.588   12.924   65.636   1.00   8.96   C       ATOM   1080   O   VAL   A   78   20.182   14.033   65.385   1.00   9.98   O       ATOM   1082   N   PRO   A   79   20.712   12.491   66.891   1.00   10.47   N       ATOM   1083   CA   PRO   A   79   20.522   13.409   68.016   1.00   11.43   C       ATOM   1085   CB   PRO   A   79   20.668   12.495   69.242   1.00   12.63   C       ATOM   1088   CG   PRO   A   79   20.418   11.101   68.726   1.00   12.60   C       ATOM   1091   CD   PRO   A   79   20.958   11.100   67.327   1.00   12.00   C       ATOM   1094   C   PRO   A   79   21.555   14.517   67.986   1.00   12.22   C       ATOM   1095   O   PRO   A   79   22.738   14.224   67.784   1.00   12.62   O       ATOM   1096   N   ARG   A   80   21.148   15.777   68.116   1.00   12.32   N       ATOM   1097   CA   ARG   A   80   22.063   16.891   67.894   1.00   15.12   C       ATOM   1099   CB   ARG   A   80   21.354   18.133   67.362   1.00   15.85   C       ATOM   1102   CG   ARG   A   80   20.509   18.823   68.365   1.00   15.55   C       ATOM   1105   CD   ARG   A   80   20.040   20.171   67.859   1.00   16.53   C       ATOM   1108   NE   ARG   A   80   19.079   20.802   68.756   1.00   16.98   N       ATOM   1110   CZ   ARG   A   80   19.358   21.768   69.639   1.00   19.02   C       ATOM   1111   NH1   ARG   A   80   20.592   22.265   69.771   1.00   18.43   N       ATOM   1114   NH2   ARG   A   80   18.399   22.260   70.413   1.00   20.74   N       ATOM   1117   C   ARG   A   80   22.889   17.306   69.114   1.00   15.78   C       ATOM   1118   O   ARG   A   80   23.793   18.125   68.960   1.00   15.13   O       ATOM   1120   N   ARG   A   81   22.553   16.792   70.301   1.00   17.14   N       ATOM   1121   CA   ARG   A   81   23.315   17.155   71.515   1.00   17.63   C       ATOM   1123   CB   ARG   A   81   24.713   16.575   71.447   1.00   18.84   C       ATOM   1126   CG   ARG   A   81   24.662   15.058   71.474   1.00   22.20   C       ATOM   1129   CD   ARG   A   81   26.000   14.448   71.540   1.00   26.32   C       ATOM   1132   NE   ARG   A   81   26.700   14.783   72.776   1.00   25.33   N       ATOM   1134   CZ   ARG   A   81   28.013   14.678   72.960   1.00   28.71   C       ATOM   1135   NH1   ARG   A   81   28.806   14.246   71.988   1.00   30.89   N       ATOM   1138   NH2   ARG   A   81   28.543   15.029   74.121   1.00   30.52   N       ATOM   1141   C   ARG   A   81   23.257   18.689   71.673   1.00   18.22   C       ATOM   1142   O   ARG   A   81   22.206   19.255   71.469   1.00   19.54   O       ATOM   1144   N   GLY   A   82   24.336   19.375   71.993   1.00   19.11   N       ATOM   1145   CA   GLY   A   82   24.162   20.830   72.148   1.00   19.74   C       ATOM   1148   C   GLY   A   82   24.141   21.627   70.843   1.00   18.66   C       ATOM   1149   O   GLY   A   82   23.956   22.852   70.894   1.00   20.16   O       ATOM   1151   N   ALA   A   83   24.300   20.958   69.699   1.00   16.48   N       ATOM   1152   CA   ALA   A   83   24.749   21.647   68.486   1.00   14.41   C       ATOM   1154   CB   ALA   A   83   25.109   20.650   67.433   1.00   14.82   C       ATOM   1158   C   ALA   A   83   23.717   22.602   67.927   1.00   15.13   C       ATOM   1159   O   ALA   A   83   22.590   22.179   67.717   1.00   15.30   O       ATOM   1161   N   VAL   A   84   24.099   23.840   67.619   1.00   13.70   N       ATOM   1162   CA   VAL   A   84   23.208   24.783   66.949   1.00   13.96   C       ATOM   1164   CB   VAL   A   84   23.285   26.201   67.506   1.00   15.82   C       ATOM   1166   CG1   VAL   A   84   22.345   27.139   66.755   1.00   16.71   C       ATOM   1170   CG2   VAL   A   84   22.898   26.204   68.979   1.00   17.60   C       ATOM   1174   C   VAL   A   84   23.456   24.739   65.425   1.00   11.78   C       ATOM   1175   O   VAL   A   84   22.524   24.853   64.652   1.00   11.60   O       ATOM   1177   N   HIS   A   85   24.702   24.618   65.002   1.00   10.16   N       ATOM   1178   CA   HIS   A   85   25.008   24.300   63.609   1.00   10.37   C       ATOM   1180   CB   HIS   A   85   25.807   25.405   62.924   1.00   11.74   C       ATOM   1183   CG   HIS   A   85   25.082   26.705   62.892   1.00   15.32   C       ATOM   1184   ND1   HIS   A   85   24.291   27.100   61.828   1.00   18.93   N       ATOM   1186   CE1   HIS   A   85   23.746   28.273   62.116   1.00   13.57   C       ATOM   1188   NE2   HIS   A   85   24.160   28.644   63.312   1.00   18.04   N       ATOM   1190   CD2   HIS   A   85   24.979   27.670   63.827   1.00   15.62   C       ATOM   1192   C   HIS   A   85   25.797   23.011   63.531   1.00   9.98   C       ATOM   1193   O   HIS   A   85   26.639   22.773   64.417   1.00   11.68   O       ATOM   1195   N   VAL   A   86   25.484   22.197   62.533   1.00   9.78   N       ATOM   1196   CA   VAL   A   86   26.186   20.955   62.280   1.00   9.44   C       ATOM   1198   CB   VAL   A   86   25.225   19.738   62.406   1.00   10.60   C       ATOM   1200   CG1   VAL   A   86   25.866   18.460   61.842   1.00   12.94   C       ATOM   1204   CG2   VAL   A   86   24.831   19.560   63.871   1.00   10.81   C       ATOM   1208   C   VAL   A   86   26.823   21.029   60.908   1.00   10.03   C       ATOM   1209   O   VAL   A   86   26.222   21.547   59.941   1.00   11.17   O       ATOM   1211   N   TYR   A   87   28.043   20.519   60.790   1.00   7.91   N       ATOM   1212   CA   TYR   A   87   28.716   20.415   59.536   1.00   7.81   C       ATOM   1214   CB   TYR   A   87   30.196   20.779   59.709   1.00   8.49   C       ATOM   1217   CG   TYR   A   87   30.356   22.226   60.090   1.00   8.70   C       ATOM   1218   CD1   TYR   A   87   30.439   23.212   59.131   1.00   10.52   C       ATOM   1220   CE1   TYR   A   87   30.548   24.542   59.496   1.00   11.11   C       ATOM   1222   CZ   TYR   A   87   30.511   24.876   60.820   1.00   12.13   C       ATOM   1223   OH   TYR   A   87   30.616   26.203   61.247   1.00   14.33   O       ATOM   1225   CE2   TYR   A   87   30.414   23.923   61.774   1.00   10.66   C       ATOM   1227   CD2   TYR   A   87   30.299   22.607   61.404   1.00   10.17   C       ATOM   1229   C   TYR   A   87   28.605   19.024   58.963   1.00   8.80   C       ATOM   1230   O   TYR   A   87   28.736   18.040   59.702   1.00   9.37   O       ATOM   1232   N   ALA   A   88   28.354   18.955   57.655   1.00   7.91   N       ATOM   1233   CA   ALA   A   88   28.258   17.688   56.937   1.00   7.02   C       ATOM   1235   CB   ALA   A   88   26.853   17.549   56.298   1.00   7.55   C       ATOM   1239   C   ALA   A   88   29.270   17.584   55.830   1.00   8.97   C       ATOM   1240   O   ALA   A   88   29.123   18.283   54.818   1.00   10.24   O       ATOM   1242   N   THR   A   89   30.290   16.765   55.996   1.00   8.71   N       ATOM   1243   CA   THR   A   89   31.290   16.569   54.944   1.00   7.77   C       ATOM   1245   CB   THR   A   89   32.686   16.393   55.511   1.00   8.61   C       ATOM   1247   OG1   THR   A   89   33.092   17.561   56.259   1.00   9.57   O       ATOM   1249   CG2   THR   A   89   33.675   16.151   54.393   1.00   8.17   C       ATOM   1253   C   THR   A   89   30.899   15.346   54.149   1.00   8.06   C       ATOM   1254   O   THR   A   89   30.762   14.265   54.682   1.00   8.00   O       ATOM   1256   N   LEU   A   90   30.700   15.571   52.842   1.00   8.21   N       ATOM   1257   CA   LEU   A   90   30.340   14.538   51.869   1.00   8.69   C       ATOM   1259   CB   LEU   A   90   29.139   15.023   51.019   1.00   9.11   C       ATOM   1262   CG   LEU   A   90   27.861   15.331   51.822   1.00   15.79   C       ATOM   1264   CD1   LEU   A   90   26.896   16.070   50.900   1.00   20.74   C       ATOM   1268   CD2   LEU   A   90   27.283   14.096   52.289   1.00   19.77   C       ATOM   1272   C   LEU   A   90   31.508   14.291   50.920   1.00   8.92   C       ATOM   1273   O   LEU   A   90   32.029   15.245   50.367   1.00   10.39   O       ATOM   1275   N   ARG   A   91   31.888   13.034   50.722   1.00   8.77   N       ATOM   1276   CA   ARG   A   91   32.911   12.662   49.732   1.00   8.68   C       ATOM   1278   CB   ARG   A   91   34.142   12.014   50.403   1.00   9.59   C       ATOM   1281   CG   ARG   A   91   34.773   12.963   51.396   1.00   9.66   C       ATOM   1284   CD   ARG   A   91   36.013   12.436   52.061   1.00   11.36   C       ATOM   1287   NE   ARG   A   91   36.469   13.307   53.142   1.00   11.87   N       ATOM   1289   CZ   ARG   A   91   37.207   14.409   52.998   1.00   10.22   C       ATOM   1290   NH1   ARG   A   91   37.516   15.118   54.108   1.00   12.10   N       ATOM   1293   NH2   ARG   A   91   37.708   14.777   51.815   1.00   12.98   N       ATOM   1296   C   ARG   A   91   32.241   11.759   48.729   1.00   9.26   C       ATOM   1297   O   ARG   A   91   31.544   10.796   49.105   1.00   8.93   O       ATOM   1299   N   PHE   A   92   32.415   12.050   47.438   1.00   7.97   N       ATOM   1300   CA   PHE   A   92   31.661   11.373   46.418   1.00   6.88   C       ATOM   1302   CB   PHE   A   92   30.239   12.000   46.308   1.00   7.83   C       ATOM   1305   CG   PHE   A   92   30.221   13.431   45.837   1.00   7.27   C       ATOM   1306   CD1   PHE   A   92   30.056   13.745   44.471   1.00   8.11   C       ATOM   1308   CE1   PHE   A   92   30.042   15.066   44.056   1.00   8.18   C       ATOM   1310   CZ   PHE   A   92   30.219   16.063   44.939   1.00   8.65   C       ATOM   1312   CE2   PHE   A   92   30.397   15.799   46.280   1.00   9.28   C       ATOM   1314   CD2   PHE   A   92   30.359   14.489   46.736   1.00   8.23   C       ATOM   1316   C   PHE   A   92   32.347   11.364   45.069   1.00   7.47   C       ATOM   1317   O   PHE   A   92   33.136   12.245   44.721   1.00   8.15   O       ATOM   1319   N   THR   A   93   32.029   10.327   44.315   1.00   7.11   N       ATOM   1320   CA   THR   A   93   32.417   10.218   42.886   1.00   7.40   C       ATOM   1322   CB   ATHR   A   93   33.136   8.982   42.504   0.50   8.62   C       ATOM   1323   CB   BTHR   A   93   32.705   8.657   42.619   0.50   7.27   C       ATOM   1326   OG1   ATHR   A   93   32.308   7.887   42.774   0.50   10.04   O       ATOM   1327   OG1   BTHR   A   93   33.752   8.147   43.485   0.50   7.05   O       ATOM   1330   CG2   ATHR   A   93   34.452   8.867   43.335   0.50   6.07   C       ATOM   1331   CG2   BTHR   A   93   33.038   8.353   41.171   0.50   6.94   C       ATOM   1338   C   THR   A   93   31.212   10.559   42.044   1.00   7.68   C       ATOM   1339   O   THR   A   93   30.073   10.205   42.401   1.00   7.10   O       ATOM   1341   N   MET   A   94   31.442   11.283   40.954   1.00   7.62   N       ATOM   1342   CA   MET   A   94   30.404   11.649   39.987   1.00   6.97   C       ATOM   1344   CB   MET   A   94   30.119   13.136   40.070   1.00   7.97   C       ATOM   1347   CG   MET   A   94   28.937   13.593   39.231   1.00   9.97   C       ATOM   1350   SD   MET   A   94   27.301   12.983   39.741   1.00   9.34   S       ATOM   1351   CE   MET   A   94   27.147   13.874   41.283   1.00   10.18   C       ATOM   1355   C   MET   A   94   30.877   11.291   38.588   1.00   7.52   C       ATOM   1356   O   MET   A   94   31.958   11.760   38.167   1.00   7.31   O       ATOM   1358   N   LEU   A   95   30.152   10.399   37.907   1.00   7.87   N       ATOM   1359   CA   LEU   A   95   30.511   10.025   36.542   1.00   7.80   C       ATOM   1361   CB   LEU   A   95   29.836   8.714   36.120   1.00   7.80   C       ATOM   1364   CG   LEU   A   95   30.586   7.423   36.437   1.00   9.86   C       ATOM   1366   CD1   LEU   A   95   31.820   7.207   35.574   1.00   11.31   C       ATOM   1370   CD2   LEU   A   95   30.907   7.368   37.943   1.00   10.48   C       ATOM   1374   C   LEU   A   95   30.176   11.134   35.520   1.00   9.01   C       ATOM   1375   O   LEU   A   95   29.127   11.817   35.573   1.00   9.51   O       ATOM   1377   N   GLU   A   96   31.105   11.287   34.588   1.00   7.72   N       ATOM   1378   CA   GLU   A   96   30.885   12.081   33.378   1.00   9.25   C       ATOM   1380   CB   GLU   A   96   32.194   12.109   32.576   1.00   9.27   C       ATOM   1383   CG   GLU   A   96   32.102   12.995   31.340   1.00   11.60   C       ATOM   1386   CD   GLU   A   96   33.104   12.676   30.232   1.00   12.47   C       ATOM   1387   OE1   GLU   A   96   33.622   11.523   30.087   1.00   15.75   O       ATOM   1388   OE2   GLU   A   96   33.299   13.608   29.422   1.00   19.07   O       ATOM   1389   C   GLU   A   96   29.757   11.441   32.528   1.00   8.51   C       ATOM   1390   O   GLU   A   96   29.860   10.294   32.115   1.00   8.64   O       ATOM   1392   N   CYS   A   97   28.667   12.175   32.302   1.00   9.62   N       ATOM   1393   CA   CYS   A   97   27.535   11.669   31.529   1.00   9.42   C       ATOM   1395   CB   CYS   A   97   26.483   12.790   31.349   1.00   8.87   C       ATOM   1398   SG   CYS   A   97   25.542   13.065   32.851   1.00   12.10   S       ATOM   1400   C   CYS   A   97   27.963   11.127   30.161   1.00   9.98   C       ATOM   1401   O   CYS   A   97   27.520   10.056   29.716   1.00   9.98   O       ATOM   1403   N   LEU   A   98   28.855   11.850   29.511   1.00   9.65   N       ATOM   1404   CA   LEU   A   98   29.404   11.373   28.223   1.00   11.52   C       ATOM   1406   CB   LEU   A   98   30.241   12.452   27.597   1.00   12.26   C       ATOM   1409   CG   LEU   A   98   29.420   13.622   27.039   1.00   15.94   C       ATOM   1411   CD1   LEU   A   98   30.349   14.683   26.518   1.00   19.86   C       ATOM   1415   CD2   LEU   A   98   28.428   13.204   25.939   1.00   19.10   C       ATOM   1419   C   LEU   A   98   30.160   10.023   28.230   1.00   10.56   C       ATOM   1420   O   LEU   A   98   30.307   9.407   27.174   1.00   10.78   O       ATOM   1422   N   SER   A   99   30.649   9.586   29.387   1.00   9.83   N       ATOM   1423   CA   SER   A   99   31.226   8.259   29.520   1.00   9.91   C       ATOM   1425   CB   SER   A   99   32.175   8.171   30.729   1.00   10.76   C       ATOM   1428   OG   SER   A   99   33.364   8.855   30.520   1.00   11.45   O       ATOM   1430   C   SER   A   99   30.230   7.132   29.658   1.00   11.32   C       ATOM   1431   O   SER   A   99   30.641   5.970   29.671   1.00   12.39   O       ATOM   1433   N   LEU   A   100   28.943   7.438   29.831   1.00   9.82   N       ATOM   1434   CA   LEU   A   100   27.958   6.400   30.119   1.00   10.93   C       ATOM   1436   CB   LEU   A   100   26.996   6.915   31.204   1.00   10.49   C       ATOM   1439   CG   LEU   A   100   27.629   7.403   32.517   1.00   11.90   C       ATOM   1441   CD1   LEU   A   100   26.615   8.112   33.387   1.00   12.68   C       ATOM   1445   CD2   LEU   A   100   28.298   6.256   33.253   1.00   12.67   C       ATOM   1449   C   LEU   A   100   27.199   6.043   28.858   1.00   10.94   C       ATOM   1450   O   LEU   A   100   26.527   6.895   28.300   1.00   11.49   O       ATOM   1452   N   PRO   A   101   27.328   4.802   28.376   1.00   12.49   N       ATOM   1453   CA   PRO   A   101   26.705   4.491   27.079   1.00   14.38   C       ATOM   1455   CB   PRO   A   101   27.164   3.049   26.780   1.00   14.56   C       ATOM   1458   CG   PRO   A   101   27.671   2.504   28.043   1.00   13.39   C       ATOM   1461   CD   PRO   A   101   28.072   3.664   28.932   1.00   12.86   C       ATOM   1464   C   PRO   A   101   25.179   4.618   27.170   1.00   16.17   C       ATOM   1465   O   PRO   A   101   24.586   4.219   28.169   1.00   17.28   O       ATOM   1466   N   ARG   A   102   24.542   5.236   26.180   1.00   18.27   N       ATOM   1467   CA   ARG   A   102   23.071   5.467   26.252   1.00   18.80   C       ATOM   1469   CB   ARG   A   102   22.288   4.167   26.058   1.00   20.13   C       ATOM   1478   C   ARG   A   102   22.501   6.186   27.484   1.00   20.78   C       ATOM   1479   O   ARG   A   102   21.292   6.102   27.722   1.00   20.36   O       ATOM   1481   N   ALA   A   103   23.344   6.848   28.278   1.00   21.29   N       ATOM   1482   CA   ALA   A   103   22.902   8.075   28.944   1.00   22.02   C       ATOM   1484   CB   ALA   A   103   24.018   8.713   29.749   1.00   21.04   C       ATOM   1488   C   ALA   A   103   22.504   8.998   27.806   1.00   23.53   C       ATOM   1489   O   ALA   A   103   23.080   8.919   26.705   1.00   26.11   O       ATOM   1491   N   GLY   A   104   21.536   9.860   28.046   1.00   24.21   N       ATOM   1492   CA   GLY   A   104   21.126   10.821   27.038   1.00   24.18   C       ATOM   1495   C   GLY   A   104   21.141   12.226   27.582   1.00   24.08   C       ATOM   1496   O   GLY   A   104   21.794   12.520   28.615   1.00   24.73   O       ATOM   1498   N   ARG   A   105   20.363   13.077   26.925   1.00   23.02   N       ATOM   1499   CA   ARG   A   105   20.319   14.505   27.210   1.00   21.51   C       ATOM   1501   CB   ARG   A   105   19.374   15.210   26.220   1.00   22.65   C       ATOM   1510   C   ARG   A   105   19.897   14.834   28.654   1.00   20.55   C       ATOM   1511   O   ARG   A   105   20.291   15.867   29.153   1.00   21.64   O       ATOM   1513   N   SER   A   106   19.133   13.946   29.300   1.00   18.47   N       ATOM   1514   CA   SER   A   106   18.572   14.125   30.627   1.00   18.10   C       ATOM   1516   CB   SER   A   106   17.404   13.135   30.738   1.00   17.99   C       ATOM   1519   OG   SER   A   106   16.607   13.369   31.835   1.00   25.30   O       ATOM   1521   C   SER   A   106   19.563   13.852   31.795   1.00   14.68   C       ATOM   1522   O   SER   A   106   19.290   14.115   32.987   1.00   15.45   O       ATOM   1524   N   CYS   A   107   20.708   13.282   31.443   1.00   12.87   N       ATOM   1525   CA   CYS   A   107   21.700   12.891   32.455   1.00   11.12   C       ATOM   1527   CB   CYS   A   107   22.817   12.123   31.753   1.00   11.59   C       ATOM   1530   SG   CYS   A   107   24.162   11.512   32.802   1.00   12.27   S       ATOM   1532   C   CYS   A   107   22.221   14.143   33.175   1.00   10.83   C       ATOM   1533   O   CYS   A   107   22.444   15.198   32.548   1.00   11.33   O       ATOM   1535   N   LYS   A   108   22.466   14.000   34.485   1.00   10.91   N       ATOM   1536   CA   LYS   A   108   22.880   15.103   35.357   1.00   10.39   C       ATOM   1538   CB   LYS   A   108   21.810   15.383   36.426   1.00   11.64   C       ATOM   1541   CG   LYS   A   108   20.441   15.745   35.847   1.00   14.77   C       ATOM   1544   CD   LYS   A   108   20.525   16.934   34.961   1.00   17.33   C       ATOM   1547   CE   LYS   A   108   19.159   17.265   34.350   1.00   19.39   C       ATOM   1550   NZ   LYS   A   108   19.274   18.369   33.346   1.00   25.41   N       ATOM   1554   C   LYS   A   108   24.195   14.732   36.042   1.00   9.99   C       ATOM   1555   O   LYS   A   108   24.544   13.535   36.099   1.00   9.47   O       ATOM   1557   N   GLU   A   109   24.893   15.755   36.537   1.00   9.09   N       ATOM   1558   CA   GLU   A   109   26.160   15.592   37.286   1.00   8.94   C       ATOM   1560   CB   GLU   A   109   27.343   16.058   36.435   1.00   9.45   C       ATOM   1563   CG   GLU   A   109   27.565   15.126   35.214   1.00   9.12   C       ATOM   1566   CD   GLU   A   109   28.416   15.737   34.096   1.00   11.55   C       ATOM   1567   OE1   GLU   A   109   28.725   16.969   34.146   1.00   12.46   O       ATOM   1568   OE2   GLU   A   109   28.695   15.006   33.114   1.00   11.28   O       ATOM   1569   C   GLU   A   109   26.107   16.264   38.660   1.00   9.52   C       ATOM   1570   O   GLU   A   109   27.103   16.795   39.154   1.00   9.16   O       ATOM   1572   N   THR   A   110   24.926   16.208   39.265   1.00   9.72   N       ATOM   1573   CA   THR   A   110   24.634   16.848   40.560   1.00   10.44   C       ATOM   1575   CB   THR   A   110   23.915   18.228   40.417   1.00   11.43   C       ATOM   1577   OG1   THR   A   110   22.567   18.038   39.910   1.00   11.72   O       ATOM   1579   CG2   THR   A   110   24.671   19.176   39.515   1.00   12.59   C       ATOM   1583   C   THR   A   110   23.711   15.949   41.378   1.00   10.11   C       ATOM   1584   O   THR   A   110   23.154   14.985   40.854   1.00   9.27   O       ATOM   1586   N   PHE   A   111   23.621   16.248   42.666   1.00   9.89   N       ATOM   1587   CA   PHE   A   111   22.630   15.628   43.565   1.00   9.35   C       ATOM   1589   CB   PHE   A   111   23.124   14.385   44.258   1.00   9.32   C       ATOM   1592   CG   PHE   A   111   24.261   14.625   45.235   1.00   9.36   C       ATOM   1593   CD1   PHE   A   111   24.050   14.561   46.582   1.00   11.62   C       ATOM   1595   CE1   PHE   A   111   25.090   14.724   47.466   1.00   11.92   C       ATOM   1597   CZ   PHE   A   111   26.381   14.950   47.011   1.00   11.03   C       ATOM   1599   CE2   PHE   A   111   26.618   15.013   45.701   1.00   10.10   C       ATOM   1601   CD2   PHE   A   111   25.569   14.828   44.782   1.00   9.30   C       ATOM   1603   C   PHE   A   111   22.240   16.729   44.561   1.00   10.26   C       ATOM   1604   O   PHE   A   111   22.954   17.724   44.726   1.00   9.99   O       ATOM   1606   N   THR   A   112   21.090   16.576   45.199   1.00   8.76   N       ATOM   1607   CA   THR   A   112   20.624   17.601   46.133   1.00   8.93   C       ATOM   1609   CB   THR   A   112   19.291   18.185   45.671   1.00   10.01   C       ATOM   1611   OG1   THR   A   112   19.472   18.700   44.324   1.00   10.82   O       ATOM   1613   CG2   THR   A   112   18.818   19.278   46.593   1.00   10.35   C       ATOM   1617   C   THR   A   112   20.554   17.039   47.567   1.00   8.49   C       ATOM   1618   O   THR   A   112   20.090   15.914   47.811   1.00   9.37   O       ATOM   1620   N   VAL   A   113   21.025   17.864   48.492   1.00   7.91   N       ATOM   1621   CA   VAL   A   113   21.098   17.515   49.910   1.00   8.28   C       ATOM   1623   CB   VAL   A   113   22.472   17.809   50.495   1.00   9.20   C       ATOM   1625   CG1   VAL   A   113   22.472   17.446   52.027   1.00   10.87   C       ATOM   1629   CG2   VAL   A   113   23.518   16.997   49.742   1.00   9.25   C       ATOM   1633   C   VAL   A   113   20.042   18.337   50.668   1.00   9.30   C       ATOM   1634   O   VAL   A   113   19.916   19.559   50.455   1.00   8.34   O       ATOM   1636   N   PHE   A   114   19.287   17.628   51.522   1.00   8.22   N       ATOM   1637   CA   PHE   A   114   18.233   18.186   52.384   1.00   8.86   C       ATOM   1639   CB   PHE   A   114   16.847   17.662   51.976   1.00   9.77   C       ATOM   1642   CG   PHE   A   114   16.447   17.939   50.536   1.00   9.99   C       ATOM   1643   CD1   PHE   A   114   15.627   19.029   50.213   1.00   10.02   C       ATOM   1645   CE1   PHE   A   114   15.245   19.261   48.927   1.00   9.70   C       ATOM   1647   CZ   PHE   A   114   15.702   18.393   47.902   1.00   9.70   C       ATOM   1649   CE2   PHE   A   114   16.454   17.308   48.214   1.00   10.86   C       ATOM   1651   CD2   PHE   A   114   16.851   17.081   49.512   1.00   9.83   C       ATOM   1653   C   PHE   A   114   18.402   17.739   53.835   1.00   8.96   C       ATOM   1654   O   PHE   A   114   19.070   16.721   54.119   1.00   8.46   O       ATOM   1656   N   TYR   A   115   17.785   18.447   54.763   1.00   8.63   N       ATOM   1657   CA   TYR   A   115   17.628   17.889   56.116   1.00   8.52   C       ATOM   1659   CB   TYR   A   115   18.717   18.352   57.092   1.00   8.85   C       ATOM   1662   CG   TYR   A   115   18.585   19.788   57.592   1.00   8.06   C       ATOM   1663   CD1   TYR   A   115   18.116   20.064   58.861   1.00   10.86   C       ATOM   1665   CE1   TYR   A   115   17.978   21.382   59.294   1.00   11.45   C       ATOM   1667   CZ   TYR   A   115   18.312   22.416   58.461   1.00   12.69   C       ATOM   1668   OH   TYR   A   115   18.216   23.747   58.908   1.00   15.40   O       ATOM   1670   CE2   TYR   A   115   18.818   22.152   57.233   1.00   12.22   C       ATOM   1672   CD2   TYR   A   115   18.906   20.837   56.791   1.00   8.82   C       ATOM   1674   C   TYR   A   115   16.241   18.195   56.674   1.00   7.78   C       ATOM   1675   O   TYR   A   115   15.548   19.067   56.162   1.00   8.01   O       ATOM   1677   N   TYR   A   116   15.862   17.463   57.721   1.00   8.13   N       ATOM   1678   CA   TYR   A   116   14.605   17.718   58.413   1.00   8.62   C       ATOM   1680   CB   TYR   A   116   13.434   16.894   57.841   1.00   8.49   C       ATOM   1683   CG   TYR   A   116   12.137   17.248   58.540   1.00   9.29   C       ATOM   1684   CD1   TYR   A   116   11.603   18.513   58.398   1.00   7.91   C       ATOM   1686   CE1   TYR   A   116   10.440   18.911   59.091   1.00   9.45   C       ATOM   1688   CZ   TYR   A   116   9.848   18.035   59.962   1.00   11.48   C       ATOM   1689   OH   TYR   A   116   8.746   18.469   60.719   1.00   14.30   O       ATOM   1691   CE2   TYR   A   116   10.383   16.747   60.125   1.00   11.31   C       ATOM   1693   CD2   TYR   A   116   11.542   16.394   59.459   1.00   12.12   C       ATOM   1695   C   TYR   A   116   14.813   17.407   59.897   1.00   8.75   C       ATOM   1696   O   TYR   A   116   15.348   16.352   60.233   1.00   8.64   O       ATOM   1698   N   GLU   A   117   14.455   18.344   60.768   1.00   9.01   N       ATOM   1699   CA   GLU   A   117   14.596   18.131   62.196   1.00   9.67   C       ATOM   1701   CB   GLU   A   117   14.807   19.445   62.934   1.00   9.99   C       ATOM   1704   CG   GLU   A   117   15.905   20.323   62.447   1.00   11.48   C       ATOM   1707   CD   GLU   A   117   16.063   21.503   63.381   1.00   13.75   C       ATOM   1708   OE1   GLU   A   117   16.333   21.243   64.577   1.00   13.79   O       ATOM   1709   OE2   GLU   A   117   15.902   22.651   62.901   1.00   17.99   O       ATOM   1710   C   GLU   A   117   13.331   17.504   62.789   1.00   9.86   C       ATOM   1711   O   GLU   A   117   12.212   17.874   62.410   1.00   10.42   O       ATOM   1713   N   SER   A   118   13.478   16.574   63.737   1.00   8.88   N       ATOM   1714   CA   SER   A   118   12.326   15.959   64.396   1.00   9.11   C       ATOM   1716   CB   SER   A   118   11.879   14.659   63.724   1.00   9.48   C       ATOM   1719   OG   SER   A   118   12.881   13.657   63.864   1.00   10.18   O       ATOM   1721   C   SER   A   118   12.681   15.716   65.875   1.00   8.87   C       ATOM   1722   O   SER   A   118   13.854   15.513   66.202   1.00   8.37   O       ATOM   1724   N   ASP   A   119   11.688   15.741   66.762   1.00   8.36   N       ATOM   1725   CA   ASP   A   119   11.956   15.650   68.203   1.00   8.09   C       ATOM   1727   CB   ASP   A   119   10.870   16.386   69.021   1.00   8.58   C       ATOM   1730   CG   ASP   A   119   11.244   17.852   69.321   1.00   9.08   C       ATOM   1731   OD1   ASP   A   119   12.453   18.141   69.540   1.00   10.16   O       ATOM   1732   OD2   ASP   A   119   10.325   18.697   69.394   1.00   9.56   O       ATOM   1733   C   ASP   A   119   12.159   14.204   68.678   1.00   7.79   C       ATOM   1734   O   ASP   A   119   12.595   13.945   69.818   1.00   9.62   O       ATOM   1736   N   ALA   A   120   11.912   13.243   67.779   1.00   7.59   N       ATOM   1737   CA   ALA   A   120   12.149   11.813   68.070   1.00   7.40   C       ATOM   1739   CB   ALA   A   120   10.978   11.212   68.854   1.00   8.33   C       ATOM   1743   C   ALA   A   120   12.326   11.074   66.768   1.00   8.16   C       ATOM   1744   O   ALA   A   120   12.084   11.616   65.707   1.00   8.25   O       ATOM   1746   N   ASP   A   121   12.737   9.810   66.857   1.00   8.59   N       ATOM   1747   CA   ASP   A   121   13.030   9.034   65.648   1.00   8.52   C       ATOM   1749   CB   ASP   A   121   14.105   8.003   65.918   1.00   8.73   C       ATOM   1752   CG   ASP   A   121   14.467   7.170   64.703   1.00   10.54   C       ATOM   1753   OD1   ASP   A   121   14.060   7.468   63.530   1.00   10.18   O       ATOM   1754   OD2   ASP   A   121   15.194   6.127   64.922   1.00   11.89   O       ATOM   1755   C   ASP   A   121   11.746   8.379   65.182   1.00   8.94   C       ATOM   1756   O   ASP   A   121   11.482   7.176   65.386   1.00   10.31   O       ATOM   1758   N   THR   A   122   10.956   9.209   64.516   1.00   8.26   N       ATOM   1759   CA   THR   A   122   9.590   8.879   64.128   1.00   8.62   C       ATOM   1761   CB   THR   A   122   8.654   10.049   64.524   1.00   9.55   C       ATOM   1763   OG1   THR   A   122   9.250   11.295   64.131   1.00   10.04   O       ATOM   1765   CG2   THR   A   122   8.384   10.050   66.013   1.00   12.30   C       ATOM   1769   C   THR   A   122   9.413   8.606   62.633   1.00   8.96   C       ATOM   1770   O   THR   A   122   8.276   8.289   62.186   1.00   9.62   O       ATOM   1772   N   ALA   A   123   10.492   8.720   61.861   1.00   8.97   N       ATOM   1773   CA   ALA   A   123   10.395   8.461   60.406   1.00   8.00   C       ATOM   1775   CB   ALA   A   123   11.726   8.688   59.757   1.00   7.19   C       ATOM   1779   C   ALA   A   123   9.923   7.059   60.106   1.00   8.48   C       ATOM   1780   O   ALA   A   123   10.148   6.108   60.915   1.00   9.30   O       ATOM   1782   N   THR   A   124   9.256   6.923   58.946   1.00   9.17   N       ATOM   1783   CA   THR   A   124   8.735   5.656   58.427   1.00   8.89   C       ATOM   1785   CB   THR   A   124   7.192   5.636   58.489   1.00   9.66   C       ATOM   1787   OG1   THR   A   124   6.643   6.543   57.507   1.00   10.24   O       ATOM   1789   CG2   THR   A   124   6.696   5.997   59.853   1.00   9.70   C       ATOM   1793   C   THR   A   124   9.171   5.492   56.967   1.00   9.28   C       ATOM   1794   O   THR   A   124   9.957   6.280   56.448   1.00   8.87   O       ATOM   1796   N   ALA   A   125   8.645   4.469   56.296   1.00   8.98   N       ATOM   1797   CA   ALA   A   125   9.009   4.281   54.880   1.00   8.70   C       ATOM   1799   CB   ALA   A   125   8.402   3.030   54.361   1.00   9.55   C       ATOM   1803   C   ALA   A   125   8.537   5.463   54.028   1.00   8.90   C       ATOM   1804   O   ALA   A   125   9.105   5.729   52.971   1.00   8.92   O       ATOM   1806   N   LEU   A   126   7.476   6.146   54.487   1.00   8.75   N       ATOM   1807   CA   LEU   A   126   6.824   7.189   53.684   1.00   8.77   C       ATOM   1809   CB   LEU   A   126   5.325   6.855   53.591   1.00   9.83   C       ATOM   1812   CG   LEU   A   126   4.982   5.534   52.898   1.00   12.28   C       ATOM   1814   CD1   LEU   A   126   3.476   5.318   52.909   1.00   13.65   C       ATOM   1818   CD2   LEU   A   126   5.463   5.531   51.482   1.00   13.01   C       ATOM   1822   C   LEU   A   126   6.924   8.590   54.227   1.00   9.15   C       ATOM   1823   O   LEU   A   126   6.493   9.552   53.551   1.00   8.84   O       ATOM   1825   N   THR   A   127   7.436   8.732   55.448   1.00   8.64   N       ATOM   1826   CA   THR   A   127   7.471   10.039   56.115   1.00   8.59   C       ATOM   1828   CB   THR   A   127   6.337   10.202   57.149   1.00   9.13   C       ATOM   1830   OG1   THR   A   127   6.472   9.200   58.181   1.00   10.34   O       ATOM   1832   CG2   THR   A   127   4.938   10.113   56.529   1.00   9.97   C       ATOM   1836   C   THR   A   127   8.798   10.216   56.857   1.00   8.79   C       ATOM   1837   O   THR   A   127   9.374   9.219   57.290   1.00   9.36   O       ATOM   1839   N   PRO   A   128   9.273   11.464   57.056   1.00   7.86   N       ATOM   1840   CA   PRO   A   128   8.749   12.723   56.502   1.00   8.31   C       ATOM   1842   CB   PRO   A   128   9.756   13.757   56.897   1.00   8.97   C       ATOM   1845   CG   PRO   A   128   10.676   13.119   57.920   1.00   11.44   C       ATOM   1848   CD   PRO   A   128   10.521   11.642   57.837   1.00   8.52   C       ATOM   1851   C   PRO   A   128   8.595   12.637   54.982   1.00   8.34   C       ATOM   1852   O   PRO   A   128   9.390   11.977   54.321   1.00   8.32   O       ATOM   1853   N   ALA   A   129   7.521   13.256   54.480   1.00   7.80   N       ATOM   1854   CA   ALA   A   129   7.226   13.185   53.048   1.00   7.67   C       ATOM   1856   CB   ALA   A   129   6.063   14.115   52.674   1.00   7.71   C       ATOM   1860   C   ALA   A   129   8.476   13.501   52.240   1.00   7.65   C       ATOM   1861   O   ALA   A   129   9.249   14.425   52.549   1.00   7.64   O       ATOM   1863   N   TRP   A   130   8.683   12.696   51.201   1.00   7.53   N       ATOM   1864   CA   TRP   A   130   9.896   12.673   50.390   1.00   7.75   C       ATOM   1866   CB   TRP   A   130   10.025   11.339   49.697   1.00   8.17   C       ATOM   1869   CG   TRP   A   130   10.217   10.140   50.611   1.00   7.44   C       ATOM   1870   CD1   TRP   A   130   9.246   9.260   51.022   1.00   8.39   C       ATOM   1872   NE1   TRP   A   130   9.803   8.288   51.843   1.00   8.80   N       ATOM   1874   CE2   TRP   A   130   11.158   8.509   51.940   1.00   7.48   C       ATOM   1875   CD2   TRP   A   130   11.456   9.690   51.220   1.00   7.51   C       ATOM   1876   CE3   TRP   A   130   12.767   10.137   51.175   1.00   9.24   C       ATOM   1878   CZ3   TRP   A   130   13.729   9.425   51.829   1.00   8.16   C       ATOM   1880   CH2   TRP   A   130   13.415   8.274   52.564   1.00   9.62   C       ATOM   1882   CZ2   TRP   A   130   12.139   7.800   52.640   1.00   8.22   C       ATOM   1884   C   TRP   A   130   9.882   13.792   49.350   1.00   8.08   C       ATOM   1885   O   TRP   A   130   9.684   13.553   48.140   1.00   9.57   O       ATOM   1887   N   MET   A   131   10.071   15.011   49.847   1.00   7.97   N       ATOM   1888   CA   MET   A   131   9.981   16.190   49.016   1.00   8.31   C       ATOM   1890   CB   MET   A   131   8.509   16.422   48.584   1.00   9.63   C       ATOM   1893   CG   MET   A   131   7.585   16.674   49.801   1.00   8.68   C       ATOM   1896   SD   MET   A   131   5.828   16.800   49.393   1.00   8.53   S       ATOM   1897   CE   MET   A   131   5.459   15.151   48.784   1.00   8.19   C       ATOM   1901   C   MET   A   131   10.452   17.392   49.823   1.00   8.65   C       ATOM   1902   O   MET   A   131   10.399   17.415   51.058   1.00   8.31   O       ATOM   1904   N   GLU   A   132   10.926   18.409   49.102   1.00   8.97   N       ATOM   1905   CA   GLU   A   132   11.142   19.723   49.712   1.00   8.68   C       ATOM   1907   CB   GLU   A   132   11.613   20.750   48.659   1.00   9.38   C       ATOM   1910   CG   GLU   A   132   12.115   22.055   49.280   1.00   9.41   C       ATOM   1913   CD   GLU   A   132   12.825   22.977   48.300   1.00   12.57   C       ATOM   1914   OE1   GLU   A   132   12.952   22.614   47.088   1.00   17.82   O       ATOM   1915   OE2   GLU   A   132   13.203   24.090   48.751   1.00   14.38   O       ATOM   1916   C   GLU   A   132   9.816   20.160   50.334   1.00   9.39   C       ATOM   1917   O   GLU   A   132   8.784   20.126   49.641   1.00   9.43   O       ATOM   1919   N   ASN   A   133   9.876   20.595   51.595   1.00   9.49   N       ATOM   1920   CA   ASN   A   133   8.699   20.897   52.432   1.00   10.02   C       ATOM   1922   CB   ASN   A   133   7.832   21.978   51.781   1.00   11.85   C       ATOM   1925   CG   ASN   A   133   8.611   23.235   51.548   1.00   13.75   C       ATOM   1926   OD1   ASN   A   133   9.246   23.732   52.480   1.00   19.98   O       ATOM   1927   ND2   ASN   A   133   8.568   23.774   50.323   1.00   20.37   N       ATOM   1930   C   ASN   A   133   7.952   19.565   52.636   1.00   9.90   C       ATOM   1931   O   ASN   A   133   6.964   19.276   51.936   1.00   10.29   O       ATOM   1933   N   PRO   A   134   8.348   18.784   53.667   1.00   8.19   N       ATOM   1934   CA   PRO   A   134   9.081   19.193   54.857   1.00   8.07   C       ATOM   1936   CB   PRO   A   134   8.806   18.075   55.835   1.00   7.79   C       ATOM   1939   CG   PRO   A   134   8.589   16.870   54.980   1.00   8.16   C       ATOM   1942   CD   PRO   A   134   7.875   17.398   53.765   1.00   7.85   C       ATOM   1945   C   PRO   A   134   10.573   19.393   54.735   1.00   7.98   C       ATOM   1946   O   PRO   A   134   11.143   20.183   55.503   1.00   9.41   O       ATOM   1947   N   TYR   A   135   11.226   18.626   53.867   1.00   7.28   N       ATOM   1948   CA   TYR   A   135   12.685   18.708   53.827   1.00   8.17   C       ATOM   1950   CB   TYR   A   135   13.272   17.691   52.860   1.00   7.94   C       ATOM   1953   CG   TYR   A   135   13.344   16.303   53.449   1.00   7.81   C       ATOM   1954   CD1   TYR   A   135   14.400   15.969   54.302   1.00   7.46   C       ATOM   1956   CE1   TYR   A   135   14.494   14.725   54.880   1.00   7.44   C       ATOM   1958   CZ   TYR   A   135   13.546   13.749   54.651   1.00   10.60   C       ATOM   1959   OH   TYR   A   135   13.623   12.511   55.280   1.00   11.23   O       ATOM   1961   CE2   TYR   A   135   12.467   14.038   53.802   1.00   9.66   C       ATOM   1963   CD2   TYR   A   135   12.382   15.327   53.205   1.00   8.82   C       ATOM   1965   C   TYR   A   135   13.147   20.120   53.469   1.00   8.11   C       ATOM   1966   O   TYR   A   135   12.553   20.824   52.626   1.00   8.60   O       ATOM   1968   N   ILE   A   136   14.224   20.520   54.144   1.00   8.41   N       ATOM   1969   CA   ILE   A   136   14.860   21.822   53.934   1.00   8.73   C       ATOM   1971   CB   ILE   A   136   15.363   22.435   55.274   1.00   9.60   C       ATOM   1973   CG1   ILE   A   136   14.201   22.577   56.267   1.00   11.04   C       ATOM   1976   CD1   ILE   A   136   14.587   22.844   57.736   1.00   13.67   C       ATOM   1980   CG2   ILE   A   136   16.095   23.749   54.978   1.00   10.67   C       ATOM   1984   C   ILE   A   136   16.032   21.629   52.965   1.00   9.36   C       ATOM   1985   O   ILE   A   136   16.973   20.828   53.217   1.00   8.57   O       ATOM   1987   N   LYS   A   137   15.979   22.326   51.833   1.00   9.57   N       ATOM   1988   CA   LYS   A   137   17.011   22.190   50.828   1.00   10.16   C       ATOM   1990   CB   LYS   A   137   16.547   22.722   49.479   1.00   10.97   C       ATOM   1993   CG   LYS   A   137   17.639   22.695   48.426   1.00   12.27   C       ATOM   1996   CD   LYS   A   137   17.156   23.116   47.044   1.00   14.11   C       ATOM   1999   CE   LYS   A   137   18.242   23.092   46.049   1.00   17.64   C       ATOM   2002   NZ   LYS   A   137   17.759   23.572   44.737   1.00   21.53   N       ATOM   2006   C   LYS   A   137   18.274   22.909   51.282   1.00   10.14   C       ATOM   2007   O   LYS   A   137   18.209   24.117   51.631   1.00   11.61   O       ATOM   2009   N   VAL   A   138   19.391   22.177   51.323   1.00   10.00   N       ATOM   2010   CA   VAL   A   138   20.662   22.750   51.744   1.00   9.75   C       ATOM   2012   CB   VAL   A   138   21.508   21.766   52.568   1.00   10.72   C       ATOM   2014   CG1   VAL   A   138   22.809   22.438   53.017   1.00   11.63   C       ATOM   2018   CG2   VAL   A   138   20.746   21.229   53.746   1.00   11.62   C       ATOM   2022   C   VAL   A   138   21.428   23.222   50.523   1.00   10.39   C       ATOM   2023   O   VAL   A   138   21.892   24.373   50.521   1.00   11.53   O       ATOM   2025   N   ASP   A   139   21.580   22.355   49.516   1.00   10.55   N       ATOM   2026   CA   ASP   A   139   22.384   22.691   48.314   1.00   9.26   C       ATOM   2028   CB   ASP   A   139   23.874   22.700   48.644   1.00   9.42   C       ATOM   2031   CG   ASP   A   139   24.738   23.339   47.558   1.00   12.48   C       ATOM   2032   OD1   ASP   A   139   24.306   24.316   46.912   1.00   15.60   O       ATOM   2033   OD2   ASP   A   139   25.895   22.865   47.416   1.00   13.71   O       ATOM   2034   C   ASP   A   139   22.166   21.658   47.252   1.00   8.41   C       ATOM   2035   O   ASP   A   139   22.045   20.489   47.573   1.00   9.94   O       ATOM   2037   N   THR   A   140   22.108   22.090   46.003   1.00   9.42   N       ATOM   2038   CA   THR   A   140   22.301   21.170   44.856   1.00   9.48   C       ATOM   2040   CB   THR   A   140   21.510   21.576   43.591   1.00   10.64   C       ATOM   2042   OG1   THR   A   140   20.096   21.488   43.845   1.00   12.64   O       ATOM   2044   CG2   THR   A   140   21.857   20.638   42.464   1.00   11.25   C       ATOM   2048   C   THR   A   140   23.809   21.192   44.615   1.00   10.29   C       ATOM   2049   O   THR   A   140   24.403   22.247   44.234   1.00   11.10   O       ATOM   2051   N   VAL   A   141   24.423   20.055   44.914   1.00   9.97   N       ATOM   2052   CA   VAL   A   141   25.890   19.898   44.924   1.00   10.16   C       ATOM   2054   CB   VAL   A   141   26.277   18.801   45.938   1.00   10.62   C       ATOM   2056   CG1   VAL   A   141   27.799   18.563   45.949   1.00   10.86   C       ATOM   2060   CG2   VAL   A   141   25.834   19.189   47.341   1.00   10.37   C       ATOM   2064   C   VAL   A   141   26.408   19.547   43.546   1.00   11.24   C       ATOM   2065   O   VAL   A   141   25.976   18.541   42.963   1.00   10.48   O       ATOM   2067   N   ALA   A   142   27.352   20.360   43.056   1.00   11.87   N       ATOM   2068   CA   ALA   A   142   27.983   20.108   41.768   1.00   13.96   C       ATOM   2070   CB   ALA   A   142   28.145   21.383   41.002   1.00   14.94   C       ATOM   2074   C   ALA   A   142   29.318   19.393   41.992   1.00   14.04   C       ATOM   2075   O   ALA   A   142   29.862   19.299   43.121   1.00   14.70   O       ATOM   2077   N   ALA   A   143   29.803   18.761   40.939   1.00   13.39   N       ATOM   2078   CA   ALA   A   143   31.028   18.031   41.014   1.00   12.05   C       ATOM   2080   CB   ALA   A   143   30.843   16.605   40.498   1.00   12.80   C       ATOM   2084   C   ALA   A   143   32.084   18.743   40.182   1.00   12.33   C       ATOM   2085   O   ALA   A   143   31.951   18.796   38.937   1.00   14.44   O       ATOM   2087   N   GLU   A   144   33.139   19.250   40.825   1.00   13.57   N       ATOM   2088   CA   GLU   A   144   34.280   19.809   40.083   1.00   13.75   C       ATOM   2090   CB   GLU   A   144   35.250   20.550   41.014   1.00   16.16   C       ATOM   2097   C   GLU   A   144   35.085   18.722   39.347   1.00   12.44   C       ATOM   2098   O   GLU   A   144   35.769   18.992   38.333   1.00   14.14   O       ATOM   2100   N   HIS   A   145   35.027   17.493   39.860   1.00   10.12   N       ATOM   2101   CA   HIS   A   145   35.796   16.368   39.332   1.00   10.38   C       ATOM   2103   CB   HIS   A   145   36.700   15.784   40.422   1.00   11.19   C       ATOM   2106   CG   HIS   A   145   37.540   16.818   41.088   1.00   14.12   C       ATOM   2107   ND1   HIS   A   145   38.612   17.412   40.461   1.00   15.31   N       ATOM   2109   CE1   HIS   A   145   39.149   18.314   41.270   1.00   15.39   C       ATOM   2111   NE2   HIS   A   145   38.484   18.302   42.410   1.00   15.57   N       ATOM   2113   CD2   HIS   A   145   37.464   17.374   42.319   1.00   15.78   C       ATOM   2115   C   HIS   A   145   34.901   15.279   38.826   1.00   9.44   C       ATOM   2116   O   HIS   A   145   34.166   14.653   39.601   1.00   9.58   O       ATOM   2118   N   LEU   A   146   34.918   15.065   37.515   1.00   8.62   N       ATOM   2119   CA   LEU   A   146   34.147   13.985   36.905   1.00   8.83   C       ATOM   2121   CB   LEU   A   146   33.532   14.458   35.583   1.00   7.80   C       ATOM   2124   CG   LEU   A   146   32.613   15.647   35.720   1.00   10.46   C       ATOM   2126   CD1   LEU   A   146   32.213   16.186   34.352   1.00   13.82   C       ATOM   2130   CD2   LEU   A   146   31.360   15.319   36.532   1.00   12.33   C       ATOM   2134   C   LEU   A   146   35.039   12.782   36.641   1.00   8.88   C       ATOM   2135   O   LEU   A   146   36.196   12.917   36.142   1.00   10.66   O       ATOM   2137   N   THR   A   147   34.519   11.603   36.989   1.00   7.96   N       ATOM   2138   CA   THR   A   147   35.160   10.340   36.676   1.00   8.03   C       ATOM   2140   CB   THR   A   147   34.756   9.277   37.693   1.00   9.05   C       ATOM   2142   OG1   THR   A   147   35.293   9.664   38.977   1.00   9.24   O       ATOM   2144   CG2   THR   A   147   35.234   7.926   37.337   1.00   9.73   C       ATOM   2148   C   THR   A   147   34.826   9.923   35.257   1.00   8.52   C       ATOM   2149   O   THR   A   147   33.661   10.037   34.830   1.00   8.12   O       ATOM   2151   N   ARG   A   148   35.858   9.490   34.542   1.00   7.65   N       ATOM   2152   CA   ARG   A   148   35.756   9.129   33.116   1.00   9.81   C       ATOM   2154   CB   ARG   A   148   36.751   9.921   32.277   1.00   10.51   C       ATOM   2157   CG   ARG   A   148   36.501   11.417   32.300   1.00   11.89   C       ATOM   2160   CD   ARG   A   148   37.608   12.217   31.636   1.00   13.56   C       ATOM   2163   NE   ARG   A   148   37.761   11.745   30.264   1.00   18.52   N       ATOM   2165   CZ   ARG   A   148   37.240   12.319   29.175   1.00   17.48   C       ATOM   2166   NH1   ARG   A   148   36.501   13.464   29.244   1.00   12.11   N       ATOM   2169   NH2   ARG   A   148   37.438   11.695   27.998   1.00   16.48   N       ATOM   2172   C   ARG   A   148   36.026   7.631   32.940   1.00   10.90   C       ATOM   2173   O   ARG   A   148   36.801   7.072   33.695   1.00   10.86   O       ATOM   2175   N   LYS   A   149   35.376   7.005   31.962   1.00   11.83   N       ATOM   2176   CA   LYS   A   149   35.681   5.589   31.597   1.00   14.09   C       ATOM   2178   CB   LYS   A   149   34.911   4.565   32.415   1.00   15.18   C       ATOM   2181   CG   LYS   A   149   35.164   3.097   31.939   1.00   16.23   C       ATOM   2184   CD   LYS   A   149   34.683   2.035   32.871   1.00   19.77   C       ATOM   2187   CE   LYS   A   149   35.136   0.618   32.360   1.00   17.69   C       ATOM   2190   NZ   LYS   A   149   35.284   0.467   30.843   1.00   22.60   N       ATOM   2194   C   LYS   A   149   35.449   5.411   30.116   1.00   16.14   C       ATOM   2195   O   LYS   A   149   34.402   5.773   29.600   1.00   16.09   O       ATOM   2197   N   ARG   A   150   36.445   4.841   29.449   1.00   16.85   N       ATOM   2198   CA   ARG   A   150   36.590   4.806   27.965   1.00   17.08   C       ATOM   2200   CB   ARG   A   150   37.942   5.349   27.720   1.00   19.68   C       ATOM   2203   CG   ARG   A   150   38.557   4.959   26.571   1.00   19.86   C       ATOM   2206   CD   ARG   A   150   37.760   5.417   25.529   1.00   22.77   C       ATOM   2209   NE   ARG   A   150   37.895   6.784   25.135   1.00   23.77   N       ATOM   2211   CZ   ARG   A   150   38.499   7.765   25.788   1.00   20.28   C       ATOM   2212   NH1   ARG   A   150   38.461   8.938   25.172   1.00   22.53   N       ATOM   2215   NH2   ARG   A   150   39.131   7.624   26.975   1.00   18.40   N       ATOM   2218   C   ARG   A   150   36.544   3.358   27.660   1.00   16.33   C       ATOM   2219   O   ARG   A   150   37.001   2.613   28.491   1.00   16.88   O       ATOM   2221   N   PRO   A   151   35.945   2.927   26.503   1.00   15.43   N       ATOM   2222   CA   PRO   A   151   35.669   1.481   26.330   1.00   14.71   C       ATOM   2224   CB   PRO   A   151   35.041   1.386   24.925   1.00   15.62   C       ATOM   2227   CG   PRO   A   151   35.376   2.710   24.211   1.00   15.64   C       ATOM   2230   CD   PRO   A   151   35.407   3.704   25.367   1.00   16.12   C       ATOM   2233   C   PRO   A   151   36.926   0.644   26.427   1.00   14.70   C       ATOM   2234   O   PRO   A   151   37.895   1.013   25.751   1.00   10.80   O       ATOM   2235   N   GLY   A   152   36.885   −0.437   27.224   1.00   11.37   N       ATOM   2236   CA   GLY   A   152   38.053   −1.334   27.452   1.00   13.67   C       ATOM   2239   C   GLY   A   152   38.962   −1.104   28.672   1.00   13.66   C       ATOM   2240   O   GLY   A   152   39.807   −1.950   29.084   1.00   12.78   O       ATOM   2242   N   ALA   A   153   38.745   0.033   29.337   1.00   13.91   N       ATOM   2243   CA   ALA   A   153   39.737   0.621   30.227   1.00   12.51   C       ATOM   2245   CB   ALA   A   153   40.168   1.917   29.612   1.00   11.34   C       ATOM   2249   C   ALA   A   153   39.258   0.882   31.660   1.00   12.62   C       ATOM   2250   O   ALA   A   153   38.043   1.004   31.877   1.00   14.96   O       ATOM   2252   N   GLU   A   154   40.182   0.992   32.614   1.00   12.32   N       ATOM   2253   CA   GLU   A   154   39.825   1.383   33.966   1.00   12.28   C       ATOM   2255   CB   GLU   A   154   40.977   1.233   34.934   1.00   13.61   C       ATOM   2262   C   GLU   A   154   39.329   2.818   34.003   1.00   11.59   C       ATOM   2263   O   GLU   A   154   39.850   3.677   33.311   1.00   9.51   O       ATOM   2265   N   ALA   A   155   38.349   3.064   34.856   1.00   12.64   N       ATOM   2266   CA   ALA   A   155   37.901   4.424   35.135   1.00   11.59   C       ATOM   2268   CB   ALA   A   155   36.676   4.385   36.073   1.00   12.13   C       ATOM   2272   C   ALA   A   155   39.026   5.256   35.750   1.00   11.54   C       ATOM   2273   O   ALA   A   155   39.922   4.759   36.495   1.00   12.39   O       ATOM   2275   N   THR   A   156   39.024   6.567   35.451   1.00   10.29   N       ATOM   2276   CA   THR   A   156   39.991   7.487   36.018   1.00   10.85   C       ATOM   2278   CB   THR   A   156   41.025   8.000   34.960   1.00   12.01   C       ATOM   2280   OG1   THR   A   156   40.344   8.740   33.942   1.00   16.35   O       ATOM   2282   CG2   THR   A   156   41.787   6.861   34.355   1.00   14.57   C       ATOM   2286   C   THR   A   156   39.242   8.676   36.572   1.00   11.26   C       ATOM   2287   O   THR   A   156   38.272   9.105   35.972   1.00   11.47   O       ATOM   2289   N   GLY   A   157   39.679   9.210   37.699   1.00   11.15   N       ATOM   2290   CA   GLY   A   157   38.910   10.275   38.306   1.00   11.21   C       ATOM   2293   C   GLY   A   157   39.438   10.644   39.671   1.00   11.02   C       ATOM   2294   O   GLY   A   157   40.298   9.944   40.220   1.00   13.12   O       ATOM   2296   N   LYS   A   158   38.941   11.766   40.139   1.00   10.68   N       ATOM   2297   CA   LYS   A   158   39.181   12.210   41.524   1.00   9.49   C       ATOM   2299   CB   LYS   A   158   39.732   13.623   41.490   1.00   9.39   C       ATOM   2302   CG   LYS   A   158   41.165   13.767   40.912   1.00   10.25   C       ATOM   2305   CD   LYS   A   158   41.557   15.195   40.711   1.00   11.46   C       ATOM   2308   CE   LYS   A   158   43.011   15.314   40.210   1.00   15.64   C       ATOM   2311   NZ   LYS   A   158   43.357   16.712   39.708   1.00   16.95   N       ATOM   2315   C   LYS   A   158   37.913   12.200   42.330   1.00   9.39   C       ATOM   2316   O   LYS   A   158   36.804   12.363   41.805   1.00   9.89   O       ATOM   2318   N   VAL   A   159   38.098   12.081   43.627   1.00   9.10   N       ATOM   2319   CA   VAL   A   159   36.990   12.188   44.564   1.00   9.25   C       ATOM   2321   CB   VAL   A   159   37.323   11.430   45.876   1.00   10.17   C       ATOM   2323   CG1   VAL   A   159   36.211   11.643   46.920   1.00   11.49   C       ATOM   2327   CG2   VAL   A   159   37.535   9.939   45.589   1.00   11.58   C       ATOM   2331   C   VAL   A   159   36.674   13.646   44.850   1.00   9.07   C       ATOM   2332   O   VAL   A   159   37.570   14.466   44.949   1.00   10.34   O       ATOM   2334   N   ASN   A   160   35.375   13.967   44.962   1.00   8.44   N       ATOM   2335   CA   ASN   A   160   34.893   15.296   45.314   1.00   7.91   C       ATOM   2337   CB   ASN   A   160   33.565   15.595   44.602   1.00   8.74   C       ATOM   2340   CG   ASN   A   160   33.729   15.628   43.113   1.00   8.92   C       ATOM   2341   OD1   ASN   A   160   34.114   16.647   42.578   1.00   9.80   O       ATOM   2342   ND2   ASN   A   160   33.475   14.502   42.443   1.00   10.16   N       ATOM   2345   C   ASN   A   160   34.614   15.359   46.825   1.00   8.46   C       ATOM   2346   O   ASN   A   160   34.234   14.366   47.435   1.00   9.78   O       ATOM   2348   N   VAL   A   161   34.776   16.542   47.378   1.00   8.68   N       ATOM   2349   CA   VAL   A   161   34.398   16.796   48.777   1.00   8.98   C       ATOM   2351   CB   VAL   A   161   35.614   16.836   49.747   1.00   10.70   C       ATOM   2353   CG1   VAL   A   161   36.624   17.942   49.409   1.00   11.76   C       ATOM   2357   CG2   VAL   A   161   35.138   16.966   51.192   1.00   9.80   C       ATOM   2361   C   VAL   A   161   33.615   18.117   48.836   1.00   9.38   C       ATOM   2362   O   VAL   A   161   33.955   19.116   48.208   1.00   10.78   O       ATOM   2364   N   LYS   A   162   32.522   18.096   49.594   1.00   9.73   N       ATOM   2365   CA   LYS   A   162   31.708   19.264   49.873   1.00   9.18   C       ATOM   2367   CB   LYS   A   162   30.374   19.207   49.057   1.00   10.14   C       ATOM   2370   CG   LYS   A   162   29.491   20.452   49.235   1.00   13.01   C       ATOM   2373   CD   LYS   A   162   30.092   21.701   48.670   1.00   16.54   C       ATOM   2376   CE   LYS   A   162   29.144   22.929   48.785   1.00   19.66   C       ATOM   2379   NZ   LYS   A   162   29.808   24.238   48.416   1.00   22.42   N       ATOM   2383   C   LYS   A   162   31.361   19.219   51.374   1.00   9.98   C       ATOM   2384   O   LYS   A   162   30.879   18.163   51.860   1.00   10.27   O       ATOM   2386   N   THR   A   163   31.558   20.331   52.077   1.00   9.42   N       ATOM   2387   CA   THR   A   163   31.096   20.469   53.452   1.00   9.80   C       ATOM   2389   CB   THR   A   163   32.246   20.807   54.403   1.00   9.67   C       ATOM   2391   OG1   THR   A   163   33.214   19.739   54.358   1.00   9.52   O       ATOM   2393   CG2   THR   A   163   31.765   21.006   55.808   1.00   11.48   C       ATOM   2397   C   THR   A   163   29.992   21.530   53.491   1.00   9.97   C       ATOM   2398   O   THR   A   163   30.157   22.652   52.999   1.00   11.36   O       ATOM   2400   N   LEU   A   164   28.855   21.128   54.042   1.00   10.53   N       ATOM   2401   CA   LEU   A   164   27.671   21.932   54.209   1.00   10.36   C       ATOM   2403   CB   LEU   A   164   26.474   21.165   53.625   1.00   11.41   C       ATOM   2406   CG   LEU   A   164   26.646   20.822   52.143   1.00   13.33   C       ATOM   2408   CD1   LEU   A   164   25.497   19.943   51.643   1.00   16.96   C       ATOM   2412   CD2   LEU   A   164   26.756   22.072   51.298   1.00   16.24   C       ATOM   2416   C   LEU   A   164   27.440   22.268   55.670   1.00   10.61   C       ATOM   2417   O   LEU   A   164   27.750   21.473   56.555   1.00   12.15   O       ATOM   2419   N   ARG   A   165   26.914   23.463   55.924   1.00   10.93   N       ATOM   2420   CA   ARG   A   165   26.586   23.874   57.284   1.00   11.96   C       ATOM   2422   CB   ARG   A   165   27.171   25.240   57.599   1.00   12.49   C       ATOM   2425   CG   ARG   A   165   26.974   25.703   59.029   1.00   13.26   C       ATOM   2428   CD   ARG   A   165   27.616   27.089   59.136   1.00   15.90   C       ATOM   2431   NE   ARG   A   165   27.727   27.688   60.469   1.00   20.51   N       ATOM   2433   CZ   ARG   A   165   27.136   28.826   60.844   1.00   21.93   C       ATOM   2434   NH1   ARG   A   165   26.352   29.490   60.013   1.00   23.30   N       ATOM   2437   NH2   ARG   A   165   27.315   29.303   62.067   1.00   23.95   N       ATOM   2440   C   ARG   A   165   25.056   23.909   57.443   1.00   12.67   C       ATOM   2441   O   ARG   A   165   24.345   24.577   56.664   1.00   14.74   O       ATOM   2443   N   LEU   A   166   24.577   23.178   58.436   1.00   11.74   N       ATOM   2444   CA   LEU   A   166   23.132   22.964   58.690   1.00   11.51   C       ATOM   2446   CB   LEU   A   166   22.792   21.486   58.930   1.00   12.12   C       ATOM   2449   CG   LEU   A   166   23.316   20.409   58.006   1.00   17.08   C       ATOM   2451   CD1   LEU   A   166   22.908   19.019   58.467   1.00   19.61   C       ATOM   2455   CD2   LEU   A   166   22.886   20.648   56.641   1.00   20.41   C       ATOM   2459   C   LEU   A   166   22.748   23.732   59.945   1.00   11.98   C       ATOM   2460   O   LEU   A   166   23.450   23.645   60.930   1.00   12.34   O       ATOM   2462   N   GLY   A   167   21.563   24.386   59.937   1.00   12.12   N       ATOM   2463   CA   GLY   A   167   21.048   25.052   61.106   1.00   12.77   C       ATOM   2466   C   GLY   A   167   20.628   26.496   60.813   1.00   14.49   C       ATOM   2467   O   GLY   A   167   20.639   26.913   59.642   1.00   14.88   O       ATOM   2469   N   PRO   A   168   20.256   27.233   61.861   1.00   14.26   N       ATOM   2470   CA   PRO   A   168   20.320   26.798   63.252   1.00   13.89   C       ATOM   2472   CB   PRO   A   168   20.073   28.093   64.030   1.00   15.57   C       ATOM   2475   CG   PRO   A   168   19.159   28.871   63.098   1.00   16.62   C       ATOM   2478   CD   PRO   A   168   19.658   28.586   61.740   1.00   15.12   C       ATOM   2481   C   PRO   A   168   19.276   25.749   63.616   1.00   13.01   C       ATOM   2482   O   PRO   A   168   18.112   25.762   63.108   1.00   14.29   O       ATOM   2483   N   LEU   A   169   19.698   24.816   64.458   1.00   12.79   N       ATOM   2484   CA   LEU   A   169   18.906   23.655   64.842   1.00   11.32   C       ATOM   2486   CB   LEU   A   169   19.767   22.400   64.948   1.00   12.93   C       ATOM   2489   CG   LEU   A   169   20.561   22.078   63.691   1.00   13.60   C       ATOM   2491   CD1   LEU   A   169   21.509   20.931   64.018   1.00   16.57   C       ATOM   2495   CD2   LEU   A   169   19.626   21.728   62.550   1.00   15.53   C       ATOM   2499   C   LEU   A   169   18.244   23.882   66.193   1.00   13.18   C       ATOM   2500   O   LEU   A   169   18.778   24.595   67.052   1.00   13.33   O       ATOM   2502   N   SER   A   170   17.052   23.329   66.370   1.00   12.97   N       ATOM   2503   CA   SER   A   170   16.352   23.474   67.646   1.00   14.51   C       ATOM   2505   CB   SER   A   170   15.393   24.637   67.507   1.00   15.01   C       ATOM   2508   OG   SER   A   170   14.303   24.316   66.678   1.00   22.23   O       ATOM   2510   C   SER   A   170   15.600   22.251   68.173   1.00   13.02   C       ATOM   2511   O   SER   A   170   15.258   22.199   69.366   1.00   17.05   O       ATOM   2513   N   LYS   A   171   15.368   21.242   67.327   1.00   11.31   N       ATOM   2514   CA   LYS   A   171   14.722   20.011   67.784   1.00   10.60   C       ATOM   2516   CB   LYS   A   171   13.782   19.493   66.691   1.00   10.19   C       ATOM   2519   CG   LYS   A   171   12.594   20.391   66.388   1.00   11.75   C       ATOM   2522   CD   LYS   A   171   11.530   19.673   65.517   1.00   11.58   C       ATOM   2525   CE   LYS   A   171   10.212   20.409   65.393   1.00   14.91   C       ATOM   2528   NZ   LYS   A   171   9.250   19.814   64.374   1.00   15.60   N       ATOM   2532   C   LYS   A   171   15.732   18.959   68.255   1.00   10.82   C       ATOM   2533   O   LYS   A   171   16.956   19.151   68.092   1.00   12.33   O       ATOM   2535   N   ALA   A   172   15.274   17.855   68.823   1.00   9.49   N       ATOM   2536   CA   ALA   A   172   16.192   16.873   69.457   1.00   8.93   C       ATOM   2538   CB   ALA   A   172   15.405   15.776   70.239   1.00   9.36   C       ATOM   2542   C   ALA   A   172   17.180   16.212   68.488   1.00   9.88   C       ATOM   2543   O   ALA   A   172   18.304   15.868   68.911   1.00   11.09   O       ATOM   2545   N   GLY   A   173   16.756   16.017   67.245   1.00   9.34   N       ATOM   2546   CA   GLY   A   173   17.600   15.356   66.238   1.00   9.33   C       ATOM   2549   C   GLY   A   173   17.131   15.694   64.837   1.00   9.73   C       ATOM   2550   O   GLY   A   173   16.217   16.515   64.646   1.00   9.04   O       ATOM   2552   N   PHE   A   174   17.827   15.117   63.865   1.00   7.56   N       ATOM   2553   CA   PHE   A   174   17.552   15.372   62.466   1.00   7.53   C       ATOM   2555   CB   PHE   A   174   18.263   16.652   61.997   1.00   8.21   C       ATOM   2558   CG   PHE   A   174   19.749   16.581   62.118   1.00   8.24   C       ATOM   2559   CD1   PHE   A   174   20.523   16.170   61.026   1.00   10.68   C       ATOM   2561   CE1   PHE   A   174   21.904   16.075   61.163   1.00   11.00   C       ATOM   2563   CZ   PHE   A   174   22.494   16.378   62.367   1.00   9.97   C       ATOM   2565   CE2   PHE   A   174   21.770   16.762   63.426   1.00   11.65   C       ATOM   2567   CD2   PHE   A   174   20.374   16.875   63.317   1.00   11.58   C       ATOM   2569   C   PHE   A   174   17.936   14.203   61.550   1.00   8.39   C       ATOM   2570   O   PHE   A   174   18.735   13.329   61.906   1.00   9.32   O       ATOM   2572   N   TYR   A   175   17.336   14.228   60.359   1.00   8.25   N       ATOM   2573   CA   TYR   A   175   17.658   13.316   59.259   1.00   7.48   C       ATOM   2575   CB   TYR   A   175   16.413   12.637   58.676   1.00   9.30   C       ATOM   2578   CG   TYR   A   175   15.584   11.889   59.688   1.00   7.58   C       ATOM   2579   CD1   TYR   A   175   15.835   10.546   59.969   1.00   8.86   C       ATOM   2581   CE1   TYR   A   175   15.095   9.842   60.902   1.00   9.03   C       ATOM   2583   CZ   TYR   A   175   14.030   10.433   61.508   1.00   8.70   C       ATOM   2584   OH   TYR   A   175   13.278   9.774   62.464   1.00   8.58   O       ATOM   2586   CE2   TYR   A   175   13.757   11.778   61.240   1.00   9.04   C       ATOM   2588   CD2   TYR   A   175   14.519   12.480   60.322   1.00   9.76   C       ATOM   2590   C   TYR   A   175   18.321   14.102   58.154   1.00   9.02   C       ATOM   2591   O   TYR   A   175   17.914   15.248   57.902   1.00   9.13   O       ATOM   2593   N   LEU   A   176   19.326   13.515   57.485   1.00   9.33   N       ATOM   2594   CA   LEU   A   176   19.782   14.072   56.220   1.00   10.45   C       ATOM   2596   CB   LEU   A   176   21.319   14.087   56.124   1.00   11.50   C       ATOM   2599   CG   LEU   A   176   22.065   15.260   55.571   1.00   19.01   C       ATOM   2601   CD1   LEU   A   176   21.729   16.554   56.106   1.00   24.20   C       ATOM   2605   CD2   LEU   A   176   23.588   15.037   55.662   1.00   16.96   C       ATOM   2609   C   LEU   A   176   19.192   13.224   55.106   1.00   10.60   C       ATOM   2610   O   LEU   A   176   19.009   11.996   55.285   1.00   11.03   O       ATOM   2612   N   ALA   A   177   18.874   13.828   53.956   1.00   9.29   N       ATOM   2613   CA   ALA   A   177   18.364   13.067   52.816   1.00   9.08   C       ATOM   2615   CB   ALA   A   177   16.871   13.142   52.676   1.00   10.99   C       ATOM   2619   C   ALA   A   177   19.051   13.561   51.558   1.00   10.04   C       ATOM   2620   O   ALA   A   177   19.398   14.737   51.438   1.00   9.75   O       ATOM   2622   N   PHE   A   178   19.222   12.627   50.630   1.00   9.02   N       ATOM   2623   CA   PHE   A   178   19.846   12.880   49.346   1.00   9.63   C       ATOM   2625   CB   PHE   A   178   21.096   12.010   49.256   1.00   9.71   C       ATOM   2628   CG   PHE   A   178   22.014   12.180   50.397   1.00   11.34   C       ATOM   2629   CD1   PHE   A   178   22.904   13.231   50.406   1.00   17.04   C       ATOM   2631   CE1   PHE   A   178   23.766   13.393   51.473   1.00   19.52   C       ATOM   2633   CZ   PHE   A   178   23.687   12.533   52.567   1.00   15.86   C       ATOM   2635   CE2   PHE   A   178   22.828   11.493   52.563   1.00   12.43   C       ATOM   2637   CD2   PHE   A   178   21.968   11.319   51.505   1.00   11.87   C       ATOM   2639   C   PHE   A   178   18.884   12.509   48.243   1.00   10.24   C       ATOM   2640   O   PHE   A   178   18.310   11.419   48.264   1.00   10.41   O       ATOM   2642   N   GLN   A   179   18.706   13.407   47.281   1.00   9.37   N       ATOM   2643   CA   GLN   A   179   17.882   13.172   46.105   1.00   9.39   C       ATOM   2645   CB   GLN   A   179   16.841   14.275   45.937   1.00   9.56   C       ATOM   2648   CG   GLN   A   179   15.926   14.032   44.737   1.00   10.70   C       ATOM   2651   CD   GLN   A   179   15.123   15.238   44.384   1.00   14.67   C       ATOM   2652   OE1   GLN   A   179   15.614   16.371   44.426   1.00   19.87   O       ATOM   2653   NE2   GLN   A   179   13.835   15.015   44.063   1.00   19.39   N       ATOM   2656   C   GLN   A   179   18.780   13.131   44.862   1.00   9.70   C       ATOM   2657   O   GLN   A   179   19.507   14.063   44.582   1.00   9.12   O       ATOM   2659   N   ASP   A   180   18.681   12.017   44.151   1.00   9.12   N       ATOM   2660   CA   ASP   A   180   19.246   11.827   42.834   1.00   8.67   C       ATOM   2662   CB   ASP   A   180   19.988   10.495   42.808   1.00   9.62   C       ATOM   2665   CG   ASP   A   180   20.230   10.004   41.384   1.00   11.84   C       ATOM   2666   OD1   ASP   A   180   21.098   10.598   40.700   1.00   9.57   O       ATOM   2667   OD2   ASP   A   180   19.506   9.069   40.929   1.00   10.67   O       ATOM   2668   C   ASP   A   180   18.165   11.825   41.811   1.00   9.18   C       ATOM   2669   O   ASP   A   180   17.071   11.293   42.046   1.00   9.26   O       ATOM   2671   N   GLN   A   181   18.429   12.401   40.653   1.00   7.59   N       ATOM   2672   CA   GLN   A   181   17.486   12.287   39.502   1.00   9.62   C       ATOM   2674   CB   GLN   A   181   16.446   13.404   39.553   1.00   9.54   C       ATOM   2677   CG   GLN   A   181   15.294   13.192   38.629   1.00   12.83   C       ATOM   2680   CD   GLN   A   181   14.240   14.249   38.781   1.00   17.44   C       ATOM   2681   OE1   GLN   A   181   13.142   13.998   39.296   1.00   25.22   O       ATOM   2682   NE2   GLN   A   181   14.536   15.437   38.295   1.00   24.11   N       ATOM   2685   C   GLN   A   181   18.323   12.339   38.220   1.00   9.56   C       ATOM   2686   O   GLN   A   181   18.688   13.405   37.760   1.00   10.29   O       ATOM   2688   N   GLY   A   182   18.706   11.170   37.715   1.00   9.26   N       ATOM   2689   CA   GLY   A   182   19.458   11.066   36.463   1.00   9.98   C       ATOM   2692   C   GLY   A   182   20.962   11.281   36.539   1.00   9.35   C       ATOM   2693   O   GLY   A   182   21.615   11.486   35.523   1.00   9.38   O       ATOM   2695   N   ALA   A   183   21.531   11.165   37.740   1.00   8.87   N       ATOM   2696   CA   ALA   A   183   22.990   11.245   37.923   1.00   8.24   C       ATOM   2698   CB   ALA   A   183   23.362   12.143   39.062   1.00   8.69   C       ATOM   2702   C   ALA   A   183   23.548   9.855   38.159   1.00   8.99   C       ATOM   2703   O   ALA   A   183   22.798   8.874   38.249   1.00   10.60   O       ATOM   2705   N   CYS   A   184   24.874   9.772   38.195   1.00   7.92   N       ATOM   2706   CA   CYS   A   184   25.549   8.477   38.316   1.00   7.85   C       ATOM   2708   CB   CYS   A   184   26.054   8.023   36.956   1.00   8.58   C       ATOM   2711   SG   CYS   A   184   26.830   6.361   36.962   1.00   9.83   S       ATOM   2713   C   CYS   A   184   26.704   8.693   39.292   1.00   7.08   C       ATOM   2714   O   CYS   A   184   27.735   9.254   38.916   1.00   8.95   O       ATOM   2716   N   MET   A   185   26.516   8.289   40.536   1.00   7.67   N       ATOM   2717   CA   MET   A   185   27.400   8.698   41.620   1.00   7.79   C       ATOM   2719   CB   MET   A   185   26.891   9.986   42.242   1.00   8.31   C       ATOM   2722   CG   MET   A   185   25.509   9.869   42.942   1.00   8.09   C       ATOM   2725   SD   MET   A   185   25.067   11.370   43.893   1.00   10.10   S       ATOM   2726   CE   MET   A   185   26.262   11.292   45.178   1.00   11.25   C       ATOM   2730   C   MET   A   185   27.555   7.657   42.707   1.00   8.04   C       ATOM   2731   O   MET   A   185   26.716   6.768   42.891   1.00   7.27   O       ATOM   2733   N   ALA   A   186   28.681   7.761   43.406   1.00   7.98   N       ATOM   2734   CA   ALA   A   186   28.926   6.985   44.617   1.00   9.39   C       ATOM   2736   CB   ALA   A   186   30.175   6.146   44.499   1.00   8.65   C       ATOM   2740   C   ALA   A   186   29.118   7.945   45.786   1.00   9.09   C       ATOM   2741   O   ALA   A   186   30.032   8.789   45.742   1.00   8.21   O       ATOM   2743   N   LEU   A   187   28.282   7.814   46.817   1.00   8.78   N       ATOM   2744   CA   LEU   A   187   28.487   8.519   48.112   1.00   9.03   C       ATOM   2746   CB   LEU   A   187   27.152   8.751   48.826   1.00   9.73   C       ATOM   2749   CG   LEU   A   187   27.259   9.515   50.135   1.00   11.78   C       ATOM   2751   CD1   LEU   A   187   27.747   10.946   49.895   1.00   13.80   C       ATOM   2755   CD2   LEU   A   187   25.896   9.537   50.804   1.00   15.87   C       ATOM   2759   C   LEU   A   187   29.421   7.629   48.946   1.00   8.46   C       ATOM   2760   O   LEU   A   187   29.051   6.559   49.435   1.00   8.87   O       ATOM   2762   N   LEU   A   188   30.666   8.065   49.036   1.00   8.40   N       ATOM   2763   CA   LEU   A   188   31.722   7.307   49.652   1.00   8.29   C       ATOM   2765   CB   LEU   A   188   33.071   7.652   49.003   1.00   9.53   C       ATOM   2768   CG   LEU   A   188   33.166   7.411   47.482   1.00   9.10   C       ATOM   2770   CD1   LEU   A   188   34.477   7.931   46.911   1.00   11.01   C       ATOM   2774   CD2   LEU   A   188   33.024   5.950   47.150   1.00   11.04   C       ATOM   2778   C   LEU   A   188   31.797   7.477   51.146   1.00   8.56   C       ATOM   2779   O   LEU   A   188   32.177   6.551   51.836   1.00   9.83   O       ATOM   2781   N   SER   A   189   31.428   8.647   51.620   1.00   8.94   N       ATOM   2782   CA   SER   A   189   31.360   8.899   53.068   1.00   8.72   C       ATOM   2784   CB   SER   A   189   32.757   8.981   53.658   1.00   10.49   C       ATOM   2787   OG   SER   A   189   33.482   10.025   53.106   1.00   12.31   O       ATOM   2789   C   SER   A   189   30.585   10.154   53.420   1.00   8.61   C       ATOM   2790   O   SER   A   189   30.426   11.093   52.632   1.00   8.28   O       ATOM   2792   N   LEU   A   190   29.981   10.099   54.613   1.00   8.03   N       ATOM   2793   CA   LEU   A   190   29.319   11.229   55.254   1.00   7.40   C       ATOM   2795   CB   LEU   A   190   27.778   11.045   55.319   1.00   7.78   C       ATOM   2798   CG   LEU   A   190   27.038   12.050   56.182   1.00   8.27   C       ATOM   2800   CD1   LEU   A   190   27.148   13.503   55.675   1.00   10.17   C       ATOM   2804   CD2   LEU   A   190   25.540   11.644   56.344   1.00   8.94   C       ATOM   2808   C   LEU   A   190   29.895   11.315   56.674   1.00   8.35   C       ATOM   2809   O   LEU   A   190   29.892   10.323   57.437   1.00   8.74   O       ATOM   2811   N   HIS   A   191   30.306   12.512   57.072   1.00   7.60   N       ATOM   2812   CA   HIS   A   191   30.745   12.781   58.457   1.00   7.90   C       ATOM   2814   CB   HIS   A   191   32.260   12.962   58.452   1.00   8.03   C       ATOM   2817   CG   HIS   A   191   32.910   12.968   59.808   1.00   8.71   C       ATOM   2818   ND1   HIS   A   191   34.281   12.895   59.947   1.00   11.85   N       ATOM   2820   CE1   HIS   A   191   34.588   12.927   61.239   1.00   11.49   C       ATOM   2822   NE2   HIS   A   191   33.467   13.013   61.940   1.00   8.44   N       ATOM   2824   CD2   HIS   A   191   32.403   13.030   61.069   1.00   8.15   C       ATOM   2826   C   HIS   A   191   30.071   14.048   58.935   1.00   8.00   C       ATOM   2827   O   HIS   A   191   30.204   15.094   58.323   1.00   9.66   O       ATOM   2829   N   LEU   A   192   29.224   13.867   59.943   1.00   8.43   N       ATOM   2830   CA   LEU   A   192   28.549   14.963   60.619   1.00   9.08   C       ATOM   2832   CB   LEU   A   192   27.099   14.577   60.975   1.00   10.10   C       ATOM   2835   CG   LEU   A   192   26.167   14.276   59.809   1.00   11.69   C       ATOM   2837   CD1   LEU   A   192   24.869   13.680   60.288   1.00   12.31   C       ATOM   2841   CD2   LEU   A   192   25.899   15.492   59.016   1.00   13.67   C       ATOM   2845   C   LEU   A   192   29.293   15.297   61.893   1.00   7.94   C       ATOM   2846   O   LEU   A   192   29.645   14.397   62.676   1.00   8.07   O       ATOM   2848   N   PHE   A   193   29.556   16.583   62.131   1.00   8.07   N       ATOM   2849   CA   PHE   A   193   30.262   17.006   63.330   1.00   7.59   C       ATOM   2851   CB   PHE   A   193   31.797   16.907   63.174   1.00   7.55   C       ATOM   2854   CG   PHE   A   193   32.371   17.852   62.160   1.00   9.51   C       ATOM   2855   CD1   PHE   A   193   32.741   19.151   62.540   1.00   9.02   C       ATOM   2857   CE1   PHE   A   193   32.253   20.032   61.585   1.00   9.94   C       ATOM   2859   CZ   PHE   A   193   33.398   19.610   60.285   1.00   8.63   C       ATOM   2861   CE2   PHE   A   193   33.023   18.360   59.896   1.00   11.72   C       ATOM   2863   CD2   PHE   A   193   32.508   17.471   60.815   1.00   10.23   C       ATOM   2865   C   PHE   A   193   29.835   18.415   63.705   1.00   8.62   C       ATOM   2866   O   PHE   A   193   29.228   19.118   62.894   1.00   8.78   O       ATOM   2868   N   TYR   A   194   30.141   18.800   64.938   1.00   8.07   N       ATOM   2869   CA   TYR   A   194   29.910   20.193   65.386   1.00   8.73   C       ATOM   2871   CB   TYR   A   194   28.589   20.329   66.175   1.00   9.62   C       ATOM   2874   CG   TYR   A   194   28.510   19.615   67.517   1.00   8.79   C       ATOM   2875   CD1   TYR   A   194   28.578   20.311   68.731   1.00   11.90   C       ATOM   2877   CE1   TYR   A   194   28.489   19.623   69.948   1.00   12.30   C       ATOM   2879   CZ   TYR   A   194   28.319   18.252   69.969   1.00   13.69   C       ATOM   2880   OH   TYR   A   194   28.213   17.570   71.188   1.00   16.83   O       ATOM   2882   CE2   TYR   A   194   28.269   17.553   68.770   1.00   13.74   C       ATOM   2884   CD2   TYR   A   194   28.363   18.232   67.581   1.00   10.43   C       ATOM   2886   C   TYR   A   194   31.068   20.698   66.219   1.00   9.43   C       ATOM   2887   O   TYR   A   194   31.923   19.929   66.662   1.00   9.21   O       ATOM   2889   N   LYS   A   195   31.104   22.018   66.437   1.00   10.08   N       ATOM   2890   CA   LYS   A   195   32.157   22.657   67.262   1.00   11.96   C       ATOM   2892   CB   LYS   A   195   32.548   24.044   66.674   1.00   13.33   C       ATOM   2899   C   LYS   A   195   31.648   22.754   68.692   1.00   12.87   C       ATOM   2900   O   LYS   A   195   30.573   23.352   68.946   1.00   12.94   O       ATOM   2902   N   LYS   A   196   32.383   22.113   69.611   1.00   14.64   N       ATOM   2903   CA   LYS   A   196   32.037   22.049   71.058   1.00   16.38   C       ATOM   2905   CB   LYS   A   196   32.025   20.593   71.561   1.00   16.65   C       ATOM   2908   CG   LYS   A   196   31.247   20.318   72.849   1.00   19.41   C       ATOM   2911   CD   LYS   A   196   31.368   18.853   73.224   1.00   20.76   C       ATOM   2914   CE   LYS   A   196   30.555   18.496   74.506   1.00   21.67   C       ATOM   2917   NZ   LYS   A   196   31.158   18.990   75.740   1.00   26.89   N       ATOM   2921   C   LYS   A   196   33.054   22.847   71.831   1.00   17.46   C       ATOM   2922   O   LYS   A   196   34.262   22.740   71.576   1.00   17.70   O       ATOM   2924   N   ASN   A   251   43.160   4.312   44.067   1.00   22.03   N       ATOM   2925   CA   ASN   A   251   42.141   5.288   44.481   1.00   21.06   C       ATOM   2927   CB   ASN   A   251   42.373   6.675   43.819   1.00   21.54   C       ATOM   2930   CG   ASN   P   251   41.459   7.820   44.415   1.00   23.63   C       ATOM   2931   OD1   ASN   P   251   41.322   8.907   43.808   1.00   25.42   O       ATOM   2932   ND2   ASN   P   251   40.886   7.585   45.615   1.00   22.93   N       ATOM   2935   C   ASN   P   251   40.751   4.645   44.149   1.00   19.88   C       ATOM   2936   O   ASN   P   251   40.317   4.563   42.982   1.00   21.13   O       ATOM   2940   N   TYR   P   252   40.098   4.148   45.183   1.00   15.93   N       ATOM   2941   CA   TYR   P   252   38.770   3.589   45.052   1.00   14.57   C       ATOM   2943   CB   TYR   P   252   38.328   2.996   46.409   1.00   14.90   C       ATOM   2946   CG   TYR   P   252   36.982   2.348   46.341   1.00   13.17   C       ATOM   2947   CD1   TYR   P   252   36.840   0.998   45.980   1.00   15.56   C       ATOM   2949   CE1   TYR   P   252   35.610   0.399   45.879   1.00   14.96   C       ATOM   2951   CZ   TYR   P   252   34.472   1.148   46.129   1.00   15.22   C       ATOM   2952   OH   TYR   P   252   33.208   0.610   46.073   1.00   13.93   O       ATOM   2954   CE2   TYR   P   252   34.589   2.455   46.537   1.00   14.09   C       ATOM   2956   CD2   TYR   P   252   35.852   3.053   46.616   1.00   13.95   C       ATOM   2958   C   TYR   P   252   37.771   4.690   44.624   1.00   13.53   C       ATOM   2959   O   TYR   P   252   37.636   5.714   45.317   1.00   14.00   O       ATOM   2961   N   LEU   P   253   37.072   4.461   43.522   1.00   12.91   N       ATOM   2962   CA   LEU   P   253   36.060   5.416   43.022   1.00   11.40   C       ATOM   2964   CB   LEU   P   253   36.359   5.843   41.580   1.00   11.85   C       ATOM   2967   CG   LEU   P   253   37.702   6.574   41.405   1.00   11.52   C       ATOM   2969   CD1   LEU   P   253   38.051   6.861   39.938   1.00   14.14   C       ATOM   2973   CD2   LEU   P   253   37.735   7.838   42.176   1.00   13.77   C       ATOM   2977   C   LEU   P   253   34.642   4.844   43.115   1.00   12.69   C       ATOM   2978   O   LEU   P   253   33.716   5.576   43.386   1.00   13.84   O       ATOM   2980   N   PHE   P   254   34.471   3.549   42.831   1.00   11.86   N       ATOM   2981   CA   PHE   P   254   33.198   2.865   42.874   1.00   12.02   C       ATOM   2983   CB   PHE   P   254   32.261   3.307   41.741   1.00   13.21   C       ATOM   2986   CG   PHE   P   254   32.806   3.116   40.346   1.00   13.27   C       ATOM   2987   CD1   PHE   P   254   32.742   1.887   39.712   1.00   15.51   C       ATOM   2989   CE1   PHE   P   254   33.218   1.718   38.441   1.00   17.28   C       ATOM   2991   CZ   PHE   P   254   33.784   2.777   37.760   1.00   18.13   C       ATOM   2993   CE2   PHE   P   254   33.848   4.025   38.396   1.00   17.44   C       ATOM   2995   CD2   PHE   P   254   33.380   4.176   39.674   1.00   15.88   C       ATOM   2997   C   PHE   P   254   33.416   1.353   42.848   1.00   11.55   C       ATOM   2998   O   PHE   P   254   34.547   0.864   42.674   1.00   12.47   O       ATOM   3000   N   SER   P   255   32.317   0.633   43.050   1.00   13.41   N       ATOM   3001   CA   SER   P   255   32.350   −0.813   43.277   1.00   13.05   C       ATOM   3003   CB   SER   P   255   31.111   −1.266   44.041   1.00   13.36   C       ATOM   3006   OG   SER   P   255   30.995   −2.681   44.116   1.00   14.10   O       ATOM   3008   C   SER   P   255   32.362   −1.565   41.971   1.00   14.28   C       ATOM   3009   O   SER   P   255   31.717   −1.153   41.010   1.00   15.30   O       ATOM   3011   N   PRO   P   256   33.069   −2.701   41.933   1.00   14.39   N       ATOM   3012   CA   PRO   P   256   32.933   −3.542   40.748   1.00   14.47   C       ATOM   3014   CB   PRO   P   256   34.011   −4.593   40.928   1.00   15.06   C       ATOM   3017   CG   PRO   P   256   34.313   −4.609   42.373   1.00   15.97   C       ATOM   3020   CD   PRO   P   256   33.979   −3.265   42.941   1.00   15.21   C       ATOM   3023   C   PRO   P   256   31.574   −4.220   40.607   1.00   14.15   C       ATOM   3024   O   PRO   P   256   31.268   −4.758   39.529   1.00   14.96   O       ATOM   3025   N   ASN   P   257   30.767   −4.179   41.655   1.00   13.76   N       ATOM   3026   CA   ASN   P   257   29.495   −4.927   41.742   1.00   14.91   C       ATOM   3028   CB   ASN   P   257   29.528   −5.761   43.019   1.00   16.24   C       ATOM   3031   CG   ASN   P   257   30.710   −6.703   43.075   1.00   19.43   C       ATOM   3032   OD1   ASN   P   257   31.147   −7.233   42.056   1.00   19.88   O       ATOM   3033   ND2   ASN   P   257   31.217   −6.940   44.283   1.00   22.73   N       ATOM   3036   C   ASN   P   257   28.233   −4.088   41.832   1.00   14.65   C       ATOM   3037   O   ASN   P   257   27.166   −4.633   42.116   1.00   14.56   O       ATOM   3039   N   GLY   P   258   28.349   −2.782   41.612   1.00   13.71   N       ATOM   3040   CA   GLY   P   258   27.226   −1.869   41.782   1.00   13.39   C       ATOM   3043   C   GLY   P   258   26.633   −1.319   40.490   1.00   13.17   C       ATOM   3044   O   GLY   P   258   26.963   −1.794   39.408   1.00   13.88   O       ATOM   3046   N   PRO   P   259   25.669   −0.356   40.634   1.00   13.28   N       ATOM   3047   CA   PRO   P   259   24.924   0.159   39.482   1.00   13.62   C       ATOM   3049   CB   PRO   P   259   23.826   1.046   40.106   1.00   14.38   C       ATOM   3052   CG   PRO   P   259   24.209   1.284   41.465   1.00   14.55   C       ATOM   3055   CD   PRO   P   259   25.169   0.197   41.902   1.00   14.06   C       ATOM   3058   C   PRO   P   259   25.791   0.979   38.544   1.00   13.22   C       ATOM   3059   O   PRO   P   259   25.481   1.101   37.327   1.00   13.10   O       ATOM   3060   N   ILE   P   260   26.879   1.524   39.081   1.00   13.54   N       ATOM   3061   CA   ILE   P   260   27.816   2.249   38.235   1.00   13.31   C       ATOM   3063   CB   ILE   P   260   28.826   3.067   39.067   1.00   12.69   C       ATOM   3065   CG1   ILE   P   260   28.069   4.128   39.881   1.00   12.98   C       ATOM   3068   CD1   ILE   P   260   28.883   4.824   40.935   1.00   14.32   C       ATOM   3072   CG2   ILE   P   260   29.810   3.759   38.138   1.00   13.16   C       ATOM   3076   C   ILE   P   260   28.538   1.293   37.279   1.00   13.17   C       ATOM   3077   O   ILE   P   260   28.536   1.480   36.056   1.00   12.37   O       ATOM   3079   N   ALA   P   261   29.132   0.236   37.826   1.00   13.12   N       ATOM   3080   CA   ALA   P   261   29.780   −0.765   36.998   1.00   13.37   C       ATOM   3082   CB   ALA   P   261   30.371   −1.875   37.861   1.00   14.02   C       ATOM   3086   C   ALA   P   261   28.830   −1.344   35.955   1.00   14.14   C       ATOM   3087   O   ALA   P   261   29.239   −1.651   34.831   1.00   15.28   O       ATOM   3089   N   ARG   P   262   27.566   −1.517   36.326   1.00   13.51   N       ATOM   3090   CA   ARG   P   262   26.558   −2.069   35.421   1.00   14.66   C       ATOM   3092   CB   ARG   P   262   25.272   −2.428   36.205   1.00   15.22   C       ATOM   3095   CG   ARG   P   262   25.455   −3.668   37.078   1.00   16.13   C       ATOM   3098   CD   ARG   P   262   24.124   −4.259   37.537   1.00   16.60   C       ATOM   3101   NE   ARG   P   262   23.470   −3.395   38.513   1.00   17.89   N       ATOM   3103   CZ   ARG   P   262   23.689   −3.419   39.816   1.00   18.17   C       ATOM   3104   NH1   ARG   P   262   24.573   −4.225   40.375   1.00   17.86   N       ATOM   3107   NH2   ARG   P   262   23.025   −2.582   40.577   1.00   20.47   N       ATOM   3110   C   ARG   P   262   26.221   −1.156   34.242   1.00   15.24   C       ATOM   3111   O   ARG   P   262   25.629   −1.634   33.239   1.00   15.81   O       ATOM   3113   N   ALA   P   263   26.605   0.121   34.320   1.00   16.39   N       ATOM   3114   CA   ALA   P   263   26.379   1.030   33.211   1.00   17.38   C       ATOM   3116   CB   ALA   P   263   26.783   2.445   33.547   1.00   17.32   C       ATOM   3120   C   ALA   P   263   27.118   0.550   31.947   1.00   18.17   C       ATOM   3121   O   ALA   P   263   26.744   0.929   30.831   1.00   18.92   O       ATOM   3123   N   TRP   P   264   28.202   −0.202   32.111   1.00   18.44   N       ATOM   3124   CA   TRP   P   264   29.019   −0.654   30.952   1.00   19.37   C       ATOM   3126   CB   TRP   P   264   30.510   −0.370   31.200   1.00   20.30   C       ATOM   3129   CG   TRP   P   264   30.730   1.090   31.441   1.00   20.52   C       ATOM   3130   CD1   TRP   P   264   30.626   2.093   30.530   1.00   24.02   C       ATOM   3132   NE1   TRP   P   264   30.859   3.305   31.129   1.00   21.70   N       ATOM   3134   CE2   TRP   P   264   31.143   3.103   32.440   1.00   23.96   C       ATOM   3135   CD2   TRP   P   264   31.054   1.711   32.678   1.00   20.21   C       ATOM   3136   CE3   TRP   P   264   31.337   1.231   33.950   1.00   21.14   C       ATOM   3138   CZ3   TRP   P   264   31.642   2.143   34.959   1.00   23.62   C       ATOM   3140   CH2   TRP   P   264   31.684   3.522   34.702   1.00   23.52   C       ATOM   3142   CZ2   TRP   P   264   31.423   4.019   33.450   1.00   20.98   C       ATOM   3144   C   TRP   P   264   28.773   −2.117   30.645   1.00   20.85   C       ATOM   3145   O   TRP   P   264   27.899   −2.714   31.272   1.00   22.43   O       ATOM   3147   OXT   TRP   P   264   29.405   −2.712   29.746   1.00   21.74   O       ATOM   3148   O   HOH   X   301   34.430   11.979   40.417   1.00   7.01   O       ATOM   3151   O   HOH   X   302   8.396   11.854   46.295   1.00   10.84   O       ATOM   3154   O   HOH   X   304   31.629   5.424   54.367   1.00   7.78   O       ATOM   3157   O   HOH   X   305   29.393   0.001   40.716   1.00   11.67   O       ATOM   3160   O   HOH   X   306   26.504   11.508   36.590   1.00   11.86   O       ATOM   3163   O   HOH   X   308   31.743   1.752   56.936   1.00   11.18   O       ATOM   3166   O   HOH   X   309   5.324   13.803   56.433   1.00   10.31   O       ATOM   3169   O   HOH   X   310   10.666   3.747   51.782   1.00   11.18   O       ATOM   3172   O   HOH   X   311   8.900   13.123   61.479   1.00   17.18   O       ATOM   3175   O   HOH   X   312   11.707   10.700   54.483   1.00   6.76   O       ATOM   3178   O   HOH   X   313   15.905   6.703   58.672   1.00   13.28   O       ATOM   3181   O   HOH   X   314   35.962   18.454   45.448   1.00   12.13   O       ATOM   3184   O   HOH   X   315   4.724   20.141   50.518   1.00   13.74   O       ATOM   3187   O   HOH   X   316   20.949   2.851   39.943   1.00   12.79   O       ATOM   3190   O   HOH   X   317   17.280   8.646   37.970   1.00   11.75   O       ATOM   3193   O   HOH   X   318   32.871   12.284   54.535   1.00   8.88   O       ATOM   3196   O   HOH   X   319   38.982   4.909   31.022   1.00   12.42   O       ATOM   3199   O   HOH   X   320   9.426   13.453   65.971   1.00   9.90   O       ATOM   3202   O   HOH   X   322   31.148   2.318   46.180   1.00   13.63   O       ATOM   3205   O   HOH   X   324   13.896   24.311   51.333   1.00   12.28   O       ATOM   3208   O   HOH   X   325   40.919   −4.284   28.002   1.00   15.70   O       ATOM   3211   O   HOH   X   328   11.597   3.904   58.174   1.00   15.64   O       ATOM   3214   O   HOH   X   329   7.013   21.318   64.262   1.00   17.19   O       ATOM   3217   O   HOH   X   330   36.700   16.628   35.841   1.00   12.75   O       ATOM   3220   O   HOH   X   331   35.919   8.860   52.061   1.00   14.21   O       ATOM   3223   O   HOH   X   333   33.936   13.026   68.542   1.00   15.84   O       ATOM   3226   O   HOH   X   334   28.439   18.984   38.377   1.00   15.56   O       ATOM   3229   O   HOH   X   335   38.475   17.080   45.414   1.00   9.88   O       ATOM   3232   O   HOH   X   336   29.059   23.743   65.349   1.00   13.08   O       ATOM   3235   O   HOH   X   337   35.124   6.275   51.954   1.00   13.92   O       ATOM   3238   O   HOH   X   338   7.219   2.126   57.698   1.00   19.91   O       ATOM   3241   O   HOH   X   339   9.763   14.968   45.726   1.00   14.47   O       ATOM   3244   O   HOH   X   340   13.387   8.617   69.453   1.00   16.22   O       ATOM   3247   O   HOH   X   341   10.796   17.916   45.998   1.00   16.33   O       ATOM   3250   O   HOH   X   342   18.031   18.962   65.202   1.00   15.58   O       ATOM   3253   O   HOH   X   344   36.069   5.290   49.609   1.00   17.02   O       ATOM   3256   O   HOH   X   345   29.619   18.922   35.833   1.00   22.31   O       ATOM   3259   O   HOH   X   346   24.143   18.471   35.696   1.00   19.85   O       ATOM   3262   O   HOH   X   348   21.129   −1.803   49.194   1.00   17.90   O       ATOM   3265   O   HOH   X   349   38.093   13.627   38.055   1.00   14.45   O       ATOM   3268   O   HOH   X   350   10.253   11.006   40.462   1.00   18.46   O       ATOM   3271   O   HOH   X   351   10.793   13.130   44.082   1.00   22.46   O       ATOM   3274   O   HOH   X   352   13.603   19.738   71.429   1.00   20.67   O       ATOM   3277   O   HOH   X   353   7.557   20.765   60.119   1.00   17.34   O       ATOM   3280   O   HOH   X   354   13.586   4.527   59.705   1.00   20.41   O       ATOM   3283   O   HOH   X   355   37.530   2.113   41.859   1.00   24.82   O       ATOM   3286   O   HOH   X   356   16.469   24.270   60.869   1.00   23.54   O       ATOM   3289   O   HOH   X   357   29.936   18.089   32.080   1.00   26.88   O       ATOM   3292   O   HOH   X   358   19.795   3.083   33.799   1.00   28.78   O       ATOM   3295   O   HOH   X   359   38.291   20.499   44.138   1.00   22.25   O       ATOM   3298   O   HOH   X   360   20.041   0.614   52.967   1.00   18.78   O       ATOM   3301   O   HOH   X   361   29.369   0.094   63.771   1.00   21.56   O       ATOM   3304   O   HOH   X   362   29.228   14.780   30.295   1.00   16.98   O       ATOM   3307   O   HOH   X   363   28.984   12.621   69.804   1.00   21.48   O       ATOM   3310   O   HOH   X   364   24.115   11.918   68.606   1.00   18.14   O       ATOM   3313   O   HOH   X   365   37.961   6.598   47.868   1.00   16.76   O       ATOM   3316   O   HOH   X   366   34.891   20.347   52.378   1.00   22.38   O       ATOM   3319   O   HOH   X   367   31.698   28.109   59.447   1.00   28.93   O       ATOM   3322   O   HOH   X   368   21.261   19.711   38.455   1.00   28.25   O       ATOM   3325   O   HOH   X   369   30.748   20.856   45.143   1.00   28.82   O       ATOM   3328   O   HOH   X   370   33.678   19.116   43.639   1.00   19.55   O       ATOM   3331   O   HOH   X   371   25.018   10.141   66.819   1.00   19.92   O       ATOM   3334   O   HOH   X   372   26.928   24.827   67.182   1.00   28.42   O       ATOM   3337   O   HOH   X   373   32.538   19.487   36.343   1.00   21.66   O       ATOM   3340   O   HOH   X   374   17.229   0.902   47.869   1.00   22.42   O       ATOM   3343   O   HOH   X   375   19.360   15.924   71.231   1.00   27.13   O       ATOM   3346   O   HOH   X   376   26.441   −6.252   39.178   1.00   25.00   O       ATOM   3349   O   HOH   X   377   39.699   7.545   31.593   1.00   20.60   O       ATOM   3352   O   HOH   X   378   7.020   9.932   60.846   1.00   28.81   O       ATOM   3355   O   HOH   X   379   32.445   −1.887   56.117   1.00   29.10   O       ATOM   3358   O   HOH   X   380   10.504   −0.374   38.640   1.00   31.66   O       ATOM   3361   O   HOH   X   381   38.643   −4.052   56.330   1.00   28.25   O       ATOM   3364   O   HOH   X   382   20.319   10.149   30.622   1.00   28.71   O       ATOM   3367   O   HOH   X   383   16.249   21.410   43.896   1.00   33.25   O       ATOM   3370   O   HOH   X   384   27.044   18.832   73.411   1.00   26.07   O       ATOM   3373   O   HOH   X   385   17.653   5.995   63.119   1.00   20.40   O       ATOM   3376   O   HOH   X   386   20.667   25.167   57.089   1.00   26.80   O       ATOM   3379   O   HOH   X   387   24.565   25.212   44.311   1.00   27.12   O       ATOM   3382   O   HOH   X   388   13.295   12.403   71.678   1.00   23.39   O       ATOM   3385   O   HOH   X   389   31.967   −3.677   46.437   1.00   20.85   O       ATOM   3388   O   HOH   X   400   23.013   1.080   36.088   1.00   20.68   O       ATOM   3391   O   HOH   X   401   13.803   12.839   31.578   1.00   47.10   O       ATOM   3394   O   HOH   X   402   35.493   −3.707   50.617   1.00   28.70   O       ATOM   3397   O   HOH   X   403   11.319   24.471   65.742   1.00   31.09   O       ATOM   3400   O   HOH   X   404   6.899   22.877   47.846   1.00   28.38   O       ATOM   3403   O   HOH   X   405   40.035   11.449   34.241   1.00   29.40   O       ATOM   3406   O   HOH   X   407   33.019   22.565   50.833   1.00   18.50   O       ATOM   3409   O   HOH   X   410   19.785   18.612   72.020   1.00   35.87   O       ATOM   3412   O   HOH   X   411   42.301   4.024   31.951   1.00   16.71   O       ATOM   3415   O   HOH   X   412   3.955   5.909   56.974   1.00   32.26   O       ATOM   3418   O   HOH   X   413   13.763   3.826   37.534   1.00   27.73   O       ATOM   3421   O   HOH   X   414   31.801   −2.267   34.382   1.00   39.99   O       ATOM   3424   O   HOH   X   415   15.515   6.216   61.471   1.00   27.52   O       ATOM   3427   O   HOH   X   416   15.020   24.864   64.030   1.00   36.11   O       ATOM   3430   O   HOH   X   417   12.455   5.600   62.319   1.00   24.57   O       ATOM   3433   O   HOH   X   419   25.773   23.290   42.244   1.00   41.56   O       ATOM   3436   O   HOH   X   420   41.722   7.186   39.109   1.00   29.19   O       ATOM   3439   O   HOH   X   421   25.130   3.183   30.595   1.00   30.39   O       ATOM   3442   O   HOH   X   422   37.744   3.789   58.380   1.00   40.22   O       ATOM   3445   O   HOH   X   423   22.867   0.681   61.281   1.00   39.84   O       ATOM   3448   O   HOH   X   424   42.153   6.744   60.740   1.00   23.29   O       ATOM   3451   O   HOH   X   426   20.288   8.153   38.618   1.00   9.57   O       ATOM   3454   O   HOH   X   427   35.253   14.363   31.838   1.00   50.83   O       ATOM   3457   O   HOH   X   428   34.212   1.381   64.196   1.00   27.07   O       ATOM   3460   O   HOH   X   429   14.434   1.392   52.833   1.00   22.25   O       ATOM   3463   O   HOH   X   430   22.194   26.212   52.485   1.00   32.80   O       ATOM   3466   O   HOH   X   432   9.238   16.975   65.774   1.00   13.96   O       ATOM   3469   O   HOH   X   433   11.593   1.653   53.574   1.00   16.99   O       ATOM   3472   O   HOH   X   434   14.051   4.174   43.951   1.00   20.14   O       ATOM   3475   O   HOH   X   435   7.175   15.078   45.065   1.00   18.73   O       ATOM   3478   O   HOH   X   437   11.480   1.805   56.261   1.00   18.06   O       ATOM   3481   O   HOH   X   438   23.385   26.963   58.403   1.00   21.12   O       ATOM   3484   O   HOH   X   440   7.211   20.077   47.511   1.00   26.15   O       ATOM   3487   O   HOH   X   441   9.162   23.023   59.414   1.00   22.52   O       ATOM   3490   O   HOH   X   442   32.407   4.550   28.277   1.00   23.52   O       ATOM   3493   O   HOH   X   443   40.924   7.587   58.411   1.00   23.57   O       ATOM   3496   O   HOH   X   444   9.907   2.424   59.932   1.00   32.11   O       ATOM   3499   O   HOH   X   445   10.243   10.245   44.133   1.00   24.03   O       ATOM   3502   O   HOH   X   446   34.992   21.525   48.756   1.00   23.33   O       ATOM   3505   O   HOH   X   447   38.379   9.025   29.474   1.00   21.23   O       ATOM   3508   O   HOH   X   449   16.335   20.049   71.265   1.00   25.31   O       ATOM   3511   O   HOH   X   450   9.418   0.204   57.103   1.00   30.20   O       ATOM   3514   O   HOH   X   451   20.747   17.031   31.596   1.00   31.73   O       ATOM   3517   O   HOH   X   452   19.502   −0.547   41.887   1.00   24.23   O       ATOM   3520   O   HOH   X   453   37.135   14.588   33.760   1.00   29.69   O       ATOM   3523   O   HOH   X   454   26.888   0.464   64.181   1.00   34.17   O       ATOM   3526   O   HOH   X   456   32.979   −4.890   37.436   1.00   35.49   O       ATOM   3529   O   HOH   X   457   14.283   20.600   45.705   1.00   29.63   O       ATOM   3532   O   HOH   X   458   26.230   25.153   53.647   1.00   27.48   O       ATOM   3535   O   HOH   X   459   34.816   18.735   35.080   1.00   27.23   O       ATOM   3538   O   HOH   X   460   4.994   3.925   56.064   1.00   37.00   O       ATOM   3541   O   HOH   X   461   17.110   19.736   41.865   1.00   40.25   O       ATOM   3544   O   HOH   X   463   22.791   −0.147   33.599   1.00   29.38   O       ATOM   3547   O   HOH   X   465   14.549   −2.299   48.175   1.00   34.82   O       ATOM   3550   O   HOH   X   466   33.884   12.558   26.982   1.00   30.87   O       ATOM   3553   O   HOH   X   467   36.830   1.795   39.777   1.00   44.80   O       ATOM   3556   O   HOH   X   468   18.656   26.477   68.955   1.00   45.51   O       ATOM   3559   O   HOH   X   469   17.163   13.979   34.729   1.00   26.64   O       ATOM   3562   O   HOH   X   470   44.148   4.270   41.881   1.00   25.80   O       ATOM   3565   O   HOH   X   471   14.388   26.009   47.237   1.00   26.58   O       ATOM   3568   O   HOH   X   472   29.188   25.033   52.227   1.00   38.08   O       ATOM   3571   O   HOH   X   473   26.480   9.255   26.925   1.00   32.77   O       ATOM   3574   O   HOH   X   474   15.463   24.100   71.378   1.00   33.75   O       ATOM   3577   O   HOH   X   475   16.379   0.644   52.055   1.00   36.71   O       ATOM   3580   O   HOH   X   476   12.848   −3.104   45.737   1.00   48.73   O       ATOM   3583   O   HOH   X   478   26.768   27.292   66.187   1.00   31.72   O       ATOM   3586   O   HOH   X   479   31.105   16.617   29.947   1.00   36.25   O       ATOM   3589   O   HOH   X   480   19.085   25.365   71.424   1.00   54.75   O       ATOM   3592   O   HOH   X   483   6.403   7.218   63.722   1.00   33.40   O       ATOM   3595   O   HOH   X   484   34.676   −2.504   31.342   1.00   39.43   O       ATOM   3598   O   HOH   X   485   29.761   6.193   26.274   1.00   33.63   O       ATOM   3601   O   HOH   X   486   19.273   −0.131   49.941   1.00   49.50   O       ATOM   3604   O   HOH   X   487   41.059   −2.510   31.457   1.00   30.75   O       ATOM   3607   O   HOH   X   488   36.672   −0.693   42.753   1.00   29.42   O       ATOM   3610   O   HOH   X   489   31.910   −3.375   54.078   1.00   24.32   O       ATOM   3613   O   HOH   X   491   41.593   2.804   48.900   1.00   33.83   O       ATOM   3616   O   HOH   X   492   36.681   0.663   35.856   1.00   27.43   O       ATOM   3619   O   HOH   X   494   37.176   7.827   22.494   1.00   16.75   O       ATOM   3622   O   HOH   X   495   14.784   3.915   46.392   1.00   17.06   O       ATOM   3625   O   HOH   X   496   21.591   24.931   45.260   1.00   18.11   O       ATOM   3628   O   HOH   X   497   29.412   27.494   64.245   1.00   26.46   O       ATOM   3631   O   HOH   X   499   26.054   6.842   24.123   1.00   30.10   O       ATOM   3634   O   HOH   X   500   19.812   24.826   43.219   1.00   31.66   O       ATOM   3637   O   HOH   X   501   9.992   −0.590   53.205   1.00   34.87   O       ATOM   3640   O   HOH   X   503   25.372   28.861   56.971   1.00   39.89   O       ATOM   3643   O   HOH   X   504   17.053   16.002   37.141   1.00   32.34   O       ATOM   3646   O   HOH   X   505   4.460   2.108   53.997   1.00   38.92   O       ATOM   3649   O   HOH   X   506   26.465   17.162   75.469   1.00   43.82   O       ATOM   3652   O   HOH   X   507   10.317   5.334   36.846   1.00   32.29   O       ATOM   3655   O   HOH   X   508   9.711   2.947   49.218   1.00   26.65   O       ATOM   3658   O   HOH   X   509   26.552   −4.697   49.755   1.00   49.34   O       ATOM   3661   O   HOH   X   510   18.594   3.807   59.418   1.00   38.30   O       ATOM   3664   O   HOH   X   511   28.435   −4.434   38.700   1.00   32.57   O       ATOM   3667   O   HOH   X   512   46.206   0.057   55.972   1.00   47.60   O       ATOM   3670   O   HOH   X   513   16.994   −2.195   41.625   1.00   45.55   O       ATOM   3673   O   HOH   X   514   17.660   11.735   25.478   1.00   45.97   O       ATOM   3676   O   HOH   X   515   26.466   12.186   74.746   1.00   57.29   O       ATOM   3679   O   HOH   X   516   34.393   18.813   32.507   1.00   42.19   O       ATOM   3682   O   HOH   X   517   11.225   13.884   36.104   1.00   37.70   O       ATOM   3685   O   HOH   X   518   31.412   −0.234   65.532   1.00   44.80   O       ATOM   3688   O   HOH   X   519   24.899   11.748   28.168   1.00   41.55   O       ATOM   3691   O   HOH   X   520   11.219   15.023   41.393   1.00   49.39   O       ATOM   3694   O   HOH   X   522   30.331   30.312   61.765   1.00   49.80   O       ATOM   3697   O   HOH   X   523   36.831   −2.809   45.024   1.00   46.29   O       ATOM   3700   O   HOH   X   524   36.482   12.740   67.772   1.00   33.34   O       ATOM   3703   O   HOH   X   525   28.208   9.531   24.690   1.00   35.59   O       ATOM   3706   O   HOH   X   526   13.689   0.204   57.175   1.00   29.37   O       ATOM   3709   O   HOH   X   527   46.067   15.993   38.976   1.00   43.28   O       ATOM   3712   O   HOH   X   528   25.883   −6.044   44.128   1.00   37.94   O       ATOM   3715   O   HOH   X   530   20.809   26.042   47.566   1.00   39.73   O       ATOM   3718   O   HOH   X   531   12.991   18.432   44.852   1.00   28.36   O       ATOM   3721   O   HOH   X   532   28.964   −5.330   36.267   1.00   38.90   O       ATOM   3724   O   HOH   X   533   22.960   2.218   31.945   1.00   33.89   O       ATOM   3727   O   HOH   X   535   36.178   20.832   44.780   1.00   37.51   O       ATOM   3730   O   HOH   X   536   4.574   1.902   51.421   1.00   46.14   O       ATOM   3733   O   HOH   X   537   17.708   5.431   57.443   1.00   32.53   O       ATOM   3736   O   HOH   X   538   32.827   13.445   73.510   1.00   38.62   O       ATOM   3739   O   HOH   X   540   34.720   −2.566   29.023   1.00   41.06   O       ATOM   3742   O   HOH   X   541   11.949   −2.854   42.648   1.00   48.23   O       ATOM   3745   O   HOH   X   542   19.770   −0.101   33.503   1.00   59.26   O       ATOM   3748   O   HOH   X   544   14.020   10.058   71.503   1.00   34.39   O       ATOM   3751   O   HOH   X   545   14.076   4.892   28.832   1.00   50.07   O       ATOM   3754   O   HOH   X   546   35.926   0.765   62.178   1.00   44.69   O       ATOM   3757   O   HOH   X   548   7.514   2.581   49.864   1.00   60.69   O       ATOM   3760   O   HOH   X   549   7.765   6.113   66.451   1.00   47.34   O       ATOM   3763   O   HOH   X   550   23.019   26.499   48.819   1.00   38.93   O       ATOM   3766   O   HOH   X   551   25.047   −0.668   28.874   1.00   61.87   O       ATOM   3769   O   HOH   X   552   7.206   −0.125   52.753   1.00   47.97   O       ATOM   3772   O   HOH   X   553   2.489   5.354   58.881   1.00   48.36   O       ATOM   3775   O   HOH   X   555   24.539   −3.993   32.641   1.00   40.61   O       ATOM   3778   O   HOH   X   556   39.684   −2.379   33.798   1.00   47.82   O       ATOM   3781   O   HOH   X   557   27.988   23.583   70.986   1.00   45.95   O       ATOM   3784   O   HOH   X   558   16.259   25.981   51.761   1.00   27.10   O       ATOM   3787   O   HOH   X   559   13.222   −0.928   53.311   1.00   63.13   O       ATOM   3790   O   HOH   X   560   20.224   29.108   69.260   1.00   57.89   O       ATOM   3793   O   HOH   X   561   18.467   22.263   41.573   1.00   43.15   O       ATOM   3796   S   SO4   Y   601   35.678   12.996   56.623   0.70   7.67   S       ATOM   3797   O1   SO4   Y   601   36.139   12.078   55.585   0.70   13.89   O       ATOM   3798   O2   SO4   Y   601   35.797   12.210   57.841   0.70   8.58   O       ATOM   3799   O3   SO4   Y   601   34.374   13.573   56.380   0.70   16.69   O       ATOM   3800   O4   SO4   Y   601   36.638   14.082   56.557   0.70   11.71   O       ATOM   3801   S   SO4   Y   602   28.397   23.856   45.015   0.70   24.73   O       ATOM   3802   O1   SO4   Y   602   27.281   24.307   45.834   0.70   25.61   O       ATOM   3803   O2   SO4   Y   602   28.429   22.409   44.818   0.70   22.84   O       ATOM   3804   O3   SO4   Y   602   29.613   24.229   45.743   0.70   29.50   O       ATOM   3805   O4   SO4   Y   602   28.371   24.551   43.749   0.70   28.60   O       ATOM   3806   S   SO4   Y   603   42.900   20.990   81.966   0.70   29.41   O       ATOM   3807   O1   SO4   Y   603   43.188   21.619   80.689   0.70   23.17   O       ATOM   3808   O2   SO4   Y   603   43.931   20.109   82.488   0.70   30.62   O       ATOM   3809   O3   SO4   Y   603   41.665   20.213   81.898   0.70   31.55   O       ATOM   3810   O4   SO4   Y   603   42.726   22.118   82.860   0.70   32.81   O       ATOM   3811   S   SO4   Y   604   34.328   18.651   77.072   0.70   36.68   S       ATOM   3812   O1   SO4   Y   604   33.645   17.961   75.979   0.70   36.62   O       ATOM   3813   O2   SO4   Y   604   34.229   17.813   78.264   0.70   37.58   O       ATOM   3814   O3   SO4   Y   604   33.640   19.910   77.283   0.70   35.92   O       ATOM   3815   O4   SO4   Y   604   35.749   18.899   76.842   0.70   32.21   O       ATOM   3816   S   SO4   Y   605   20.767   −0.638   38.261   0.70   22.29   S       ATOM   3817   O1   SO4   Y   605   21.835   −1.312   37.474   0.70   17.77   O       ATOM   3818   O2   SO4   Y   605   20.750   0.822   37.951   0.70   20.00   O       ATOM   3819   O3   SO4   Y   605   20.968   −1.030   39.620   0.70   20.92   O       ATOM   3820   O4   SO4   Y   605   19.500   −1.224   37.828   0.70   28.20   O       ATOM   3821   S   SO4   Y   606   29.483   −6.067   47.771   0.70   27.74   S       ATOM   3822   O1   SO4   Y   606   30.669   −5.901   46.925   0.70   29.74   O       ATOM   3823   O2   SO4   Y   606   29.713   −7.052   48.825   0.70   30.93   O       ATOM   3824   O3   SO4   Y   606   28.393   −6.449   46.875   0.70   29.72   O       ATOM   3825   O4   SO4   Y   606   29.111   −4.839   48.457   0.70   18.37   O       ATOM   3826   S   SO4   Y   607   39.989   16.559   37.193   0.70   24.82   S       ATOM   3827   O1   SO4   Y   607   39.493   17.029   35.901   0.70   31.09   O       ATOM   3828   O2   SO4   Y   607   40.305   15.142   37.088   0.70   26.22   O       ATOM   3829   O3   SO4   Y   607   38.909   16.710   38.115   0.70   24.47   O       ATOM   3830   O4   SO4   Y   607   41.271   17.168   37.535   0.70   23.92   O       ATOM   3831   S   SO4   Y   608   31.245   20.872   79.064   0.70   129.03   S       ATOM   3832   O1   SO4   Y   608   30.482   20.410   77.908   0.70   128.90   O       ATOM   3833   O2   SO4   Y   608   31.998   19.756   79.631   0.70   129.11   O       ATOM   3834   O3   SO4   Y   608   30.330   21.401   80.071   0.70   129.13   O       ATOM   3835   O4   SO4   Y   608   32.164   21.927   78.647   0.70   129.06   O       ATOM   3836   O3   GOL   A   1   20.441   14.331   40.631   1.00   11.20   O       ATOM   3838   C3   GOL   A   1   20.040   15.547   40.073   1.00   11.44   C       ATOM   3841   C2   GOL   A   1   19.516   16.587   41.042   1.00   13.43   C       ATOM   3843   O2   GOL   A   1   20.554   17.176   41.804   1.00   14.62   O       ATOM   3845   C1   GOL   A   1   18.490   16.011   42.030   1.00   14.51   C       ATOM   3848   O1   GOL   A   1   17.955   17.070   42.775   1.00   17.23   O       ATOM   3850   O3   GOL   A   2   37.747   20.476   54.065   1.00   40.41   O       ATOM   3852   C3   GOL   A   2   37.169   19.407   53.339   1.00   36.60   C       ATOM   3855   C2   GOL   A   2   38.227   18.479   52.776   1.00   32.19   C       ATOM   3857   O2   GOL   A   2   38.442   17.656   53.815   1.00   26.25   O       ATOM   3859   C1   GOL   A   2   39.572   19.037   52.365   1.00   29.78   C       ATOM   3862   O1   GOL   A   2   40.418   18.008   51.922   1.00   38.17   O                  
 
         [0110]    
       
         
               
               
             
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 1A 
               
             
             
               
                   
               
               
                   
               
               
                 IC 50  values of peptides and ephrin-B2 for 
                   
               
               
                 inhibition of mouse ephrin-B2 alkaline 
               
               
                 phosphatase (AP) binding to immobilized 
               
               
                 mouse EphB4 ectodomain Fc fusion protein 
               
               
                 using ELISA binding assays. 
               
             
          
           
               
                   
                 Inhibitor 
                 IC 50   
               
               
                   
                   
               
             
          
           
               
                   
                 ephrin-B2 Fc 
                   9 nM 
                   
               
               
                   
                   
               
               
                   
                 Human ephrin-B2 monomer 
                  10 nM 
               
               
                   
                   
               
               
                   
                 TNYLFSPNGPIARAW 
                  15 nM 
               
               
                   
                 (TNYL-RAW; SEQ ID NO:1)* 
               
               
                   
                   
               
               
                   
                 -NYLFSPNGPIARAW 
                  40 nM 
               
               
                   
                 (NYLF-RAW; SEQ ID NO:30) 
               
               
                   
                   
               
               
                   
                 --YLFSPNGPIARAW 
                  40 nM 
               
               
                   
                 (YLFS-RAW; SEQ ID NO:31) 
               
               
                   
                   
               
               
                   
                 ---LFSPNGPIARAW 
                 &gt;10 μM 
               
               
                   
                 (LFSP-RAW; SEQ ID NO:32) 
               
               
                   
                   
               
               
                   
                 TNYLFSPNGPIA 
                 150 μM 
               
               
                   
                 (TNYL; SEQ ID NO:33) 
               
               
                   
                   
               
               
                   
                 TNYLFSPNGPIAGSGSK-biotin 
                  50 μM 
               
               
                   
                 (TNYL-biotin; SEQ ID NO:34) 
               
               
                   
                   
               
               
                   
                   *Ephrin-B2 G-H loop: KFQE FSPN LWGLEFQK (SEQ ID NO:35)    
               
             
          
         
       
     
         [0111]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 1B 
               
             
             
               
                   
               
               
                   
               
               
                 Binding of peptides and human ephrin-B2 
               
               
                 to human EphB4 ephrin-binding domain. 
               
             
          
           
               
                 Ligand 
                 K d  (nM)* 
                 ΔG (kcal mol −1 ) 
                 ΔH (kcal mol −1 ) 
                 TΔS (kcal mol −1 ) 
               
               
                   
               
               
                 TNYL-RAW 
                 71 ± 14 
                 −9.8 ± 0.1 
                 −14.7 ± 0.2 
                 −4.9 ± 0.2 
               
               
                 NYLF-RAW 
                 65 ± 7  
                 −9.8 ± 0.1 
                 −15.5 ± 0.1 
                 −5.7 ± 0.1 
               
               
                 YLFS-RAW 
                 80 ± 36 
                 −9.7 ± 0.2 
                 −13.8 ± 0.5 
                 −4.1 ± 0.4 
               
               
                 LFSP-RAW 
                 3,500 ± 680   
                 −7.4 ± 0.1 
                  −5.3 ± 0.5 
                  2.1 ± 0.4 
               
               
                 TNYL 
                 ≧140,000 
                 ND 
                  −9.6 ± 0.3 
                 ND 
               
               
                 ephrin-B2 
                 40 ± 20 
                 −10.2 ± 0.3  
                  3.3 ± 0.1 
                 13.4 ± 0.4 
               
               
                   
               
               
                   Experiments were performed at 25° C. in 50 mM Tris pH 7.8, 150 mM NaCl, 1 mM CaCl 2 . All values (except for TNYL) represent the average of at least two experiments.    
               
               
                   *The K d  value for the TNYL peptide is a lower limit assuming a stoichiometry of 1 and at least 70% saturation of binding at a final peptide concentration of 300 μM.    
               
             
          
         
       
     
         [0112]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                   
               
               
                 Crystallographic Statistics for the EphB4-TNYL-RAW Complex 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Resolution (Å) 1   
                 40-1.65 (1.71-1.65) 
               
               
                   
                 Space Group 
                 P4 1 2 1 2 
               
               
                   
                 Unit Cell Dimensions (Å) 
                 a = b = 60.97, c = 151.7 
               
               
                   
                 Completeness (%) 
                 100 (99.7) 
               
               
                   
                 R sym  (%) 2   
                 3.9 (20.8) 
               
               
                   
                 I/σ 
                 42.7 (7.2) 
               
               
                   
                 Mean Redundancy 
                 3.7 (3.2) 
               
               
                   
                 No. Reflections 
                 32,786 
               
               
                   
                 R cryst  (%) 3   
                 16.0 (17.4) 
               
               
                   
                 R free  (%) 4   
                 19.1 (20.2) 
               
               
                   
                 R.m.s. deviations 
               
               
                   
                 Bond length (Å) 
                 0.02 
               
               
                   
                 Bond angle (°) 
                 1.7 
               
               
                   
                 Improper (°) 
                 1.4 
               
               
                   
                 Number of atoms 
               
               
                   
                 Protein 
                 1486 
               
               
                   
                 Solvent 
                 214 
               
               
                   
                 Peptide 
                 115 
               
               
                   
                 Sulfate 
                 8 
               
               
                   
                 Glycerol 
                 3 
               
               
                   
                   
               
               
                   
                     1 Number in parentheses is for the highest shell.    
               
               
                   
                     2 R sym  = |I I|/I, where I is the observed intensity and I is the average intensity of multiple symmetry-related observations of that reflection.    
               
               
                   
                     3 R cryst  = F obs | |F calc /|F obs |, where F obs  and F calc  are the observed and calculated structure factors. R sym  = |I I|/I, where I is the observed intensity and I is the average intensity of multiple symmetry-related observations of that reflection.    
               
               
                   
                     4 R free  = F obs | |F calc /|F obs | for 10% of the data not used at any stage of structural refinement.    
               
             
          
         
       
     
       EXAMPLES  
       [0113]     Aspects of the present teachings may be further understood in light of the following examples, which should not be construed as limiting the scope of the present teachings in any way.  
       Example 1  
       [0114]     Construct design, expression and purification of EphB4: Twelve sequential 4 amino acid truncations in human EphB4 were designed based on EphB4-EphB2 sequence alignment in the region C-terminal to the last β-strand in the EphB2 structure. The resulting fragments were cloned into the insect cell expression vector pBAC6 (Novagen, WI) under control of the heterologous GP64 signal peptide and containing a N-terminal six histidine tag. Constructs were sequence verified, and baculovirus was generated using homologous recombination into Sapphire Baculovirus DNA (Orbigen, CA) using the manufacturers protocol. After 3 rounds of viral amplification, a small scale expression screen was conducted for all constructs in both Sf9 and Hi5 insect cells. Briefly, 5E10+6 cells were infected with baculovirus at an MOI of 2 in 38 mm tissue culture dishes; cells were harvested at 48 hours post infection and supernatant containing secreted EphB4 was concentrated 10-fold and buffer exchanged into 50 mM Tris pH 7.8, 400 mM NaCl, and 5 mM imidazole using an Amicon Ultra 5K concentrator (Millipore, MA). The secreted protein was bound to Ni-NTA magnetic beads (Qiagen, CA), washed with 50 mM Tris pH7.8, 400 mM NaCl, 20 mM Imidazole buffer and eluted with 50 mM Tris pH 7.8, 400 mM NaCl, 250 mM Imidazole. Based on analysis of immobilized metal affinity chromatography (IMAC) elutes, the EphB4 (17-196) construct was identified as the highest expressor at ˜6 mg/L in Hi5 insect cells. Large scale expression was conducted using Wave Bioreactors(Wave Biotech LLC, NJ) at a MOI of 2 for 48 hours in Hi5 insect cells. Media containing secreted EphB4 was concentrated and buffer exchanged using a Hydrosart Crossflow filter (Sartorius, NY). Following IMAC purification on ProBond resin (Invitrogen, CA) as described above, EphB4 was concentrated to 5 mg/ml and loaded on a Superdex 75 16/60 column (GE HealthCare, NY). A small amount of aggregated material was removed by preparative size exclusion chromatography, while most of the sample eluted in a single peak corresponding to an EphB4 (17-196) monomer. The complete removal of the GP64secretion sequence and protein identity were confirmed by MALDI analysis.  
       Example 2  
       [0115]     Crystallization: Purified EphB4 was concentrated to 10 mg/mL in 25 mM Tris, pH 7.8, 150 mM NaCl, and 5 mM CaCl2 in the presence of a 3-fold molar excess of TNYL-RAW peptide (SEQ ID NO: 1; Biopeptide, Inc.). The EphB4 17-196 construct was crystallized by sitting drop vapor diffusion at 20° C. against a reservoir of 2.2 M ammonium sulfate and 200 mM NaCl, and cryoprotected in 25% glycerol.  
       Example 3  
       [0116]     Structure Determination: Crystals of the EphB4-TNYL complex grew in the P41212 space group (a=60.92, c=151.93). A single crystal diffracted to 1.65 Å resolution at 100 K on beamline 5-1 at the Advanced Light Source (Berkeley, Calif.), and were integrated, reduced and scaled using HKL2000 (Otwinowski, 1997). The structure was determined by molecular replacement with MolRep (CCP4i) (CCP4, 1994; Vagin, 1997) using the structure of apo EphB2 (pdb id:1NUK (Himanen et al., 1998)) as a search model. The structure was refined with CNS using torsion angle dynamics and the maximum likelihood function target (Table 2), and manual model building performed with the program O (Bringer et al., 1998; Jones et al., 1991). Electron density for the TNYL-RAW peptide was clear after the first round of refinement, with the positioning of the critical RAW sequence clearly evident in the initial |Fobs|−|Fcalc| maps ( FIG. 2 ). The peptide was initially built as a polyalanine chain, while unbiased electron density for the peptide from simulated annealing omit maps was used to build the full peptide. Residues 17-196 from EphB4, and 14 of 15 residues from the TNYL-RAW peptide, could be readily traced into electron density. The final structure exhibits good geometry with no Ramachandran outliers. Figures were created with PyMol, Molscript, Raster3D, Dino, and Povray (DeLano, 2002; Esnouf, 1997;Kraulis, 1991; Merritt and Murphy, 1994).  
       Example 4  
       [0117]     Isothermal titration calorimetry and ELISA experiments: EphB4and ephrin-B2 were either dialyzed or buffer exchanged into 50 mM Tris-Cl (pH 7.8 at 25° C.), 150 mM NaCl, 1 mM CaCl 2 , prior to use in calorimetry experiments. Peptides were dissolved into the same buffer used for the dialysis of EphB4. The concentration of EphB4, ephrin-B2 and the peptides was determined by measuring the A 280  and using the theoretical-extinction coefficient (Gill and von Hippel, 1989). ITC experiments were performed with a Microcal MCS ITC at 25° C. Following an initial injection of 2 μl, titrations were performed by making 20 13 μl injections of peptide into EphB4 in the sample cell to produce an approximate final 2:1 ratio of injectant to sample in the cell. For most titrations the sample cell contained 15 μM EphB4 and the injection syringe contained a 200 μM solution of the peptide. Titrations with ephrin-B2 contained 13 μM EphB4 in the sample cell and 290 μM ephrin-B2 in the syringe. Prior to loading the sample cell, EphB4 was centrifuged at 18,000 g for 5 min at 4° C. to remove aggregates and degassed for 5 minutes at room temperature. Corrections for heats of dilution for the peptides and ephrin-B2 were determined by performing titrations of peptide or ephrin-B2 solutions into buffer. Dilution data were fit to a line and subtracted from the corresponding titration data. Titration data were analyzed using Origin ITC software (Version 5.0, Microcal Software Inc.) and curves were fit to a single binding site model (Wiseman et al., 1989). The low affinity of the TNYL peptide and the limited availability of EphB4 (17-196) precluded accurate determination of the K d  for this interaction by ITC. A lower limit for the binding constant was determined by performing a titration in which the sample cell contained 30 μM EphB4 and the injection syringe contained a 1.45 mM solution of the peptide, producing a final ratio of peptide to EphB4 of 10:1. The data was fit assuming a stoichiometry of 1 and at least 60% saturation of binding at the final peptide concentration (Turnbull and Daranas, 2003).  
         [0118]     The ability of peptides to compete the binding of mouse ephrin-B2 alkaline phosphatase to immobilized mouse EphB4-Fc-His (R&amp;D Systems) was measured by ELISA as previously described (Koolpe et al., 2005).  
       Other Embodiments  
       [0119]     The detailed description set-forth above is provided to aid those skilled in the art in practicing the present invention. However, the invention described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed because these embodiments are intended as illustration of several aspects of the invention. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description which do not depart from the spirit or scope of the present inventive discovery. Such modifications are also intended to fall within the scope of the appended claims.  
       REFERENCES CITED  
       [0120]     All publications, patents, patent applications and other references cited in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application or other reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Citation of a reference herein shall not be construed as an admission that such is prior art to the present invention. Publications incorporated herein by reference in their entirety include:  
         [0121]     Adams, R. H., Wilkinson, G. A., Weiss, C., Diella, F., Gale, N. W., Deutsch, U., Risau, W., and Klein, R. (1999). Roles of ephrin-B ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev 13, 295-306.  
         [0122]     Brantley-Sieders, D. M., and Chen, J. (2004). Eph receptor tyrosine kinases in angiogenesis: from development to disease. Angiogenesis 7, 17-28.  
         [0123]     Brunger, A. T., Adams, P. D., Clore, G. M., DeLano, W. L., Gros, P., Grosse-Kunstleve, R. W., Jiang, J. S., Kuszewski, J., Nilges, M., Pannu, N. S., et al. (1998). Crystallography &amp; NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr D Biol Crystallogr 54 (Pt 5), 905-921.  
         [0124]     Carmeliet, P., and Collen, D. (1999). Role of vascular endothelial growth factor and vascular endothelial growth factor receptors in vascular development. Curr Top Microbiol Immunol 237, 133-158.  
         [0125]     CCP4 (1994). The CCP4 suite: Programs for X-ray crystallography. Acta Crystallogr D Biol Crystallogr 50, 760-763.  
         [0126]     Cheng, N., Brantley, D. M., and Chen, J. (2002). The ephrins and Eph receptors in angiogenesis. Cytokine Growth Factor Rev 13, 75-85.  
         [0127]     DeLano, W. L. (2002). The PyMOL molecular graphics system. world wide web.  
         [0128]     Dodelet, V. C., and Pasquale, E. B. (2000). Eph receptors and ephrin ligands: embryogenesis to tumorigenesis. Oncogene 19, 5614-5619.  
         [0129]     Eph Nomenclature Committee (1997). Unified nomenclature for Eph family receptors and their ligands, the ephrins. Cell 90, 403-404.  
         [0130]     Esnouf, R. M. (1997). An extensively modified version of MolScript that includes greatly enhanced coloring capabilities. J Mol Graph Model 15, 132-134, 112-133.  
         [0131]     Ferrara, N. (1999). Vascular endothelial growth factor: molecular and biological aspects. Curr Top Microbiol Immunol 237, 1-30.  
         [0132]     Fuller, T., Korff, T., Kilian, A., Dandekar, G., and Augustin, H. G. (2003). Forward EphB4 signaling in endothelial cells controls cellular repulsion and segregation from ephrinB2 positive cells. J Cell Sci 116, 2461-2470.  
         [0133]     Gale, N. W., Holland, S. J., Valenzuela, D. M., Flenniken, A., Pan, L., Ryan, T. E., Henkemeyer, M., Strebhardt, K., Hirai, H., Wilkinson, D. G., et al. (1996). Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis. Neuron 17, 9-19.  
         [0134]     Gale, N. W., and Yancopoulos, G. D. (1999). Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev 13, 1055-1066.  
         [0135]     Gerety, S. S., Wang, H. U., Chen, Z. F., and Anderson, D. J. (1999). Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol Cell 4, 403-414.  
         [0136]     Gill, S. C., and von Hippel, P. H. (1989). Calculation of protein extinction coefficients from amino acid sequence data. Anal Biochem 182, 319-326.  
         [0137]     Hamada, K., Oike, Y., Ito, Y., Maekawa, H., Miyata, K., Shimomura, T., and Suda, T. (2003). Distinct roles of ephrin-B2 forward and EphB4 reverse signaling in endothelial cells. Arterioscler Thromb Vasc Biol 23, 190-197.  
         [0138]     Himanen, J. P., Chumley, M. J., Lackmann, M., Li, C., Barton, W. A., Jeffrey, P. D., Vearing, C., Geleick, D., Feldheim, D. A., Boyd, A. W., et al. (2004). Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling. Nat Neurosci 7, 501-509.  
         [0139]     Himanen, J. P., Henkemeyer, M., and Nikolov, D. B. (1998). Crystal structure of the ligand-binding domain of the receptor tyrosine kinase EphB2. Nature 396, 486-491.  
         [0140]     Himanen, J. P., Rajashankar, K. R., Lackmann, M., Cowan, C. A., Henkemeyer, M., and Nikolov, D. B. (2001). Crystal structure of an Eph receptor-ephrin complex. Nature 414, 933-938.  
         [0141]     cones, T. A., Zou, J. Y., Cowan, S. W., and Kjeldgaard (1991). Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr A 47 (Pt 2), 110-119.  
         [0142]     Koolpe, M., Burgess, R., Dail, M., and Pasquale, E. B. (2005). EphB receptor-binding peptides identified by phage display enable design of an antagonist with ephrin-like affinity. J Biol Chem 280, 17301-17311.  
         [0143]     Koolpe, M., Dail, M., and Pasquale, E. B. (2002). An ephrin mimetic peptide that selectively targets the EphA2 receptor. J Biol Chem 277, 46974-46979.  
         [0144]     Kraulis, P. J. (1991). MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures. J Applied Crystallography 24, 946-950.  
         [0145]     Kullander, K., and Klein, R. (2002). Mechanisms and functions of Eph and ephrin signalling. Nat Rev Mol Cell Biol 3, 475-486.  
         [0146]     Martiny-Baron, G., Korff, T., Schaffner, F., Esser, N., Eggstein, S., Marme, D., and Augustin, H. G. (2004). Inhibition of tumor growth and angiogenesis by soluble EphB4. Neoplasia 6, 248-257.  
         [0147]     Merritt, E. A., and Murphy, M. E. (1994). Raster3D Version 2.0. A program for photorealistic molecular graphics. Acta Crystallogr D Biol Crystallogr 50, 869-873.  
         [0148]     Murai, K. K., Nguyen, L. N., Koolpe, M., McLennan, R., Krull, C. E., and Pasquale, E. B. (2003). Targeting the EphA4 receptor in the nervous system with biologically active peptides. Mol Cell Neurosci 24, 1000-1011.  
         [0149]     Nikolov, D. B., Li, C., Barton, W. A., and Himanen, J. P. (2005). Crystal structure of the ephrin-b1 ectodomain: implications for receptor recognition and signaling. Biochemistry 44, 10947-10953.  
         [0150]     Noren, N. K., Lu, M., Freeman, A. L., Koolpe, M., and Pasquale, E. B. (2004). Interplay between EphB4 on tumor cells and vascular ephrin-B2 regulates tumor growth. Proc Natl Acad Sci USA 101, 5583-5588.  
         [0151]     Otwinowski, Z., Minor, W. (1997). Processing of x-ray diffraction data collected in oscillation mode, Vol 276 (New York, Academic Press).  
         [0152]     Pasquale, E. B. (2005). Eph receptor signalling casts a wide net on cell behaviour. Nat Rev Mol Cell Biol 6, 462-475.  
         [0153]     Smith, F. M., Vearing, C., Lackmann, M., Treutlein, H., Himanen, J., Chen, K., Saul, A., Nikolov, D., and Boyd, A. W. (2004). Dissecting the EphA3/Ephrin-A5 interactions using a novel functional mutagenesis screen. J Biol Chem 279, 9522-9531.  
         [0154]     Stephenson, S. A., Slomka, S., Douglas, E. L., Hewett, P. J., and Hardingham, J. E. (2001). Receptor protein tyrosine kinase EphB4 is up-regulated in colon cancer. BMC Mol Biol 2, 15.  
         [0155]     Takemoto, M., Fukuda, T., Sonoda, R., Murakami, F., Tanaka, H., and Yamamoto, N. (2002). Ephrin-B3-EphA4 interactions regulate the growth of specific thalamocortical axon populations in vitro. Eur J Neurosci 16, 1168-1172.  
         [0156]     Turnbull, W. B., and Daranas, A. H. (2003). On the value of c: can low affinity systems be studied by isothermal titration calorimetry? J Am Chem Soc 125, 14859-14866.  
         [0157]     Vagin, A., Teplyakov, A. (1997). MOLREP: an automated program for molecular replacement. J Appl Crystallogr 30, 1022-1025.  
         [0158]     Wang, H. U., Chen, Z. F., and Anderson, D. J. (1998). Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93, 741-753.  
         [0159]     Wilkinson, D. G. (2000). Eph receptors and ephrins: regulators of guidance and assembly. Int Rev Cytol 196, 177-244.  
         [0160]     Wiseman, T., Williston, S., Brandts, J. F., and Lin, L. N. (1989). Rapid measurement of binding constants and heats of binding using a new titration calorimeter. Anal Biochem 179, 131-137.  
         [0161]     Xia, G., Kumar, S. R., Masood, R., Zhu, S., Reddy, R., Krasnoperov, V., Quinn, D. I., Henshall, S. M., Sutherland, R. L., Pinski, J. K., et al. (2005). EphB4 expression and biological significance in prostate cancer. Cancer Res 65, 4623-4632.  
         [0162]     Yuan, K., Hong, T. M., Chen, J. J., Tsai, W. H., and Lin, M. T. (2004). Syndecan-1 up-regulated by ephrinB2/EphB4 plays dual roles in inflammatory angiogenesis. Blood 104, 1025-1033.  
         [0163]     Zamora, D. O., Davies, M. H., Planck, S. R., Rosenbaum, J. T., and Powers, M. R. (2005). Soluble forms of EphrinB2 and EphB4 reduce retinal neovascularization in a model of proliferative retinopathy. Invest Ophthalmol Vis Sci 46, 2175-2182.