Abstract:
Soluble polypeptide fraction consisting of all or part one  of at least one of the four immunoglobulin-type extracellular LAG-3 protein domains (amino acids 1-159, 160-230  239, 240-330 and 331-412 of the SEQ ID NO:1 sequence) or consisting of one peptide sequence derived from these domains by replacement, addition or deletion of one or more amino acids. The fraction of the invention has a specificity at least equal to that of LAG-3 in relation to its ligand.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a §371 application of PCT/FR95/00593, filed May 5, 1995. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The invention relates to soluble forms derived from the LAG-3 membrane protein which are useful as immunosuppressants, as well as antibodies capable of preventing the specific binding of the LAG-3 protein to MHC (major histocompatibility complex) Class II molecules as immunostimulants. 
     2. Description of the Related Art 
     In WO-A 91/10682, a protein designated LAG-3 has been described. 
     The LAG-3 protein is a protein selectively expressed by NK cells and activated T lymphocytes. Similarity of the amino acid sequence, the comparative exon/intron organization and the chromosomal localization show that LAG-3 is related to CD4. The initial characterization of the LAG-3 gene has been described by TRIEBEL et al. (1). 
     The corresponding DNA codes for a type I transmembrane protein of 498 amino acids containing 4 extra-cellular sequences of the immunoglobulin type. LAG-3 is a member of the immunoglobulin superfamily. 
     The mature protein comprises 476 amino acids (SEQ ID No. 1) with a theoretical molecular weight of 52 kD. The extracellular region contains 8 cysteine residues and 4 potential N-glycosylation sites. By Western blot analysis, it was shown that LAG-3 inside PRA-blasts or activated NK cells has an apparent mass Mr of 70,000. After treatment with N-glycosidase F, a reduction in size to 60 kD was obtained, thereby demonstrating that native LAG-3 is glycosylated. Fuller details are described in WO-A 91/10682. 
     BAIXERAS et al., in J. Exp. Med. 176, 327-337 (2), have, in addition, described their finding that rosette formation between cells transfected with LAG-3 (expressing LAG-3 at their surface) and B lymphocytes expressing MHC Class II was specifically dependent on LAG-3/MHC Class II interaction. 
     Surprisingly, this ligand for MHC Class II was detected with higher levels on activated CD8 +  lymphocytes (MHC Class I-restricted) than on activated CD4 +  lymphocytes. In vivo, only a few disseminated LAG-3 +  cells (MHC Class II-restricted) were to be found in non-hyperplastic lymphoid tissue comprising the primary lymphoid organs, that is to say thymus and bone marrow. LAG-3 +  cells were to be found in hyperplastic lymphoid nodules and tonsils, as well as among peripheral blood mononuclear cells (PBMC) of patients receiving injections of high doses of IL-2. 
     These observations confirm that LAG-3 is an activation antigen in contrast to CD4 expressed in a subpopulation of resting lymphocytes and other cell types, in particular macrophages. 
     The MHC comprises Class I and Class II molecules which are membrane glycoproteins which present fragments of protein antigens to the T lymphocyte receptors (TCR). Class I molecules are responsible for the presentation to CD8 +  cytotoxic cells of peptides derived in large part from endogenously synthesized proteins, while Class II molecules present to CD4 +  helper lymphocytes peptides originating in the first place from foreign proteins which have entered the endocytic, that is to say exogenous, pathway. T helper lymphocytes regulate and amplify the immune response, while cytotoxic lymphocytes are needed to destroy cells irrespective of the tissues expressing “non-self” antigens, for example viral antigens. The mechanism of recognition involves intercellular signals leading to an effective activity of T lymphocytes. 
     It is apparent that, to initiate an immune response mediated by T (CD4 + ) lymphocytes, the foreign antigens must be captured and internalized in the form of peptides by specialized cells, the antigen presenting cells (APC). The resulting antigenic peptides are reexpressed at the surface of the antigen presenting cells, where they are combined with MHC Class II molecules. This MHC Class I II/peptide complex is specifically recognized by the T lymphocyte receptor, resulting in an activation of the T helper lymphocytes. 
     Moreover, animal models created by recombination techniques have made it possible to emphasize the part played in vivo by MHC Class II molecules and their ligands. 
     Thus, mice deficient in MHC Class II molecules (3) and possessing almost no peripheral CD4 +  T lymphocytes and having only a few immature CD4 +  lymphocytes in the thymus have proved to be completely incapable of responding to T-dependent antigens. 
     CD4 − / −  mutant mice (4) have a substantially decreased T lymphocyte activity but show normal development and function of the CD8 +  T lymphocytes, demonstrating that the expression of CD4 on the daughter cells and CD4 +  CD8 +  thymocytes is not obligatory for the development. Compared to normal mice, these CD4-deficient mice have a large amount of CD4 −  CD8 −  cells. 
     These doubly negative cells are restricted to MHC Class II and capable of recognizing the antigen. 
     When they are infected with Leishmania, these mice show a population of functional T helper lymphocytes despite the absence of CD4. These cells are restrictive to MHC Class II and produce interferon-γ when they are activated by the antigen. This indicates that the lineage of the T lymphocytes and their peripheral function need not necessarily depend on the function of CD4. 
     It is now recognized that the proteins encoded by MHC Class II region are involved in many aspects of immune recognition, including the interaction between different lymphoid cells such as lymphocytes and antigen presenting cells. Different observations have also shown that other mechanisms which do not take place via CD4 participate in the effector function of T helper lymphocytes. 
     These different observations underline the pivotal role played by MHC Class II and its ligands in the immune system. 
     Moreover, the importance is known of chimeric molecules composed of the extracytoplasmic domain of proteins capable of binding to ligands and a constant region of human immunoglobulin (Ig) chains for obtaining soluble forms of proteins and of cell receptors which are useful, in particular, as therapeutic agents. 
     Thus, soluble forms of CD4 have proven their efficacy in inhibiting an HIV infection in vitro in a dose-dependent manner. 
     Nevertheless, clinical trials with soluble CD4 molecules, in particular of CD4-Ig, have not enabled a significant decrease in viral titres to be demonstrated. Transgenic mice expressing up to 20 μg/ml of soluble CD4 in their serum were created. These mice showed no difference as regards their immune function relative to control mice. Hitherto, no direct biding to MHC Class II of molecules derived from CD4 has been reported. This strongly suggests that soluble CD4 molecules do not interact in vivo with MHC Class II molecules. 
     SUMMARY OF THE INVENTION 
     Surprisingly, the authors of the present invention have shown that soluble molecules containing different fragments of the extracytoplasmic domain of the LAG-3 protein were capable of binding to MHC Class II molecules and of having an immunosuppressant action. 
     The extracytoplasmic region of LAG-3 represented by the sequence SEQ ID No. 1 comprises the domains D1, D2, D3 and D4 extending from amino acids 1 to 159, 160 to 239, 240 to 330 and 331 to 412, respectively. 
     Thus, the subject of the invention is a soluble polypeptide fraction consisting of all or part of at least one of the 4 immunoglobulin type extracellular domains of the LAG-3 protein (amino acid 1 to 159, 160 to 239, 240 to 330 and 331 to 412 of the sequence SEQ ID No. 1), or of a peptide sequence derived from these domains by replacement, addition and/or deletion of one or more amino acids, and which possesses a specificity at least equal to or greater than that of LAG-3 for its ligand. 
     The present invention encompasses, in particular, soluble polypeptide fractions having a sequence derived from the native LAG-3 sequence originating from the well-known phenomenon of polytypy. 
     The soluble polypeptide fraction is characterized in that it comprises the peptide region of LAG-3 responsible for the affinity of LAG-3 for MHC Class II molecules. 
     The soluble polypeptide fraction comprises, in particular, a peptide sequence derived from these domains by replacement, addition and/or deletion of one or more amino acids, and which possess a specificity equal to or greater than that of LAG-3 for its ligand, for example the whole of the first two immunoglobulin type domains of LAG-3, or the 4 immunoglobulin type domains of the extracytoplasmic domain of LAG-3. 
     Advantageously, the soluble polypeptide fraction is comprised of all or part of at least one of the four immunoglobulin type extracellular domains of the LAG-3 protein (amino acid 1 to 149, 150   159 ,  160 to 239, 240 to 330 and 331 to 412 of sequence SEQ ID No. 1) comprising one or more of the arginine (Arg) rests at the positions 73, 75 and 76 of sequence SEQ ID No. 1 substituted with glutamic acid (Glu). 
     Preferably, the soluble polypeptide fraction comprises a loop in which the average position of the atoms forming the basic linkage arrangement is given by the position of amino acids 46 to 77 (SEQ ID No. 1) appearing in Table 1 or Table 2 or differs therefrom by not more than 5%. 
     The soluble polypeptide fraction advantageously comprises, in addition, the second immunoglobulin type extracellular domain (D2) of LAG-3 (amino acids 150   160 to 241 239 ). 
     Advantageously, the soluble polypeptide fraction comprises, besides the peptide sequence of LAG-3 as defined above, a supplementary peptide sequence at its C-terminal and/or N-terminal end, so as to constitute a fusion protein. The term “fusion protein” means a portion of any protein permitting modification of the physicochemical features of the subfragments of the extracytoplasmic domain of the LAG-3 protein. Examples of such fusion proteins contain fragments of the extracytoplasmic domain of LAG-3 as are defined above, bound to the heavy chain —CH2—CH3 junction region of a human immunoglobulin, preferably an isotype IgG4 immunoglobulin. 
     Such fusion proteins may be dimeric or monomeric. These fusion proteins may be obtained by recombination techniques well known to a person skilled in the art, for example a technique such as that described by Traunecker et al. (5). 
     Generally speaking, the method of production of these fusion proteins comprising an immunoglobulin region fused with a peptide sequence of LAG-3 as defined above consists in inserting into a vector the fragments of cDNA coding for the polypeptide regions corresponding to LAG-3 or derived from LAG-3, where appropriate after amplification by PCR, and the cDNA coding for the relevant region of the immunoglobulin, this cDNA being fused with cDNA coding for the corresponding polypeptide regions or derivatives of LAG-3, and in expressing after transfection the fragments cDNA in an expression system, in particular mammalian cells, for example hamster ovary cells. 
     The fusion proteins according to the invention may also be obtained by cleavage of a LAG-3/ Ig conjugate constructed so as to contain a suitable cleavage site. 
     The subject of the invention is also a therapeutic composition having immunosuppressant activity comprising a soluble polypeptide fraction according to the invention. This composition will be useful for treating pathologies requiring immunosuppression, for example autoimmune diseases. 
     The subject of the invention is also the use of antibodies directed against LAG-3 or soluble polypeptide fractions derived from LAG-3 as are defined above, or fragments of such antibodies, in particular the Fab, Fab′ and F(ab′) 2  fragments, for the preparation of a therapeutic composition having immunostimulatory activity. “Immunostimulatory” means a molecular entity capable of stimulating the maturation, differentiation, proliferation and/or function of cells expressing LAG-3, that is to say T lymphocytes or active NK cells. The anti-LAG-3 antibodies may be used as potentiators of vaccines or immunostimulants in immunosuppressed patients, such as patients infected with HIV or treated with immunosuppressant substances, or be used to stimulate the immune system by elimination of self cells displaying abnormal behaviour, for example cancer cells. 
     Immunostimulatory activity of anti-LAG-3 anti-bodies is surprising, inasmuch as anti-CD4 antibodies have an immunosuppressant action. 
     Such antibodies may be polyclonal or monoclonal; however, monoclonal antibodies are preferred. The polyclonal antibodies may be prepared according to well-known methods, such as that described by BENEDICT A. A. et al. (6). Monoclonal antibodies are preferred, on account of the fact that they are specific for a single epitope and yield results with better reproducibility. Methods of production of monoclonal antibodies are well known from the prior art, especially the one described by KOHLER and MILSTEIN. This method, together with variants thereof, are described by YELTON et al. (7). 
     The subject of the invention is also anti-idiotype antibodies directed against the antibodies according to the invention, which contain the internal image of LAG-3 and are consequently capable of binding to MHC Class II. Such antibodies may be used, in particular, as immunosuppressants, and, for example, in autoimmune pathologies. 
     The therapeutic compositions according to the present invention comprise soluble LAG-3 proteins or antibodies as are defined above, as well as a pharmaceutically acceptable vehicle. These compositions may be formulated according to the usual techniques. The vehicle can vary in form in accordance with the chosen administration route: oral, parenteral, sublingual, rectal or nasal. 
     For the compositions for parenteral administration, the vehicle will generally comprise sterile water as well as other possible ingredients promoting the solubility of the composition or its ability to be stored. The parenteral administration routes can consist of intravenous, intramuscular or subcutaneous injections. 
     The therapeutic composition can be of the sustained-release type, in particular for long-term treatments, for example in autoimmune diseases. The dose to be administered depends on the subject to be treated, in particular on the capacity of his/her immune system to achieve the desired degree of protection. The precise amounts of active ingredient to be administered may be readily determined by the practitioner who will initiate the treatment. 
     The therapeutic .compositions  compositions according to the invention can comprise, in addition to soluble LAG-3 or the antibodies according to the invention, another active ingredient, where apprto LAG-3 or to anmical  appropriate, bound via a chemical bond to LAG-3 or to an antibody according to the invention. As an example, there may be mentioned soluble LAG-3 proteins according to the invention fused to a toxin, for example ricin or diphtheria toxoid, capable of binding to MHC Class II molecules and of killing the target cells, for example leukaemic or melanoma cells, or fused to a radioisotope. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 shows a comparison of the proliferation of T cells incubated with F(ab) fragments of 17B4 to the proliferation of T cells incubated with intact 17B4 monoclonal antibody. 
     FIG. 2 shows the proliferation of Clone 28 in response to tetanus toxoid when co-cultured with 17B4 or control antibody 10H3. 
     FIG. 3 shows the expression vector pCDM7 used for manufacturing the recombinant LAG-3 proteins and a recombinant CD8 immunoadhesin control. 
     FIG. 4 shows the pCLH3 AXS V2 DHFR hα IVS vector used to express amplified LAG-3 sequences. 
     FIG. 5A shows the inhibition of MHC Class II interaction with LAG-3 by recombinant LAG-3 D1-D4 and FIG. 5B shows the potential inhibition of MHC Class II interaction with CD4. 
     FIG. 6 shows the inhibition of Clone 28 proliferation by recombinant LAG-3 D1-D4. 
     FIG. 7 shows the inhibition of Clone 154 proliferation by LAG-3 Ig. 
     FIG. 8 shows the binding of LAG-3 to B cell lines expressing MHC class II haplotypes or human class II-transfected mouse cells. 
     FIG. 9 shows the binding of LAG-3 Ig to MHC Class II expressing Daudi cells. 
     FIG. 10 shows that preincubation of HLA class II expressing cells with 17B4 inhibits LAG-3 Ig binding. 
     FIGS. 11A-11C show the inhibition of clone T154 proliferation by crosslinked LAG-3 Ig. 
     FIG. 12 compares inhibition of T cell proliferation by anti-Class II antibodies to inhibition of T cell proliferation by LAG-3 Ig. 
     FIGS. 13A-13D show that T cell proliferation in response to OKT3 (FIG.  13 A), lectins (FIG. 13B) and low-concentration IL 2  (FIG. 13C) is inhibited by LAG-3 Ig but proliferation in response to high-concentration IL 2  is not inhibited by LAG-3 Ig (FIG.  13 D). 
     FIG. 14 shows clone S1B5 cytotoxicity towards Epstein-Barr virus transformed human B cells. 
     FIG. 15 shows peripheral blood lymphocyte cytotoxicity towards HLA Class I −  Daudi cells. 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The examples which follow, together with the attached reference figures, will illustrate the invention in greater detail. 
     EXAMPLE 1 
     Proliferation of active T lymphocyte lines in the presence of anti-LAG-3 monoclonal antibodies 
     The anti-LAG-3 monoclonal antibodies used were 17B4, described in BAIXERAS et al. (2) and deposited at the CNCM under No. I-1240 on Jul. 10, 1992, and 11E3, described in HUARD et al. (8). 
     These antibodies belong to the isotype IgG1. These antibodies were tested for their biological effects on activated T lymphocytes, stimulated by specific antigenic peptides or processed antigens presented by MHC Class II molecules expressed by autologous antigen presenting cells, expressing LAG-3. 
     An anti-CD48 monoclonal antibody designated 10 H3 was used as irrelevant IgG1 antibody (negative control). 
     The saturating concentrations of anti-LAG-3 and anti-CD48 antibodies were determined by immunofluorescence on PHA (phytohaemagglutinin)-blasts and cell lines transformed by Epstein-Barr virus (EBV). In the proliferation tests, the monoclonal antibodies were added in the proportion of 5 times the saturating concentration. 
     The T lymphocyte lines used were, on the one hand the clone 154 derived from peripheral blood lymphocytes, raised against a peptide mimicking an influenza haemagglutinin (HA) fragment having an amino acid sequence extending from amino acid 306 to 329 (p20 peptide), and on the other hand the clone 28, a T lymphocyte clone derived from peripheral lymphocytes of a single human donor, raised against diphtheria toxoid (DT). The antigen presenting cells (APC) corresponding to clone 154 were EBV-transformed B lymphocytes of the same donor (DR3/DR11) as T 154. The antigen presenting cells corresponding to clone 28 were EBV-transformed B lymphocytes of the same donor. This clone was restricted to HLA DR7. 
     For clone 154, the APC (5×10 6 ) were incubated at 37° C. for one and a half hours with variable doses of the p20 peptide, then washed and irradiated (10,000 rad). The cells were plated out on 96-well microtitration plates at the same time as the clone 154 cells (0.5×10 5  to 10×10 5  cells/ml) in a 3:1 ratio. For clone 28, the responding cells/stimulating cells ratio was 1. 
     The HLA DR7/EBV APC cells were either treated with mitomycin or irradiated, then added to the T lymphocytes in the presence of DT (which remained in the culture). The final concentration of clone 28 cells was 100,000 cells/ml. 
     [ 3 H]Thymidine (1 μCi/well) was added at varying time intervals from day 2 to day 10 of culture. 
     Each experiment was carried out in triplicate. 
     The results were expressed as the mean cpm and after subtraction of the cpm found in the negative control (T lymphocytes cocultured with APC unladen with immunogens). The proliferation tests were carried out on 96-well plates. The absorption of tritiated thymidine in the individual 200 μl wells was measured after adding 1 μCi of thymidine for the last 18 hours of culture. The results were expressed in the form of the mean of 3 tests. The standard deviation was usually less than 12% (a little more in the case of very low cpm measurements). Moreover, mixed culture (clone 154/APC) supernatants were combined, filtered through 0.22 μm membranes, divided into samples and frozen at −20° C. until the time of titration using commercial immunoassay kits: Immunotech IL-2 and INF-α titration kit, Genzyme IFN-γ kit and Cayman Chemicals IL-4 kit. 
     A dose determination study was carried out to establish the proliferation profiles of clone 154 brought into contact with the p20 specific antigen at varying concentrations and in the presence or absence of anti-LAG-3 monoclonal antibodies or irrelevant monoclonal antibodies (negative control). 
     The individual results of 16 separate tests showed that, irrespective of the concentration of added antigen, the initial point up to the peak of proliferation was not modified, but a significant prolongation of the proliferation of T lymphocytes incubated with the anti-LAG-3 monoclonal antibodies was observed systematically. Fab fragments of the monoclonal antibody 17B4 were prepared and used in a test of proliferation of clone 154. The proliferation profile of T lymphocytes activated by the antigen with the 17B4 Fab fragments (15 μg/ml) was similar to that of cells incubated in the presence of whole 17B4 monoclonal antibody (40 μg/ml) (FIG.  1 ). These results show that the observed biological effects are not attributable to a non-specific reaction induced by the Fc region of the anti-LAG-3 monoclonal antibodies. 
     Similar results were obtained with the 11E3 anti-LAG-3 monoclonal antibodies. 
     Clone 28 was also stimulated with the antigen (tetanus toxoid 10 μg/ml) in the presence of 17B4 monoclonal antibodies after coculture with the corresponding APC in the presence of DT. The results are shown in FIG.  2 . 
     The effects of the anti-LAG-3 monoclonal antibodies observed with clone 28, namely the prolongation of proliferation, are similar to those observed with clone 154. 
     Tests were carried out designed to measure the miscellaneous cellular events occurring after the antigenic stimulation of clone 154 cells incubated in the presence of anti-LAG-3 monoclonal antibodies. 
     The cells were harvested during conventional antigenic stimulation of clone 154 in the presence of anti-LAG-3 or anti-CD48 monoclonal antibodies or in the absence of antibodies, and tested for the expression of LAG-3 and CD25 transmembrane receptors, and samples of culture supernatants were collected at different time intervals after stimulation and tested for the presence of IFN-γ, TNF-α, IL-4 and IL-2. 
     Two-colour direct immunofluorescence tests (anti-CD3 monoclonal antibodies and anti-CD25 monoclonal antibodies) showed that IL-2 receptors were weakly but significantly increased 5 days after the antigenic stimulation. Similar tests with anti-CD3 and 11E3 (anti-LAG-3) monoclonal antibodies showed that LAG-3 was over-expressed from the day following activation onwards. In addition, the secretion of IL-2, IL-4, IFN-γ and TNF-α was also modulated by incubation with anti-LAG-3 monoclonal antibodies, thus showing that different cellular events are modified by the presence of anti-LAG-3 monoclonal antibodies and that some events already take place 24 hours after stimulation. 
     These results show indirectly that LAG-3 plays a regulatory role for CD4 +  cells. The fact that anti-LAG-3 monoclonal antibodies increase proliferation, and hence act as immunopotentiators, suggest that LAG-3 is involved in the “deactivation” of CD4 +  T lymphocytes with a negative role of LAG-3 on the antigen-dependent stimulation. 
     EXAMPLE 2 
     Transient expression of LAG-3 fusion proteins 
     Soluble proteins derived from LAG-3 were obtained by a recombinant DNA technique using suitable vectors comprising DNA coding for LAG-3 and DNA coding for an immunoglobulin fragment. The transient expression system consisted of transfected Cos cells. This system makes it possible to produce several mg of recombinant fusion proteins. Recombinant DNA techniques were carried out as described by MANIATIS et al. (22). The modifications were made as recommended by the manufacturer. 
     Construction of LAG-3 D1-D4 Ig and LAG-3 D1D2 Ig 
     Fragments coding for the D1D2 or D1-D4 regions were amplified (30 cycles) from a fragment of cDNA (FDC sequence) encompassing LAG-3 cDNA (TRIEBEL et al. (1)), using Taq polymerase free from 5′-endonuclease activity and relatively resistant to an exposure to very high temperature; the amplification was followed by a denaturation at 98° C. (with a Perkin Elmer Cetus “DNA thermal cycle”). Specific primers were used as recorded in the table below. 
     The resulting amplified fragments (739 bp and 1312 bp for LAG-3 D1-D2 and LAG-3 D1-D4, respectively) were inserted into a pBS plasmid (Stratagene). 
     Inserts were prepared after digestion with XhoI and BglII and introduced into the XhoI/BamHI sites of the vector pCDM7-CD8-IgG1 (pCDM7 being derived from pCDM8 marketed by Stratagene), as illustrated in FIG. 3, so as to exchange the DNA sequences coding for CD8 for those coding for the subfragments of LAG-3. The resulting expression vectors contained the sequences coding for D1D2 or D1-D4 fused to the DNA sequences coding for the —CH 2 —CH 3  junction region of a human IgG1 chain. 
     
       
         
               
             
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Primers used to amplify LAG-3 DNA sequences by PCR 
               
             
          
           
               
                   
                 Resulting 
               
               
                   
                 encoded subfrag- 
               
               
                   
                 ment fused with 
               
               
                 Primers used for amplification of the DNA 
                 a subfragment Ig 
               
               
                   
               
               
                 Primer (5′) 
                 LAG-3 D1D2 
               
               
                 5′ GCGC CTCGA GGCCCAGACCATAGGAGAG ATG T 3′ (SEQ ID NO: 2) 
                 from the leader 
               
               
                        coupling   untranslated   start of 
                 sequence to 
               
               
                        site       5′ sequences   translation 
                 amino acid241  
               
               
                   
                 
                   239 
                 
               
               
                 Primer (3′) 
               
               
                 5′ GCGC AGATCT CTCCAGACCCAGAACAGTGAGGTTATACAT 3′ (SEQ ID NO: 3) 
               
               
                        BglII coup-                End of D2 
               
               
                        ling site 
               
               
                 Primer (5′) 
                 LAG-3 D1-D4 
               
               
                 identical to LAG-3 D1D2 
                 from the leader 
               
               
                 Primer (3′) 
                 sequence to 
               
               
                 5′ GCGC AGATCT ACCTGGGCTAGACAGCTCTGTGAA 3′  (SEQ ID NO: 4) 
                 amino acid 412 
               
               
                        BglII coup-          End of D4 
               
               
                        ling site 
               
               
                   
               
             
          
         
       
     
     CDM7 is a eukaryotic expression vector derived from the vectors developed by SEED et al. (10) for the cloning of DNA and its expression in E. coli and eukaryotic cells. CDM7 possesses the following features: (i) the human cytomegalovirus promoter for transient expression in mammalian cells; (ii) a viral origin of SV40 for an autosomal replication of mammalian cells expressing T antigen; (iii) πVX (type Col E1) as plasmid origin for a high copy number; (iv) a Sup F selection for resistance to ampicillin and tetracycline in Tet amb  and Amp amb  E. coli strains; (v) an origin of replication of M13 for the release of a single strand; (vi) a T7 RNA promoter; and (vii) a polylinker for an efficient cloning of heterologous DNA. 
     Transient expression in COS cells 
     Cos cells (5×10 6 ) were transfected with 30 μg of DNA of suitable expression vectors (coding for either LAG-3 D1D2 Ig, or LAG-3 D1-D4 Ig, or CD8 Ig) by electroporation (200 V, 1500 μF, 30-40 msec) using a Cellject apparatus (Eurogentech, Liège, BE). The cells were plated out again and cultured on a medium containing 5% of foetal calf serum. The supernatants were withdrawn 6 days after transfection. 
     The synthesis of the resulting fusion proteins was analysed from the supernatants as well as from cell extracts of transfected cells, by Western blot analysis with the 17B4 monoclonal antibodies. Immunoreactive materials were observed in the supernatant of cells transfected with DNA coding for LAG-3 D1D2 Ig or LAG-3 D1-D4 Ig. 
     Concomitantly, a recombinant CD8 immunoadhesin (CD8 Ig) was obtained as negative control using the same expression system and the expression vector pCDM7-CD8 (FIG.  3 ). 
     The recombinant proteins LAG-3 D1D2 Ig. LAG-3 D1-D4 Ig and CD8 Ig were purified by means of the standard method on protein A-Sepharose. The resulting material was analysed by SDS-PAGE, followed by Coomassie staining or a Western blot analysis using anti-human Ig antibody. 
     EXAMPLE 3 
     Production of soluble subfragments of LAG-3 
     In order to produce large amounts of recombinant proteins, a stable expression system consisting of transfected mammalian cells was developed. The host cells are anchorage-dependent hamster ovary (CHO) cells isolated from CHO cells deficient in dihydrofolate reductase (DHFR) and consequently necessitating glycine, a purine and thymidine for their growth. The pivotal role of DHFR in the synthesis of nucleic acid precursors, combined with the sensitivity of DHFR-deficient cells with respect to tetrahydrofolate analogues such as methotrexate (MTX), has two major advantages. Transfection of these cells with expression vectors containing the DHFR gene permits the secretion of recombinant DHFR-resistant clones, and the culturing of these cells on selective media containing increasing amounts of MTX results in amplification of the DHFR gene and the DNA associated therewith. 
     Construction of LAG-3 D1, LAG-3 D1D2, LAG-3 D1-D4 
     Fragments of DNA coding for the D1, D1D2 or D1-D4 regions were amplified using a PCR method identical to the one described previously, using the primers specified in the table below. 
     
       
         
               
             
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 Primers used for amplifying LAG-3 DNA sequences by PCR 
               
             
          
           
               
                   
                 Resulting 
               
               
                   
                 encoded 
               
               
                 Primers used for amplification of the DNA 
                 subfragment 
               
               
                   
               
               
                 Primer (5′) 
                 LAG-3 D1 
               
               
                 5′ CGCC GTCGAC CGCTGCCCAGACCATAGGAGAGATGTG 3′ (SEQ ID NO:5) 
                 from the leader 
               
               
                 SalI coup-    untranslated   start of 
                 sequence to 
               
               
                 ling site     5′ sequences   translation 
                 amino acid 149 159 
               
               
                 Primer (3′) 
               
               
                 5′ GCGC GTCGAC TTAACCCAGAACAGTGAGGTTATAC 3′ (SEQ ID NO: 6) 
               
               
                 SalI coup-                  End of D1 
               
               
                 ling site 
               
               
                 Primer (5′) 
                 LAG-3 D1D2 
               
               
                 identical to LAG-3 D1 
                 from the leader 
               
               
                 Primer (3′) 
                 sequence to 
               
               
                 5′ GCGC GTCGAC TTAACCCAGAACAGTGAGGTTATAC 3′ (SEQ ID NO: 7) 
                 amino acid 239 
               
               
                        SalI[II]  coup-       End of D2 
               
               
                        ling site 
               
               
                 Primer (3′)  
                 amino acid 149 
               
               
                 5′ GCGCGTCGACTTAACCCAGAACAGTGAGGTTATAC 3′ (SEQ ID NO: 6) 
               
               
                        SalI coup-           End of D1 
               
               
                        ling site  
               
               
                 Primer (5′) 
                 LAG-3 D1-D4 
               
               
                 identical to LAG-3 D1 
                 from the leader 
               
               
                 Primer (3′) 
                 sequence to 
               
               
                 5′ GCGC GTCGAC TTAACCCTGGGCTAGACAGCTCTCTGTG 3′ (SEQ ID NO:8) 
                 amino acid 412 
               
               
                        SalI coup-              End of D4 
               
               
                        ling site 
               
               
                   
               
             
          
         
       
     
     The resulting amplified fragments were digested with SalI and inserted into the SalI site of pUC 18 (Stratagene). 
     The amplified sequences were verified, and the inserts subcloned into the expression vector pCLH3 AXS V2 DHFR hα IVS as described by COLE et al. (Biotechnology 11, 1014-1024, 1993) (FIG.  4 ). 
     This vector is a eukaryotic expression vector which is multifunctional for the expression C cDNA and its amplification in eukaryotic cells. It possesses the following features: (i) the murine promoter of the metallothionein-1 gene and a polyadenylation sequence SV 40 (comprising a donor-acceptor splicing site) to bring about transcription of the gene of interest, (ii) a human intervening sequence A containing the donor-acceptor splicing site of the gene for the subunit of α glycoprotein for obtaining high levels of transcription of cDNA, (iii) the pML sequence containing the origin of replication of pBR322 and a gene for resistance to aampicillin  ampicillin for bacterial amplification, and (iv) a DHFR transcription unit of SV 40 to bring about transcription of the sequences used for selection and amplification of the transfectants. 
     Stable expression in CHO cells 
     The expression vectors coding for LAG-3 D1, LAG-3 D1D2 and LAG-3 D1-D4 were used to transfect CHO DUKX cells, and these cells were cultured on a selective medium. Cells capable of multiplying under these conditions were combined and cultured on a medium containing increasing amounts of MTX. Levels of expression were measured by Western blot analysis using the 17B4 monoclonal antibody. Clones producing high levels of recombinant soluble molecules derived from LAG-3 were propagated in bioreactors, and the material derived from LAG-3 was purified by ion exchange chromatography and immunoaffinity. 
     Western blot analyses revealed, in supernatants of cells transfected with expression vectors coding for LAG-3 D1, LAG-3 D1D2 and LAG-3 D1-D4, bands with apparent Mr values of 15 to 18 kD, 34-36 kD (doublets) and 55 kD (2 possible bands). The respective Mr values of these immunoreactive materials corresponded to the expected Mr values of glycosylated LAG-3 D1 Ig (139 amino acids and a putative N-glycosylation site), glycosylated LAG-3 D1D2 Ig (239 amino acids containing 3 glycosylation sites) and glycosylated LAG-3 D1-D4 (412 amino acids containing 4 glycosylation sites). 
     EXAMPLE 4 
     Specific binding of LAG-3 Ig to cells expressing MHC Class II 
     The reactivity of the monoclonal antibodies and of LAG-3 D1-D4 Ig was studied by indirect immunofluorescence. Target cells (4×10 5 ) were incubated for 30 minutes at 4° C. in the presence of LAG-3 D1-D4 Ig, CD8 Ig, a murine monoclonal antibody, (949) anti-human MHC Class II (DR, DP, DQ) conjugated to FITC (isothiocyanate fluoride) from a Coulter clone, or murine Ig-FITC; an irrelevant immunoglobulin G conjugated to FITC. The cells were washed and incubated at 4° C. for 30 minutes with either a goat anti-human Ig polyclonal F(ab′) 2  conjugated to fluorescein or a goat anti-mouse Ig polyclonal antibody conjugated to fluorescein (Coulter clone). 
     To confirm the LAG-3/MHC Class II binding, LAG-3 D1-D4 Ig was incubated with MHC Class II-positive or -negative cells. Four B lymphocyte lines expressing MHC Class II(L31, Phil EBV, Raji, Sanchez and Personnaz) were treated with anti-Class II monoclonal antibody 949, or the supernatants for Cos cells transfected with DNA coding either for LAG-3 D1-D4 Ig or for CD8 Ig. The five cell lines expressing the different haplotypes of MHC Class II molecules were recognized by LAG-3 Ig in the same way as by the anti-Class II monoclonal antibodies (positive control), while the supernatant containing CD8 Ig (negative control) did not bind to these cell lines, as could be expected. Four MHC Class II-negative cell lines (CEM, RJ, HSB2, K562) were treated with the same reagents as above. None reacted, either with the anti-MHC Class II (negative control) or with LAG-3 D1-D4 Ig, showing that the binding of LAG-3 D1-D4 is specific to MHC Class II molecules. 
     Further experiments were carried out using (i) mouse fibroblasts transfected or otherwise with genes coding for human DR7 or human DP4, (ii) mouse cells expressing or otherwise MHC Class II molecules, (iii) activated human CD4 +  or CD8 +  cells, and (iv) T lymphocyte lines expressing the different haplotypes of MHC Class II molecules (FIG.  8 ). 
     Unlike CD8 Ig, LAG-3 D1-D4 Ig binds to all cells expressing MHC Class II as efficiently as the anti-MHC Class II monoclonal antibody 949. LAG-3 D1-D4 Ig binds to all DR and DP haplotypes tested, to human MHC Class II molecules expressed by transfected mouse cells, to murine MHC Class II molecules and also to MHC Class II molecules expressed by CD4 +  or CD8 +  T lymphocytes. 
     These results represent for the first time proof that soluble molecules derived from a ligand for MHC Class II are capable of binding to cells expressing MHC Class II. 
     Similar experiments showed that LAG-3 D1D2 bound to cells expressing MHC Class II in as specific a manner and with the same efficiency as LAG-3 D1-D4. 
     Binding activity of LAG-3Ig and cellular distribution of ligands for LAG-3Ig 
     The capacity of this immunoadhesin to bind to cell ligands is measured using a fluorescein-labeled goat serum directed against human immunoglobulins. 
     In these experiments, the target cells are first incubated with a human monoclonal antibody or an immunoadhesin for 30 min at 4° C. in RPMI 1640 containing 10% of FCS (foetal calf serum). The cells are then incubated with an FITC-labelled goat anti-mouse immunoglobulin serum (Coulter) for the murine monoclonal antibodies or with an FITC-labelled goat anti-human immunoglobulin serum (Tago) for the immunoadhesins. The fluorescence is measured after two washes, analyzing 3,000 cells with an Elite cytometer (Coultronics, Hialeah, Fla.). FIG. 9 shows the degrees of binding of LAG-3Ig, CD8Ig, antibody 949 or antibody OKT3 (anti-CD3, ATCC), represented by the number of cells counted as a function of the logarithm of the measured fluorescence intensity. 
     LAG-3Ig binds to mouse fibroblasts transfected for the gene for the HLA DR 4  molecule, and does not bind to untransfected cells. CD8Ig is incapable of binding to HLA DR 4   +  fibroblasts under the same conditions. 
     The cellular distribution of the ligands for LAG-3Ig was evaluated on a cell population sample by immunofluorescence. 
     LAG-3Ig is visualized on all positive Class II cells tested, including B cell lines transformed by Epstein-Barr virus (derived from genetically unrelated donors, including 10 homozygous lines of DR 1  to DR 10  typing), as well as on activated T and NK cells. 
     FIG. 9 shows, by way of example, the binding of LAG-3Ig to Daudi cells which are positive for Class II antigens. 
     The mean fluorescence intensity with LAG-3Ig is similar to that observed with antibody 949 which is specific for Class II antigens. The binding of LAG-3Ig to DR 4  (FIG.  9 ). DR 2 , DR 7  or DPw4 (not shown) expressed at the surface of mouse fibroblasts is, in contrast, weaker than that observed for antibody 949. 
     No binding is detected on cell lines which are negative for Class II antigens of T origin (peripheral blood T cells, CEM, HSB2, REX lines), of B origin (RJ 2.2.5 line) or of non-lymphoid origin (human lines, K562 of erythromyoloid origin and line originating from melanoma cells (not shown)). 
     Moreover, LAG-3Ig binds to xenogeneic Class II molecules of the MHC, such as the antigens expressed by mouse lymphoid A 20 and the monkey Classes II expressed by phytohaemagglutinin-stimulated blasts (data not shown). 
     The specificity of binding of LAG-3Ig was also verified using the monoclonal antibodies 17B4, whose capacity to block LAG-3/MHC Class II interactions in cell adhesion tests was demonstrated beforehand (FIG.  10 ). 
     In these experiments, the LAG-3Ig molecules are preincubated for 30 minutes at 4° C. either with medium alone, or with 17B4 (1 mg/ml), or with OKT3 (1 mg/ml), before being brought into contact with Daudi cells. 
     FIG. 10 shows that a preincubation of LAG-3Ig with 17B4 inhibits the binding to Class II +  cells, whereas no inhibition is detected with the OKT3 control. 
     EXAMPLE 5 
     Inhibition of LAG-3/MHC Class II interaction by soluble fragments of LAG-3 
     The inhibition of LAG-3/MHC Class II interaction by the soluble fragments of LAG-3 may be observed directly in relation to the binding of LAG-3Ig by Class II MHC molecules, by competitive experiments with the soluble fragments. 
     To verify whether the soluble LAG-3D 1 D 2  fragments produced by CHO cells could displace the binding of immunoadhesins derived from LAG-3, the following tests were carried out: 
     Daudi cells are incubated with soluble LAG3-D 1 D 2  fragments so as to permit the binding of these molecules to the MHC Class II antigens expressed at the surface of the Daudi cells. 
     In a second step, the cells are incubated in the presence of LAG-3D 1 D 4 Ig in dimeric form or LAG-3D 1 D 2 Ig in monomeric form. 
     The binding of these immunoadhesins derived from LAG-3 is measured using a goat anti-human Ig F(ab′) 2  conjugated to fluorescein (GAH-FITC). 
     The control groups are represented by Daudi cells incubated with dimeric LAG-3D 1 D 4 Ig or monomeric LAG-3D 1 D 2 Ig without preincubation with the soluble LAG-3D1D2 fragments. 
     The results are recorded in Table 5, which shows that the soluble LAG-3D 1 D 2  fragments are capable of displacing the immunoadhesins derived from LAG-3 in monoor  mono or dimeric form. 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 5 
               
               
                   
               
               
                   
                   
                 Mean Fluor- 
                   
               
               
                 Reactants 
                 Detection 
                 escence 
                 Conclusion 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 — 
                 GAH-FITC 
                 0.3 
                 GAH does not 
               
               
                   
                   
                   
                 interfere 
               
               
                 Dimeric 
                 GAH-FITC 
                 20.8 
                 The binding of 
               
               
                 LAG-3D1D4Ig 
                   
                   
                 CHO/LAG-3D1D2 
               
               
                   
                   
                   
                 inhibits the binding 
               
               
                 CHO/LAG-3D1D2, 
                 GAH-FITC 
                 8.5 
                 of dimeric 
               
               
                 then dimeric 
                   
                   
                 LAG-3D1D4Ig (58%) 
               
               
                 LAG-3D1D4Ig 
               
               
                 Monomeric 
                 GAH-FITC 
                 62.5 
                 The binding of 
               
               
                 LAG-3D1D2Ig 
                   
                   
                 CHO/LAG-3D1D2 
               
               
                   
                   
                   
                 inhibits the binding 
               
               
                 CHO/LAG-3D1D2 
                 GAH-FITC 
                 10.9 
                 of monomeric 
               
               
                 then monomeric 
                   
                   
                 LAG-3D1D2Ig (27%) 
               
               
                 LAG-3D1D2Ig 
               
               
                   
               
             
          
         
       
     
     These data confirm that the soluble LAG-3D1D2 fragments bind to MHC Class II molecules. 
     Inhibition of LAG-3/MHC Class II and CD4/MHC Class II interaction 
     Rosette formation between Cos cells transfected with wild-type LAG-3 and B lymphocytes transformed with EBV expressing MHC Class II molecules was demonstrated by BAIXERAS et al. (2). This interaction is inhibited both by anti-LAG-3 and anti-MHC Class II monoclonal antibodies. 
     The method described in this publication was modified by replacing the visualization and counting of Cos cells binding to B lymphocytes by counting the radioactivity remaining after incubation of  51 Cr-labelled B lymphocytes with Cos cells expressing LAG-3 (binding assay). 
     The possible inhibitory effects of soluble molecules derived from LAG-3 on LAG-3/MHC Class II interaction, and also on CD4/MHC Class II interaction, were studied. 
     Cos cells transfected with a suitable expression vector (coding for wild-type LAG-3 or for CD4). Two days later, the Cos cells were treated with trypsin and plated out again on the basis of 0.05×106 cells/well on a flat-bottomed 12-well tissue culture plates, 24 hours later.  51 Cr-labelled Daudi cells (5.5×10 6 ) were incubated on this monolayer of Cos cells (final vol.: 1 ml) for 1 hour. The target B cells were then aspirated off and the wells washed 5 to 7 times, gently adding 1 ml of medium dropwise. The edges of the wells were washed by suction using a Pasteur pipette. The remaining cells were lysed with 1 ml of PBS, 1% Triton for 15 minutes at 37° C. The lysates were centrifuged at 3000 rpm for 10 minutes, and 100 μl of the resulting supernatant were counted. 
     LAG-3 D1-D4 Ig was used to inhibit LAG-3/MHC Class II and CD4/MHC Class II interaction in the  51 Cr binding assay. Human CD8 Ig and IgG1 were tested in parallel and used as negative controls. 
     A significant inhibition of LAG-3/Class II interaction by LAG-3 D1-D4 Ig was detected (FIG.  5 A). However, the LAG-3/MHC Class II interaction can be partially and non-specifically inhibited by human CD8 Ig and IgG1. Moreover, LAG-3 Ig proved to be a potential inhibitor of CD4/Class II interaction (FIG. 5B) under experimental conditions in which CD4/MHC Class II interaction was not modified by human CD8 Ig or IgG1. This suggests that LAG-3/Class II interaction is weaker than CD4/Class II interaction. These results represent the first proof of a possible competition of soluble molecules in an interaction of MHC Class II with its ligands. 
     EXAMPLE 6 
     Immunosuppressant activity of LAG-3 D1-D4 Ig 
     Functional tests were performed using the proliferation tests described above for the biological activity of the anti-LAG-3 monoclonal antibodies. 
     3 days and 5 days (D3 and D5) after antigenic stimulation, LAG-3 D1-D4 Ig showed a strong inhibition of the proliferation of clone 28, while human CD8 Ig and IgG had no effect (FIG.  6 ). Similar experiments were carried out with clone 154 (FIG.  7 ), and showed a partial inhibition in the presence of LAG-3 Ig. A control carried out with anti-LAG-3 monoclonal antibodies had the reverse effects, as observed previously. 
     A significant inhibition of the cell proliferation of cells incubated in the presence of LAG-3 D1-D4 Ig was also observed for clone 28. 
     These observations show that LAG-3 D1-D4 Ig is a potential immunosuppressant of the proliferation of T lymphocytes stimulated by an antigen, and indicate that LAG-3 might act as an “extinguisher” of the secondary immune response induced by activated CD4 +  T helper lymphocytes. 
     Role of LAG-3Ig in the negative regulation of the immune responses of T cells 
     To demonstrate that a soluble form of LAG-3, mimicking the functions of the membrane molecule, could inhibit the activation of CD 4   +  T clones stimulated by an antigen, the following tests were carried out on clone T154: the T cells are incubated beforehand with a saturating amount of LAG-3Ig (100 nM). The cells are then washed twice with cold RPMI and incubated with 10 μg/ml of goat antibodies directed against human immunoglobulins (Tago) at 4° C. for 30 minutes. 
     After two more washes, the cells are resuspended in RPMI containing 10% of foetal calf serum and incubated for 2 hours at 37° C. before adding the signal. To couple (“cross-link”) the monoclonal antibodies, a goat anti-mouse antibody at a concentration of 10 μg/ml (Tago) is used. 
     FIG. 11 depicts an experiment in which clone T154 has been preincubated with LAG-3Ig bound (“cross-linked”) to a second reactant (polyclonal serum specific for the constant region of human immunoglobulins). The degree of binding of LAG-3Ig to the cells is measured by immunofluorescence (FIG.  11 A). FIG. 11B shows that a more than 50% inhibition of the proliferation of clone T154 is produced by LAG-3Ig. Under the same experimental conditions, no effect is observed with the control CD8Ig or with LAG-3Ig without “cross-linking” (not shown in the figure). 
     FIG. 11C also shows that no effect is observed when LAG-3Ig is used to bind (“cross-link”) the MHC Class II molecules expressed by antigen-presenting B cells. 
     The possible effects of bound (“cross-linked”) anti-Class II monoclonal antibodies in relate to the proliferation of T cells were compared to those of LAG-3Ig. A weak inhibition (less than 50%) is observed with antibody 949 and antibody D1.12 (anti-DR) bound to a goat anti-mouse polyclonal serum (FIG.  12 ). The inhibition of proliferation is hence epitope-dependent, the largest effect being obtained with the epitope of LAG-3 specific for the binding to Classes  Class II. 
     The effects of LAG-3 Ig on the proliferation of T cells were also studied using different signals on another CD 4   +  T clone, clone TDEL specific for peptide 34-53 of the basic myelin protein. 
     An inhibition of proliferation is observed (n=2) when TDEL is stimulated with the antigen (not shown), with immobilized OKT3 (FIG.  13 A), with lectins (PHA+PMA) (FIG. 13B) and with 5 IU/ml of IL 2  (FIG.  13 C). No inhibition is observed with 100 IU/ml of IL 2  (FIG.  13 D). 
     In conclusion, these results collectively show that LAG-3 and MHC Class II molecules, which are each T cell-activating antigens, may be likened to effector molecules involved in the phase of inactivation of T cell responses. Moreover, these results illustrate the importance of interactions between T cells in the control of the cellular immune response. 
     EXAMPLE 7 
     Stimulation of cell cytotoxicity by LAG-3Ig 
     The role of LAG-3Ig in relation to cell cytotoxicity is studied on two types of effector cells: 
     freshly drawn human peripheral blood lymphocytes (PBL), 
     S1B5 line cells (clone of human NK cells). 
     The cytotoxic activity of these cells is measured by counting the  51 Cr released into the medium by previously labelled target cells, in the presence or absence of LAG-3Ig in the medium. 
     FIG. 14 shows the degree of cytotoxicity of S1B5 for a line of human B cells transformed by Epstein-Barr virus and carrying major histocompatibility complex Class I and II antigens (LAZ 388 line), as a function of different reactants added to the cultures. 
     Measurements are carried out after 4 hours of coculture for effector/target (S1B5/LAZ 388) cell ratios of 3:1 (clear columns) or 1:1 (shaded columns). 
     The negative controls consist of medium alone (MED), the immunoadhesin CD8Ig and the monoclonal antibody 17.B4 (anti-LAG-3). 
     The positive controls consist of three different monoclonal antibodies: 
     antibody L243 directed against Class II DR antigens, 
     antibody 9.49 directed against Class II DR, DP, DQ antigens, 
     antibody W632 directed against human major histocompatibility complex Class I antigens. 
     Anti-HLA Class I (W632) or Class II (L243) antibodies increase the lysis of the target cells (and not the 17B4 control). The immunoadhesin LAG-3Ig increases the lysis. The CD8Ig control has no effect. 
     FIG. 15 shows the results of an experiment similar to the above, in which the cytotoxicity of PBL with respect to Daudi cells (HLA Class I − ) is measured, for effector/target ratios of 50:1 (clear columns) and 15:1 (shaded columns). The reactants added to the medium are the same as the ones used in the first experiment, except for antibody 9.49 and antibody 17.B4. Antibody 10H3 is an isotype IgG1 immunoglobulin specific for the CD45 surface antigen. It is used as negative control. 
     No change is observed with an antibody directed against major histocompatibility complex Class I antigens (W632). 
     The data from these two series of measurements shown that, compared to negative controls, LAG-3Ig activates the cytotoxicity of NK cells. This effect is similar to the one observed with antibodies directed against MHC Class II molecules. 
     BIBLIOGRAPHIC REFERENCES 
     1. TRIEBEL T. et al., 1990, J. Exp. Med. 171, 1393-1405 
     2. BAIXERAS E. et al., 1992, J. Exp. Med. 176, 327-337 
     3. COSGROVE D. et al., 1991, Cell 66, 1051-1066 
     4. RAHEMTULLA A. et al., 1991, Nature 353, 180-184 
     5. TRAUNECKER A. et al., 1988, Nature 351, 84-86 
     6. BENEDICT A. A. et al., 1967, Methods in Immunology 1, 197-306 (1967) 
     7. YELTON D. E. et al., Ann. Rev. of Biochem. 50, 657-680 (1981) 
     8. HUARD B. et al., Immunogenetics 39: 213 
     9. MANIATIS T. et al. (1982), Molecular cloning: A laboratory manual—Cold Spring Harbor Laboratory, New-York. 
     10. SEED B., 1987, Nature 329, 840-842 
     11. COLE S. C. et al., Biotechnology 11, 1014-1024, 1993 
     12. COLE S. C. et al., Biotechnology 11, 1014-1024, 1993. 
     
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE NO. 1 
               
               
                   
               
               
                   
                   
                   
                   
                 residue 
                 atom type, 
               
               
                 Atom 
                   
                   
                   
                 name and 
                 charge and 
               
               
                 name 
                 x 
                 y 
                 z 
                 no. 
                 no. 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 N 
                 25.172370911 
                 27.259836197 
                 67.855064392 
                 AP-n 
                 40 n3 
                 −0.5000 
                 1 
               
               
                 NN2 
                 25.667764664 
                 26.471963882 
                 67.420585632 
                 AP-n 
                 40 hn 
                 0.1300 
                 2 
               
               
                 CA 
                 24.625223160 
                 26.867494583 
                 69.180244446 
                 AP-n 
                 40 ca 
                 0.1200 
                 3 
               
               
                 NN1 
                 24.393711090 
                 27.474891663 
                 67.220008850 
                 AP-n 
                 42 hn 
                 0.1300 
                 4 
               
               
                 MA 
                 23.936895370 
                 27.680395126 
                 69.464080811 
                 AP-n 
                 40 h 
                 0.0700 
                 5 
               
               
                 C 
                 25.662780726 
                 26.773513794 
                 70.350120544 
                 AP-n 
                 40 c′ 
                 0.3800 
                 6 
               
               
                 O 
                 25.295415878 
                 27.090747833 
                 71.482070923 
                 AP-n 
                 40 o′ 
                 −0.4100 
                 7 
               
               
                 CB 
                 23.766021729 
                 25.587018967 
                 68.990669250 
                 AP-n 
                 40 c2 
                 −0.2600 
                 8 
               
               
                 MB1 
                 23.060285568 
                 25.72443695 
                 68.152351379 
                 AP-n 
                 40 h 
                 0.0700 
                 9 
               
               
                 MB2 
                 24.413969040 
                 24.744903564 
                 68.686981201 
                 AP-n 
                 40 h 
                 0.0700 
                 10 
               
               
                 CG 
                 22.921775818 
                 25.153419495 
                 70.196960449 
                 AP-n 
                 40 c− 
                 0.3400 
                 11 
               
               
                 DD1 
                 22.069602966 
                 25.929233551 
                 70.676017761 
                 AP-n 
                 40 o− 
                 −0.5700 
                 12 
               
               
                 DD2 
                 23.115716934 
                 24.009321213 
                 70.667663574 
                 AP-n 
                 40 o− 
                 −0.5700 
                 13 
               
               
                 M 
                 26.906179428 
                 26.304588318 
                 70.124969482 
                 SER 
                 41 n 
                 −0.5000 
                 14 
               
               
                 CA 
                 27.860145569 
                 25.912786484 
                 71.207519531 
                 SER 
                 41 ca 
                 0.1200 
                 15 
               
               
                 HN 
                 27.120641708 
                 26.221813202 
                 69.126319885 
                 SER 
                 41 hn 
                 0.2800 
                 16 
               
               
                 MA 
                 27.374551773 
                 25.088045120 
                 71.766326904 
                 SER 
                 41 h 
                 0.1000 
                 17 
               
               
                 C 
                 28.252065659 
                 27.005065918 
                 72.271789551 
                 SER 
                 41 c′ 
                 −0.3800 
                 18 
               
               
                 O 
                 27.987834930 
                 28.200620651 
                 72.115295410 
                 SER 
                 41 o′ 
                 −0.3800 
                 19 
               
               
                 CB 
                 29.083601227 
                 25.298025131 
                 70.494880676 
                 SER 
                 41 c2 
                 −0.1700 
                 20 
               
               
                 MB1 
                 28.786190033 
                 24.599395752 
                 69.690521240 
                 SER 
                 41 h 
                 0.1000 
                 21 
               
               
                 MB2 
                 29.691858292 
                 26.092912674 
                 70.004081726 
                 SER 
                 41 h 
                 0.1000 
                 22 
               
               
                 OG 
                 29.905221939 
                 24.578149796 
                 71.424118042 
                 SER 
                 41 oh 
                 −0.3800 
                 23 
               
               
                 HG 
                 30.662555695 
                 24.231645584 
                 70.939277649 
                 SER 
                 41 ho 
                 0.3500 
                 24 
               
               
                 N 
                 28.857526779 
                 26.558052063 
                 73.387054443 
                 GLY 
                 42 n 
                 −0.5000 
                 25 
               
               
                 CA 
                 29.199718475 
                 27.440891266 
                 74.535232544 
                 GLY 
                 42 cg 
                 0.0200 
                 26 
               
               
                 MN 
                 29.251720428 
                 25.616510391 
                 73.267890930 
                 GLY 
                 42 hn 
                 0.2800 
                 27 
               
               
                 MA1 
                 28.520187378 
                 28.312047958 
                 74.591857910 
                 GLY 
                 42 h 
                 0.1000 
                 28 
               
               
                 MA2 
                 28.983697891 
                 26.890144348 
                 75.468444824 
                 GLY 
                 42 h 
                 0.1000 
                 29 
               
               
                 C 
                 30.691051483 
                 27.875793457 
                 74.601707458 
                 GLY 
                 42 c′ 
                 0.3800 
                 30 
               
               
                 O 
                 31.504199982 
                 27.026502609 
                 74.980445862 
                 GLY 
                 42 o′ 
                 −0.3800 
                 31 
               
               
                 N 
                 31.113182068 
                 29.132183075 
                 74.266487122 
                 PRO 
                 43 n 
                 −0.4200 
                 32 
               
               
                 CA 
                 32.858349609 
                 29.476200104 
                 74.126792908 
                 PRO 
                 43 ca 
                 0.0600 
                 33 
               
               
                 HA 
                 33.096603394 
                 28.605407715 
                 73.708091736 
                 PRO 
                 43 h 
                 0.1000 
                 34 
               
               
                 CD 
                 30.24075089 
                 30.174203873 
                 73.722633362 
                 PRO 
                 43 c2 
                 0.0600 
                 35 
               
               
                 MD1 
                 29.467987061 
                 30.516298294 
                 74.466743469 
                 PRO 
                 43 h 
                 0.1000 
                 36 
               
               
                 MD2 
                 29.664882660 
                 29.799777985 
                 72.838768005 
                 PRO 
                 43 h 
                 0.1000 
                 37 
               
               
                 C 
                 33.318023682 
                 29.988374710 
                 75.414916992 
                 PRO 
                 43 c′ 
                 0.3800 
                 38 
               
               
                 O 
                 32.682361603 
                 30.557033539 
                 76.312332153 
                 PRO 
                 43 o′ 
                 −0.3800 
                 39 
               
               
                 CB 
                 32.483139038 
                 30.574260712 
                 73.043136597 
                 PRO 
                 43 c2 
                 −0.2000 
                 40 
               
               
                 MB1 
                 33.350620270 
                 31.263189316 
                 73.049049377 
                 PRO 
                 43 h 
                 0.1000 
                 41 
               
               
                 MB2 
                 32.463790894 
                 30.110534668 
                 72.036743164 
                 PRO 
                 43 h 
                 0.1000 
                 42 
               
               
                 CG 
                 31.160949707 
                 31.299722672 
                 73.307487488 
                 PRO 
                 43 c2 
                 −0.2000 
                 43 
               
               
                 MG1 
                 31.279897690 
                 32.024162292 
                 74.137779236 
                 PRO 
                 43 h 
                 0.1000 
                 44 
               
               
                 MG2 
                 30.794561386 
                 31.862808228 
                 72.428352356 
                 PRO 
                 43 h 
                 0.1000 
                 45 
               
               
                 K 
                 34.683673859 
                 29.902477264 
                 75.503486633 
                 PRO 
                 44 n 
                 −0.4200 
                 46 
               
               
                 CA 
                 35.485736847 
                 30.679145813 
                 76.490524292 
                 PRO 
                 44 ca 
                 0.0600 
                 47 
               
               
                 KA 
                 35.018527985 
                 30.645456314 
                 77.491592407 
                 PRO 
                 44 h 
                 0.1000 
                 48 
               
               
                 CD 
                 35.509281158 
                 29.014368057 
                 74.655700684 
                 PRO 
                 44 c2 
                 0.0600 
                 49 
               
               
                 MD1 
                 35.411357880 
                 29.247959137 
                 73.577461243 
                 PRO 
                 44 h 
                 0.1000 
                 50 
               
               
                 MD2 
                 35.214973450 
                 27.955932617 
                 74.801994324 
                 PRO 
                 44 h 
                 0.1000 
                 51 
               
               
                 C 
                 35.700843811 
                 32.172924042 
                 76.063224792 
                 PRO 
                 44 c′ 
                 0.3800 
                 52 
               
               
                 O 
                 36.448230743 
                 32.477428436 
                 75.126922607 
                 PRO 
                 44 o′ 
                 −0.3800 
                 53 
               
               
                 CB 
                 36.779544830 
                 29.842718124 
                 76.547348022 
                 PRO 
                 44 c2 
                 −0.2000 
                 54 
               
               
                 HB1 
                 37.662769315 
                 30.430650711 
                 75.863670149 
                 PRO 
                 44 h 
                 0.1000 
                 55 
               
               
                 HB2 
                 36.667564392 
                 29.027103424 
                 77.288825989 
                 PRO 
                 44 h 
                 0.1000 
                 56 
               
               
                 CG 
                 36.940769196 
                 29.250995636 
                 75.143180867 
                 PRO 
                 44 c2 
                 −0.2000 
                 57 
               
               
                 MG1 
                 37.446662903 
                 29.982709885 
                 74.483322144 
                 PRO 
                 44 h 
                 0.1000 
                 58 
               
               
                 MG2 
                 37.553295135 
                 26.329860667 
                 75.134750366 
                 PRO 
                 44 h 
                 0.1000 
                 59 
               
               
                 N 
                 35.026676178 
                 33.104183197 
                 76.753837585 
                 ALA 
                 45 h 
                 −0.5000 
                 60 
               
               
                 CA 
                 35.034278870 
                 34.544979095 
                 76.400695801 
                 ALA 
                 45 ca 
                 0.1200 
                 61 
               
               
                 MN 
                 34.452354431 
                 32.747509003 
                 77.536170959 
                 ALA 
                 45 hn 
                 0.2800 
                 62 
               
               
                 MA 
                 35.105010986 
                 34.659946442 
                 75.298950195 
                 ALA 
                 45 h 
                 0.1000 
                 63 
               
               
                 C 
                 36.209384918 
                 35.322113037 
                 77.076705833 
                 ALA 
                 45 c′ 
                 0.3800 
                 64 
               
               
                 O 
                 36.163528442 
                 35.637268066 
                 78.268325806 
                 ALA 
                 45 o′ 
                 −0.3800 
                 65 
               
               
                 CB 
                 33.646369934 
                 35.083190918 
                 76.800727844 
                 ALA 
                 45 c3 
                 −0.3000 
                 66 
               
               
                 MB1 
                 33.534698486 
                 36.150661469 
                 76.535202026 
                 ALA 
                 45 h 
                 0.1000 
                 67 
               
               
                 MB2 
                 32.828392029 
                 34.539138794 
                 76.290328979 
                 ALA 
                 45 h 
                 0.1000 
                 68 
               
               
                 MB3 
                 33.465579987 
                 35.001335144 
                 77.890525818 
                 ALA 
                 45 h 
                 0.1000 
                 69 
               
               
                 N 
                 37.266757965 
                 35.613758087 
                 76.297294617 
                 ALA 
                 46 n 
                 −0.5000 
                 70 
               
               
                 MN 
                 37.216701508 
                 35.231555939 
                 75.346885681 
                 ALA 
                 46 hn 
                 0.2800 
                 71 
               
               
                 CA 
                 38.489383698 
                 36.310386658 
                 76.786270142 
                 ALA 
                 46 ca 
                 0.1200 
                 72 
               
               
                 MA 
                 38.262126923 
                 36.871456146 
                 77.716934204 
                 ALA 
                 46 h 
                 0.1000 
                 73 
               
               
                 C 
                 39.058414459 
                 37.311935425 
                 75.727844238 
                 ALA 
                 46 c′ 
                 0.3800 
                 74 
               
               
                 O 
                 38.922710419 
                 37.100418091 
                 74.516731262 
                 ALA 
                 46 o′ 
                 −0.3800 
                 75 
               
               
                 CB 
                 39.526046753 
                 35.215301514 
                 77.108406067 
                 ALA 
                 46 c3 
                 −0.3000 
                 76 
               
               
                 MB1 
                 40.446556091 
                 35.633434296 
                 77.555480957 
                 ALA 
                 46 h 
                 0.1000 
                 77 
               
               
                 MB2 
                 39.131206512 
                 34.469978333 
                 77.822120667 
                 ALA 
                 46 h 
                 0.1000 
                 78 
               
               
                 MB3 
                 39.821903229 
                 34.663463593 
                 76.197715759 
                 ALA 
                 46 h 
                 0.1000 
                 79 
               
               
                 N 
                 39.737388611 
                 38.384365082 
                 76.180320740 
                 ALA 
                 47 n 
                 −0.5000 
                 80 
               
               
                 CA 
                 40.295833588 
                 39.429889679 
                 75.275863647 
                 ALA 
                 47 ca 
                 0.1200 
                 81 
               
               
                 MN 
                 39.717037201 
                 38.512592316 
                 77.196357727 
                 ALA 
                 47 hn 
                 0.2800 
                 82 
               
               
                 MA 
                 39.901103973 
                 39.219335938 
                 74.245994568 
                 ALA 
                 47 h 
                 0.1000 
                 83 
               
               
                 C 
                 41.869789124 
                 39.413467407 
                 75.170806885 
                 ALA 
                 47 c′ 
                 0.3800 
                 84 
               
               
                 O 
                 42.518333435 
                 40.166862488 
                 75.906578044 
                 ALA 
                 47 o′ 
                 −0.3800 
                 85 
               
               
                 CB 
                 39.722030640 
                 40.769996643 
                 75.786285400 
                 ALA 
                 47 c3 
                 −0.3000 
                 86 
               
               
                 MB1 
                 40.045078278 
                 41.611721039 
                 75.145561218 
                 ALA 
                 47 h 
                 0.1000 
                 87 
               
               
                 MB2 
                 38.615306854 
                 40.778987885 
                 75.787467957 
                 ALA 
                 47 h 
                 0.1000 
                 88 
               
               
                 MB3 
                 40.059757233 
                 41.007873535 
                 76.813346863 
                 ALA 
                 47 h 
                 0.1000 
                 89 
               
               
                 N 
                 42.537422180 
                 38.621597290 
                 74.274406433 
                 PRO 
                 48 n 
                 −0.4200 
                 90 
               
               
                 CA 
                 44.009857178 
                 38.718185425 
                 74.045745850 
                 PRO 
                 48 ca 
                 0.0600 
                 91 
               
               
                 MA 
                 44.539390564 
                 38.855972290 
                 75.008773804 
                 PRO 
                 48 h 
                 0.1000 
                 92 
               
               
                 CD 
                 41.903011322 
                 37.522361755 
                 73.516281128 
                 PRO 
                 48 c2 
                 0.0600 
                 93 
               
               
                 MD1 
                 41.081176758 
                 37.871139526 
                 72.860626221 
                 PRO 
                 48 h 
                 0.1000 
                 94 
               
               
                 MD2 
                 41.490711312 
                 36.761222839 
                 74.206848145 
                 PRO 
                 48 h 
                 0.1000 
                 95 
               
               
                 C 
                 44.448683322 
                 39.844142914 
                 73.044319153 
                 PRO 
                 48 c′ 
                 0.3800 
                 96 
               
               
                 O 
                 43.693031311 
                 40.225761414 
                 72.144134521 
                 PRO 
                 48 o′ 
                 −0.3800 
                 97 
               
               
                 CB 
                 44.302902771 
                 37.304885864 
                 73.500595093 
                 PRO 
                 48 c2 
                 −0.2000 
                 98 
               
               
                 MB1 
                 45.227554321 
                 37.245840894 
                 72.897834778 
                 PRO 
                 48 h 
                 0.1000 
                 99 
               
               
                 MB2 
                 44.442562103 
                 36.597515106 
                 74.341529846 
                 PRO 
                 48 h 
                 0.1000 
                 100 
               
               
                 CG 
                 43.051033020 
                 36.925685883 
                 72.702011108 
                 PRO 
                 48 c2 
                 −0.2000 
                 101 
               
               
                 MG1 
                 43.084365845 
                 37.389282227 
                 71.696128845 
                 PRO 
                 48 h 
                 0.1000 
                 102 
               
               
                 MG2 
                 42.948661804 
                 35.835418701 
                 72.555740356 
                 PRO 
                 48 h 
                 0.1000 
                 103 
               
               
                 N 
                 45.700798035 
                 40.324272156 
                 73.165817261 
                 GLY 
                 49 n 
                 −0.5000 
                 104 
               
               
                 CA 
                 46.289730072 
                 41.291931152 
                 72.184875488 
                 GLY 
                 49 cg 
                 0.0200 
                 105 
               
               
                 MN 
                 46.207077026 
                 39.986907959 
                 73.991729736 
                 GLY 
                 49 hn 
                 0.2800 
                 106 
               
               
                 MA1 
                 45.620616913 
                 41.460151672 
                 71.317451477 
                 GLY 
                 49 h 
                 0.1000 
                 107 
               
               
                 MA2 
                 46.357063293 
                 42.283206940 
                 72.672386169 
                 GLY 
                 49 h 
                 0.1000 
                 108 
               
               
                 C 
                 47.682319641 
                 40.950855255 
                 71.600997925 
                 GLY 
                 49 c′ 
                 0.3800 
                 109 
               
               
                 O 
                 48.560806274 
                 41.811416626 
                 71.601501465 
                 GLY 
                 49 o′ 
                 −0.3800 
                 110 
               
               
                 N 
                 47.842975616 
                 39.718383789 
                 71.091018677 
                 HIS 
                 50 n 
                 −0.5000 
                 111 
               
               
                 MN 
                 46.947166443 
                 39.222202301 
                 71.052452087 
                 HIS 
                 50 hn 
                 0.2800 
                 112 
               
               
                 CA 
                 49.020114899 
                 39.216835022 
                 70.306198120 
                 HIS 
                 50 ca 
                 0.1200 
                 113 
               
               
                 MA 
                 49.324539185 
                 38.296181652 
                 70.836235046 
                 HIS 
                 50 h 
                 0.1000 
                 114 
               
               
                 C 
                 50.400863647 
                 39.993576050 
                 70.182159941 
                 HIS 
                 50 c′ 
                 0.3800 
                 115 
               
               
                 O 
                 50.733478546 
                 40.446022034 
                 69.081466675 
                 HIS 
                 50 o′ 
                 −0.3800 
                 116 
               
               
                 CB 
                 48.455345154 
                 38.673969269 
                 68.953773499 
                 HIS 
                 50 c2 
                 −0.2000 
                 117 
               
               
                 HB1 
                 49.238502502 
                 38.051708221 
                 68.481765747 
                 HIS 
                 50 h 
                 0.1000 
                 118 
               
               
                 HB2 
                 47.639427185 
                 37.951225281 
                 69.144165039 
                 HIS 
                 50 h 
                 0.1000 
                 119 
               
               
                 CG 
                 47.954322815 
                 39.695293427 
                 67.919425964 
                 HIS 
                 50 c5 
                 0.1000 
                 120 
               
               
                 MD1 
                 46.759342194 
                 40.404747009 
                 68.035293579 
                 HIS 
                 50 np 
                 −0.4200 
                 121 
               
               
                 CE1 
                 46.825572968 
                 41.133701324 
                 66.873245239 
                 HIS 
                 50 c5 
                 0.2700 
                 122 
               
               
                 NE2 
                 47.887611389 
                 40.964004517 
                 66.014495850 
                 HIS 
                 50 np 
                 −0.5000 
                 123 
               
               
                 CD2 
                 48.617565155 
                 40.019775391 
                 66.717041016 
                 HIS 
                 50 c5 
                 0.0100 
                 124 
               
               
                 ME1 
                 46.043247223 
                 41.852840424 
                 66.655242920 
                 HIS 
                 50 h 
                 0.1300 
                 125 
               
               
                 ME2 
                 48.092224121 
                 41.403381348 
                 65.108955383 
                 HIS 
                 50 hn 
                 0.2800 
                 126 
               
               
                 MD2 
                 49.566501617 
                 39.599807739 
                 66.396347046 
                 HIS 
                 50 h 
                 0.1300 
                 127 
               
               
                 N 
                 51.278770447 
                 40.105480194 
                 71.226615906 
                 PRO 
                 51 n 
                 −0.4200 
                 128 
               
               
                 CA 
                 52.667034149 
                 40.618915558 
                 71.077911377 
                 PRO 
                 51 ca 
                 0.0600 
                 129 
               
               
                 MA 
                 52.723186493 
                 41.393623352 
                 70.287094116 
                 PRO 
                 51 h 
                 0.1000 
                 130 
               
               
                 CD 
                 50.956447601 
                 39.767082214 
                 72.624496469 
                 PRO 
                 51 c2 
                 0.0600 
                 131 
               
               
                 MD1 
                 50.920970917 
                 38.670558929 
                 72.747383118 
                 PRO 
                 51 h 
                 0.1000 
                 132 
               
               
                 MD2 
                 49.988422394 
                 40.190521240 
                 72.947166443 
                 PRO 
                 51 h 
                 0.1000 
                 133 
               
               
                 C 
                 53.707103729 
                 39.478122711 
                 70.804489136 
                 PRO 
                 51 c′ 
                 0.3800 
                 134 
               
               
                 O 
                 53.623699188 
                 38.391666412 
                 71.391418457 
                 PRO 
                 51 o′ 
                 −0.3800 
                 135 
               
               
                 CB 
                 52.846694946 
                 41.283794403 
                 72.455955505 
                 PRO 
                 51 c2 
                 −0.2000 
                 136 
               
               
                 MB1 
                 53.907955170 
                 41.442169189 
                 72.729286194 
                 PRO 
                 51 h 
                 0.1000 
                 137 
               
               
                 MB2 
                 52.373264313 
                 42.285846710 
                 72.449127197 
                 PRO 
                 51 h 
                 0.1000 
                 138 
               
               
                 CG 
                 52.105823517 
                 40.370025635 
                 73.440398170 
                 PRO 
                 51 c2 
                 −0.2000 
                 139 
               
               
                 MG1 
                 52.782051086 
                 39.565395355 
                 73.789718628 
                 PRO 
                 51 h 
                 0.1000 
                 140 
               
               
                 MG2 
                 51.753723145 
                 40.912036896 
                 74.337333679 
                 PRO 
                 51 h 
                 0.1000 
                 141 
               
               
                 N 
                 54.704883575 
                 39.729522705 
                 69.933471680 
                 LEU 
                 52 n 
                 −0.5000 
                 142 
               
               
                 CA 
                 55.791530609 
                 35.746330261 
                 69.603820801 
                 LEU 
                 52 ca 
                 0.1200 
                 143 
               
               
                 MN 
                 54.653743744 
                 40.652229308 
                 69.490356445 
                 LEU 
                 52 hn 
                 0.2800 
                 144 
               
               
                 MA 
                 56.479202271 
                 39.288208008 
                 68.927917480 
                 LEU 
                 52 h 
                 0.1000 
                 145 
               
               
                 C 
                 35.301837921 
                 37.525024414 
                 68.745040894 
                 LEU 
                 52 c′ 
                 0.3800 
                 146 
               
               
                 O 
                 55.637695313 
                 37.425930023 
                 67.562049866 
                 LEU 
                 52 o′ 
                 −0.3800 
                 147 
               
               
                 CB 
                 56.671585083 
                 38.316761017 
                 70.829437256 
                 LEU 
                 52 c2 
                 −0.2000 
                 148 
               
               
                 MB1 
                 56.036743164 
                 37.710464478 
                 71.502593994 
                 LEU 
                 52 h 
                 0.1000 
                 149 
               
               
                 MB2 
                 57.445541382 
                 37.602729797 
                 70.487434387 
                 LEU 
                 52 h 
                 0.1000 
                 150 
               
               
                 CG 
                 57.363307953 
                 39.420749664 
                 71.675102234 
                 LEU 
                 52 c1 
                 −0.1000 
                 151 
               
               
                 MG 
                 56.617557526 
                 40.200679779 
                 71.926834106 
                 LEU 
                 52 h 
                 0.1000 
                 152 
               
               
                 CD1 
                 57.875057220 
                 38.833915710 
                 73.004547119 
                 LEU 
                 52 c3 
                 −0.3000 
                 153 
               
               
                 MD11 
                 58.353130341 
                 39.601875305 
                 73.642135620 
                 LEU 
                 52 h 
                 0.1000 
                 154 
               
               
                 MD12 
                 57.048751831 
                 38.403957367 
                 73.601577759 
                 LEU 
                 52 h 
                 0.1000 
                 155 
               
               
                 MD13 
                 58.618564606  
                 38.028480530 
                 72.852462769 
                 LEU 
                 52 h 
                 0.1000 
                 156 
               
               
                 CD2 
                 58.531608582 
                 40.085853577 
                 70.927200317 
                 LEU 
                 52 c3 
                 −0.3000 
                 157 
               
               
                 MD21 
                 59.028976440 
                 40.857166290 
                 71.545303345 
                 LEU 
                 52 h 
                 0.1000 
                 158 
               
               
                 MD22 
                 59.309509277 
                 39.355545044 
                 70.634819031 
                 LEU 
                 52 h 
                 0.1000 
                 159 
               
               
                 MD23 
                 58.192760468 
                 40.592193604 
                 70.005569458 
                 LEU 
                 52 h 
                 0.1000 
                 160 
               
               
                 N 
                 54.534648895 
                 36.601863861 
                 69.354270935 
                 ALA 
                 53 h 
                 −0.5000 
                 161 
               
               
                 CA 
                 53.940563202 
                 35.420303345 
                 68.673507690 
                 ALA 
                 53 ca 
                 0.1200 
                 162 
               
               
                 MN 
                 54.159572601 
                 36.958141327 
                 70.246543884 
                 ALA 
                 53 hn 
                 0.2800 
                 163 
               
               
                 HA 
                 53.600482941 
                 35.753322601 
                 67.671340942 
                 ALA 
                 53 h 
                 0.1000 
                 164 
               
               
                 C 
                 52.639778137 
                 34.883575439 
                 69.383995056 
                 ALA 
                 53 c′ 
                 0.3800 
                 165 
               
               
                 O 
                 51.628326416 
                 34.818698883 
                 68.677047729 
                 ALA 
                 53 o′ 
                 −0.3800 
                 166 
               
               
                 CB 
                 55.008785248 
                 34.330768585 
                 68.423698425 
                 ALA 
                 53 c3 
                 −0.3000 
                 167 
               
               
                 MB1 
                 54.582756042 
                 33.460170746 
                 67.892036438 
                 ALA 
                 53 h 
                 0.1000 
                 168 
               
               
                 MB2 
                 55.828662872 
                 34.711517334 
                 67.787284851 
                 ALA 
                 53 h 
                 0.1000 
                 169 
               
               
                 MB3 
                 55.479701896 
                 33.961406708 
                 69.351325989 
                 ALA 
                 53 h 
                 0.1000 
                 170 
               
               
                 N 
                 52.555103302 
                 34.484893799 
                 70.698265076 
                 PRO 
                 54 n 
                 −0.4200 
                 171 
               
               
                 CA 
                 51.304950714 
                 33.917499542 
                 71.286506653 
                 PRO 
                 54 ca 
                 0.0600 
                 172 
               
               
                 MA 
                 50.878768921 
                 33.172523499 
                 71.584587097 
                 PRO 
                 54 h 
                 0.1000 
                 173 
               
               
                 CD 
                 53.705833435 
                 34.435420990 
                 71.626182556 
                 PRO 
                 54 c2 
                 0.0600 
                 174 
               
               
                 MD1 
                 54.215991974 
                 35.409980774 
                 71.739936829 
                 PRO 
                 54 h 
                 0.1000 
                 175 
               
               
                 MD2 
                 54.453365326 
                 33.693523407 
                 71.288909912 
                 PRO 
                 54 h 
                 0.1000 
                 176 
               
               
                 C 
                 50.177021027 
                 34.945980072 
                 71.642837524 
                 PRO 
                 54 c′ 
                 0.3800 
                 177 
               
               
                 O 
                 50.377983093 
                 36.164409637 
                 71.677795410 
                 PRO 
                 54 o′ 
                 −0.3800 
                 178 
               
               
                 CB 
                 51.867893219 
                 33.173828125 
                 72.519187927 
                 PRO 
                 54 c2 
                 −0.2000 
                 179 
               
               
                 MB1 
                 51.135505676 
                 33.051830292 
                 73.340660095 
                 PRO 
                 54 h 
                 0.1000 
                 180 
               
               
                 MB2 
                 52.181377411 
                 32.150829315 
                 72.232276917 
                 PRO 
                 54 h 
                 0.1000 
                 181 
               
               
                 CG 
                 53.087123871 
                 33.989192963 
                 72.949317932 
                 PRO 
                 54 c2 
                 −0.2000 
                 182 
               
               
                 MG1 
                 52.768703461 
                 34.871643066 
                 73.538475037 
                 PRO 
                 54 h 
                 0.1000 
                 183 
               
               
                 MG2 
                 53.791828156 
                 33.414070129 
                 73.579086304 
                 PRO 
                 54 h 
                 0.1000 
                 184 
               
               
                 N 
                 48.977436066 
                 34.414421082 
                 71.936706543 
                 GLY 
                 55 n 
                 0.5000 
                 185 
               
               
                 CA 
                 47.822620392 
                 35.225021362 
                 72.404747009 
                 GLY 
                 55 cg 
                 0.0200 
                 186 
               
               
                 MN 
                 48.958133698 
                 33.389709473 
                 71.929512024 
                 GLY 
                 55 hn 
                 0.2800 
                 187 
               
               
                 MA1 
                 47.830284119 
                 36.238574982 
                 71.983676453 
                 GLY 
                 55 h 
                 0.1000 
                 188 
               
               
                 MA2 
                 46.896526337 
                 34.772380829 
                 72.004432678 
                 GLY 
                 55 h 
                 0.1000 
                 189 
               
               
                 C 
                 47.670829773 
                 35.263648987 
                 73.950416565 
                 GLY 
                 55 c′ 
                 0.3800 
                 190 
               
               
                 O 
                 47.247509003 
                 34.242198944 
                 74.498336792 
                 GLY 
                 55 o′ 
                 −0.3800 
                 191 
               
               
                 N 
                 47.956153870 
                 36.372848511 
                 74.696281433 
                 PRO 
                 56 n 
                 −0.4200 
                 192 
               
               
                 CA 
                 47.830066681 
                 36.396587372 
                 76.179130554 
                 PRO 
                 56 ca 
                 0.0600 
                 193 
               
               
                 MA 
                 48.225147247 
                 35.457695007 
                 76.619560242 
                 PRO 
                 56 h 
                 0.1000 
                 194 
               
               
                 CD 
                 48.653686523 
                 37.556163788 
                 74.163940430 
                 PRO 
                 56 c2 
                 0.0600 
                 195 
               
               
                 MD1 
                 48.108860016 
                 38.040233612 
                 73.332565308 
                 PRO 
                 56 h 
                 0.1000 
                 196 
               
               
                 MD2 
                 49.652721405 
                 37.256084442 
                 73.799308777 
                 PRO 
                 56 h 
                 0.1000 
                 197 
               
               
                 C 
                 46.361907959 
                 36.804877472 
                 76.668052673 
                 PRO 
                 56 c′ 
                 0.3800 
                 198 
               
               
                 O 
                 45.890090942 
                 37.732730865 
                 76.845039368 
                 PRO 
                 56 o′ 
                 −0.3800 
                 199 
               
               
                 CB 
                 48.804897308 
                 37.531764984 
                 76.560951233 
                 PRO 
                 56 c2 
                 −0.2000 
                 200 
               
               
                 MB1 
                 48.542221069 
                 38.034294128 
                 77.511970520 
                 PRO 
                 56 h 
                 0.1000 
                 201 
               
               
                 MB2 
                 49.825592041 
                 37.124942236 
                 76.697402954 
                 PRO 
                 56 h 
                 0.1000 
                 202 
               
               
                 CG 
                 48.782566071 
                 38.488700867 
                 75.368530273 
                 PRO 
                 56 c2 
                 −0.2000 
                 203 
               
               
                 MG1 
                 47.903289795 
                 39.158111572 
                 75.434867859 
                 PRO 
                 56 h 
                 0.1000 
                 204 
               
               
                 MG2 
                 49.679012299 
                 39.133480072 
                 75.321792603 
                 PRO 
                 56 h 
                 0.1000 
                 205 
               
               
                 N 
                 45.650573730 
                 35.488880157 
                 76.896896362 
                 HIS 
                 57 n 
                 −0.5000 
                 206 
               
               
                 MN 
                 46.046119690 
                 34.657379150 
                 76.439048767 
                 HIS 
                 57 hn 
                 0.2800 
                 207 
               
               
                 CA 
                 44.244419098 
                 35.504474640 
                 77.387596130 
                 HIS 
                 57 ca 
                 0.1200 
                 208 
               
               
                 MA 
                 43.667560577 
                 36.207649231 
                 76.759368896 
                 HIS 
                 57 h 
                 0.1000 
                 209 
               
               
                 C 
                 44.173530579 
                 35.943927765 
                 78.901000977 
                 HIS 
                 57 c′ 
                 0.3800 
                 210 
               
               
                 O 
                 44.750030518 
                 35.234142303 
                 79.736030579 
                 HIS 
                 57 o′ 
                 −0.3800 
                 211 
               
               
                 CB 
                 43.610416412 
                 34.095542908 
                 77.185058594 
                 HIS 
                 57 c2 
                 −0.2000 
                 212 
               
               
                 MB1 
                 44.270858765 
                 33.323795319 
                 77.623748779 
                 HIS 
                 57 h 
                 0.1000 
                 213 
               
               
                 MB2 
                 42.689029694 
                 34.034877777 
                 77.796188354 
                 HIS 
                 57 h 
                 0.1000 
                 214 
               
               
                 CB 
                 43.250400543 
                 33.671833038 
                 75.751731873 
                 HIS 
                 57 c5 
                 0.1000 
                 215 
               
               
                 MD1 
                 44.116428375 
                 33.723646257 
                 74.666069031 
                 HIS 
                 57 np 
                 −0.4200 
                 216 
               
               
                 CE1 
                 43.325973511 
                 33.139041901 
                 73.713264465 
                 HIS 
                 57 c5 
                 0.2700 
                 217 
               
               
                 ME2 
                 42.066158295 
                 32.716590881 
                 74.036811829 
                 HIS 
                 57 np 
                 −0.5000 
                 218 
               
               
                 CD2 
                 42.045005798 
                 33.048488617 
                 75.379264832 
                 HIS 
                 57 c5 
                 0.0100 
                 219 
               
               
                 ME1 
                 43.722070465 
                 33.001682281 
                 72.711807251 
                 HIS 
                 57 h 
                 0.1300 
                 220 
               
               
                 ME2 
                 41.370864868 
                 32.229383759 
                 73.464263916 
                 HIS 
                 57 hn 
                 0.3800 
                 221 
               
               
                 MD2 
                 41.236827850 
                 32.815635681 
                 76.058380127 
                 HIS 
                 57 h 
                 0.1300 
                 222 
               
               
                 N 
                 43.513858795 
                 37.068405151 
                 79.318038940 
                 PRO 
                 58 n 
                 −0.4200 
                 223 
               
               
                 CA 
                 43.593978882 
                 37.569736481 
                 80.719970703 
                 PRO 
                 58 ca 
                 0.0600 
                 224 
               
               
                 MA 
                 44.657642365 
                 37.630668640 
                 81.026939392 
                 PRO 
                 58 h 
                 0.1000 
                 225 
               
               
                 CD 
                 42.833599091 
                 38.010932922 
                 78.407653809 
                 PRO 
                 58 c2 
                 0.0600 
                 226 
               
               
                 MD1 
                 42.093353271 
                 37.516807556 
                 77.751007080 
                 PRO 
                 58 h 
                 0.1000 
                 227 
               
               
                 MD2 
                 43.569110870 
                 38.527889252 
                 77.758674622 
                 PRO 
                 58 h 
                 0.1000 
                 228 
               
               
                 C 
                 42.805988312 
                 36.695770264 
                 81.747009277 
                 PRO 
                 58 c′ 
                 0.3800 
                 229 
               
               
                 O 
                 41.569808960 
                 36.693984985 
                 81.769706726 
                 PRO 
                 58 o′ 
                 −0.3800 
                 230 
               
               
                 CB 
                 43.072513580 
                 39.016571045 
                 80.579101563 
                 PRO 
                 58 c2 
                 −0.2000 
                 231 
               
               
                 MB1 
                 42.559799194 
                 39.392253876 
                 81.485702515 
                 PRO 
                 58 h 
                 0.1000 
                 232 
               
               
                 MB2 
                 43.920654297 
                 39.706352234 
                 80.398040771 
                 PRO 
                 58 h 
                 0.1000 
                 233 
               
               
                 CG 
                 42.156440735 
                 38.999496460 
                 79.353399631 
                 PRO 
                 58 c2 
                 −0.2000 
                 234 
               
               
                 MG1 
                 41.151851654 
                 38.629653931 
                 79.634307861 
                 PRO 
                 58 h 
                 0.1000 
                 235 
               
               
                 MG2 
                 42.023620605 
                 39.998752594 
                 78.896965027 
                 PRO 
                 58 h 
                 0.1000 
                 236 
               
               
                 N 
                 43.540618896 
                 35.961261749 
                 82.605430603 
                 ALA 
                 59 n 
                 −0.5000 
                 237 
               
               
                 MN 
                 44.537330627 
                 35.932937622 
                 82.365699768 
                 ALA 
                 59 hn 
                 0.2800 
                 238 
               
               
                 CA 
                 42.949653625 
                 34.946208954 
                 83.526855469 
                 ALA 
                 59 ca 
                 0.1200 
                 239 
               
               
                 MA 
                 42.197692871 
                 34.355514526 
                 82.965911865 
                 ALA 
                 59 h 
                 0.1000 
                 240 
               
               
                 C 
                 42.208984375 
                 35.488883972 
                 84.803985596 
                 ALA 
                 59 c′ 
                 0.3800 
                 241 
               
               
                 O 
                 42.496433258 
                 35.127353668 
                 85.948333740 
                 ALA 
                 59 o′ 
                 −0.3800 
                 242 
               
               
                 CB 
                 44.107444763 
                 33.975612640 
                 83.839767456 
                 ALA 
                 59 c3 
                 −0.3000 
                 243 
               
               
                 MB1 
                 43.761249542 
                 33.130538940 
                 84.463287354 
                 ALA 
                 59 h 
                 0.1000 
                 244 
               
               
                 MB2 
                 44.544620514 
                 33.531585693 
                 82.924507141 
                 ALA 
                 59 h 
                 0.1000 
                 245 
               
               
                 MB3 
                 44.925910950 
                 34.467308044 
                 84.399597168 
                 ALA 
                 59 h 
                 0.1000 
                 246 
               
               
                 N 
                 41.192062378 
                 36.323741913 
                 84.559051514 
                 ALA 
                 60 n 
                 −0.5000 
                 247 
               
               
                 MN 
                 41.124549866 
                 36.554992676 
                 83.555343628 
                 ALA 
                 60 hn 
                 0.2800 
                 248 
               
               
                 CA 
                 40.203086853 
                 36.790748596 
                 85.562988281 
                 ALA 
                 60 ca 
                 0.1200 
                 249 
               
               
                 MA 
                 40.023948669 
                 35.965785980 
                 86.283721924 
                 ALA 
                 60 h 
                 0.1000 
                 250 
               
               
                 C 
                 38.823528290 
                 37.027305602 
                 84.846977234 
                 ALA 
                 60 c′ 
                 0.3800 
                 251 
               
               
                 O 
                 37.897804260 
                 36.283885956 
                 85.186340332 
                 ALA 
                 60 o′ 
                 −0.3800 
                 252 
               
               
                 CB 
                 40.756233215 
                 37.971691132 
                 86.389617920 
                 ALA 
                 60 c3 
                 −0.3000 
                 253 
               
               
                 MB1 
                 40.004146578 
                 38.357006073 
                 87.102043152 
                 ALA 
                 60 h 
                 0.1000 
                 254 
               
               
                 MB2 
                 41.631908417 
                 37.656120300 
                 86.987319946 
                 ALA 
                 60 h 
                 0.1000 
                 255 
               
               
                 MB3 
                 41.090072632 
                 38.818138123 
                 85.765472412 
                 ALA 
                 60 h 
                 0.1000 
                 256 
               
               
                 N 
                 38.616340637 
                 37.921970367 
                 83.823921204 
                 PRO 
                 61 n 
                 −0.4200 
                 257 
               
               
                 CA 
                 37.403762817 
                 37.874496460 
                 82.948486328 
                 PRO 
                 61 ca 
                 0.0600 
                 258 
               
               
                 MA 
                 36.491020223 
                 37.824863434 
                 83.573593140 
                 PRO 
                 61 h 
                 0.1000 
                 259 
               
               
                 CD 
                 39.556003571 
                 39.003845215 
                 83.459777832 
                 PRO 
                 61 c2 
                 0.0600 
                 260 
               
               
                 MD1 
                 40.594814301 
                 38.658158052 
                 83.304046631 
                 PRO 
                 61 h 
                 0.1000 
                 261 
               
               
                 MD2 
                 39.571029663 
                 39.778694153 
                 84.250648498 
                 PRO 
                 61 h 
                 0.1000 
                 262 
               
               
                 C 
                 37.275394440 
                 36.712963104 
                 81.892074585 
                 PRO 
                 61 c′ 
                 0.3800 
                 263 
               
               
                 O 
                 36.366387939 
                 36.670307159 
                 81.183484568 
                 PRO 
                 61 o′ 
                 −0.3800 
                 264 
               
               
                 CB 
                 37.473857880 
                 39.266963959 
                 82.286987305 
                 PRO 
                 61 c2 
                 −0.2000 
                 265 
               
               
                 MB1 
                 36.949714661 
                 39.321308136 
                 81.312759399 
                 PRO 
                 61 h 
                 0.1000 
                 266 
               
               
                 MB2 
                 36.985511780 
                 40.017913818 
                 82.938987732 
                 PRO 
                 61 h 
                 0.1000 
                 267 
               
               
                 CG 
                 38.968631744 
                 39.571613312 
                 82.168632507 
                 PRO 
                 61 c2 
                 −0.2000 
                 268 
               
               
                 HG1 
                 39.397396088 
                 39.046298981 
                 81.292793274 
                 PRO 
                 61 h 
                 0.1000 
                 269 
               
               
                 HG2 
                 39.180202484 
                 40.649600983 
                 82.039207458 
                 PRO 
                 61 h 
                 0.1000 
                 270 
               
               
                 N 
                 38.242324829 
                 35.777751923 
                 81.785034180 
                 SER 
                 62 n 
                 −0.5000 
                 271 
               
               
                 CA 
                 38.186004639 
                 34.624855042 
                 80.844123840 
                 SER 
                 62 ca 
                 0.1200 
                 272 
               
               
                 MN 
                 39.035541534 
                 35.827360535 
                 82.416992185 
                 SER 
                 62 hn 
                 0.2800 
                 273 
               
               
                 MA 
                 37.921787262 
                 35.006183624 
                 79.841125488 
                 SER 
                 62 h 
                 0.1000 
                 274 
               
               
                 C 
                 37.145660400 
                 33.532897949 
                 81.261909485 
                 SER 
                 62 c′ 
                 0.3800 
                 275 
               
               
                 O 
                 37.466091156 
                 32.626064301 
                 82.041137695 
                 SER 
                 62 o′ 
                 −0.3800 
                 276 
               
               
                 CB 
                 39.620265961 
                 34.048240662 
                 80.725196835 
                 SER 
                 62 c2 
                 −0.1700 
                 277 
               
               
                 MB1 
                 39.660293579 
                 33.306644440 
                 79.904281616 
                 SER 
                 62 h 
                 0.1000 
                 278 
               
               
                 MB2 
                 40.349685669 
                 34.832687378 
                 80.442802429 
                 SER 
                 62 h 
                 0.1000 
                 279 
               
               
                 OG 
                 40.032703400 
                 33.414188385 
                 81.938880920 
                 SER 
                 62 oh 
                 −0.3800 
                 280 
               
               
                 MG 
                 39.252223969 
                 32.931293488 
                 82.256263733 
                 SER 
                 62 ho 
                 0.3500 
                 281 
               
               
                 N 
                 35.902244568 
                 33.647918701 
                 80.764541626 
                 SER 
                 63 n 
                 −0.5000 
                 282 
               
               
                 CA 
                 34.747528076 
                 32.874965942 
                 81.297317505 
                 SER 
                 63 cg 
                 0.1200 
                 283 
               
               
                 MN 
                 35.768447876 
                 34.503852844 
                 80.205200195 
                 SER 
                 63 hn 
                 0.2800 
                 284 
               
               
                 MA 
                 35.064254761 
                 32.265518188 
                 82.170570374 
                 SER 
                 63 h 
                 0.1000 
                 285 
               
               
                 C 
                 34.106758118 
                 31.936998367 
                 80.231674194 
                 SER 
                 63 c′ 
                 0.3800 
                 286 
               
               
                 O 
                 33.716896657 
                 32.367130280 
                 79.142120361 
                 SER 
                 63 o′ 
                 −0.3800 
                 287 
               
               
                 CB 
                 33.716815948 
                 33.889484406 
                 81.843544006 
                 SER 
                 63 c2 
                 −0.1700 
                 288 
               
               
                 MB1 
                 34.199871063 
                 34.571354430 
                 82.572105408 
                 SER 
                 63 h 
                 0.1000 
                 289 
               
               
                 MB2 
                 33.22880719 
                 34.543502808 
                 81.036796570 
                 SER 
                 63 h 
                 0.1000 
                 290 
               
               
                 OG 
                 33.634590149 
                 33.222091675 
                 82.496467590 
                 SER 
                 63 oh 
                 −0.3800 
                 291 
               
               
                 MG 
                 32.159793854 
                 32.710407257 
                 81.832328796 
                 SER 
                 63 ho 
                 0.3500 
                 292 
               
               
                 N 
                 33.914913177 
                 30.658897400 
                 80.588378906 
                 TRP 
                 64 n 
                 −0.5000 
                 293 
               
               
                 CA 
                 33.112319946 
                 29.694124222 
                 79.783546448 
                 TRP 
                 64 ca 
                 0.1200 
                 294 
               
               
                 MN 
                 34.221500397 
                 30.422899246 
                 81.538955658 
                 TRP 
                 64 hn 
                 0.2800 
                 295 
               
               
                 MA 
                 33.404731750 
                 29.812168121 
                 78.721931458 
                 TRP 
                 64 h 
                 0.1000 
                 296 
               
               
                 C 
                 31.573041916 
                 29.961977005 
                 79.883049011 
                 TRP 
                 64 c′ 
                 0.3800 
                 297 
               
               
                 O 
                 30.996980667 
                 29.940891266 
                 80.975959778 
                 TRP 
                 64 o′ 
                 −0.3800 
                 298 
               
               
                 CB 
                 33.525466919 
                 26.235471725 
                 80.142707825 
                 TRP 
                 64 c2 
                 −0.2000 
                 299 
               
               
                 MB1 
                 32.950366974 
                 27.534402847 
                 79.508041382 
                 TRP 
                 64 h 
                 0.1000 
                 300 
               
               
                 MB2 
                 34.571674347 
                 28.078489304 
                 79.816658020 
                 TRP 
                 64 h 
                 0.1000 
                 301 
               
               
                 CG 
                 33.405326843 
                 27.783784866 
                 81.611763000 
                 TRP 
                 64 c5 
                 0.0000 
                 302 
               
               
                 CD1 
                 32.267101288 
                 27.214570999 
                 82.221214294 
                 TRP 
                 64 c5 
                 0.1000 
                 303 
               
               
                 NE1 
                 32.481933594 
                 26.953943253 
                 83.590408325 
                 TRP 
                 64 np 
                 −0.5000 
                 304 
               
               
                 CE2 
                 33.781952422 
                 27.378627777 
                 83.812339783 
                 TRP 
                 64 c5 
                 0.1100 
                 305 
               
               
                 CD2 
                 34.355152230 
                 27.881061554 
                 82.617965698 
                 TRP 
                 64 c5 
                 0.0000 
                 306 
               
               
                 MD1 
                 31.322025528 
                 27.036033630 
                 81.708480835 
                 TRP 
                 64 h 
                 0.1000 
                 307 
               
               
                 ME1 
                 31.820940018 
                 26.578481674 
                 84.279945374 
                 TRP 
                 64 hn 
                 0.2800 
                 308 
               
               
                 CE3 
                 35.681034088 
                 28.394184113 
                 82.615905762 
                 TRP 
                 64 cp 
                 −0.1000 
                 309 
               
               
                 ME3 
                 36.128986359 
                 28.784986496 
                 81.714393616 
                 TRP 
                 64 h 
                 0.1000 
                 310 
               
               
                 CE3 
                 36.396430969 
                 28.387191772 
                 83.815704346 
                 TRP 
                 64 cp 
                 −0.1000 
                 311 
               
               
                 ME3 
                 37.405311584 
                 28.776082993 
                 83.832160950 
                 TRP 
                 64 h 
                 −0.1000 
                 312 
               
               
                 CM2 
                 35.830604553 
                 27.888952255 
                 84.994210925 
                 TRP 
                 64 cp 
                 0.1000 
                 313 
               
               
                 MM2 
                 36.410472870 
                 27.896844844 
                 85.506951904 
                 TRP 
                 64 h 
                 0.1000 
                 314 
               
               
                 CZ2 
                 34.527233124 
                 27.382776260 
                 85.014289856 
                 TRP 
                 64 cp 
                 0.1000 
                 315 
               
               
                 MZ2 
                 34.097515106 
                 27.006088257 
                 85.929389954 
                 TRP 
                 64 h 
                 0.1000 
                 316 
               
               
                 N 
                 30.921349498 
                 30.232547760 
                 78.740600586 
                 GLY 
                 65 n 
                 0.5000 
                 317 
               
               
                 CA 
                 29.460748672 
                 30.504768372 
                 78.692192078 
                 GLY 
                 65 cg 
                 0.0200 
                 318 
               
               
                 MN 
                 31.520374298 
                 30.302478790 
                 77.901519775 
                 GLY 
                 65 hn 
                 0.2800 
                 319 
               
               
                 MA1 
                 29.073087692 
                 30.896234512 
                 79.650825500 
                 GLY 
                 65 h 
                 0.1000 
                 320 
               
               
                 MA2 
                 29.288171768 
                 31.333106995 
                 77.981094360 
                 GLY 
                 65 h 
                 0.1000 
                 321 
               
               
                 C 
                 28.633579254 
                 29.293350220 
                 78.197364807 
                 GLY 
                 65 c′ 
                 0.3800 
                 322 
               
               
                 O 
                 25.866907883 
                 29.137302399 
                 76.975486755 
                 GLY 
                 65 o′ 
                 −0.3800 
                 323 
               
               
                 N 
                 27.969013672 
                 28.429246902 
                 79.038352966 
                 PRO 
                 66 n 
                 0.0200 
                 324 
               
               
                 CA 
                 27.282257080 
                 27.212890625 
                 78.846752930 
                 PRO 
                 66 ca 
                 0.0600 
                 325 
               
               
                 MA 
                 27.989650726 
                 26.634012222 
                 77.917152405 
                 PRO 
                 66 h 
                 0.1000 
                 326 
               
               
                 CD 
                 28.016592026 
                 28.832529831 
                 80.511337280 
                 PRO 
                 66 c2 
                 0.0600 
                 327 
               
               
                 MD1 
                 27.731332779 
                 29.836006927 
                 80.880874634 
                 PRO 
                 66 h 
                 0.1000 
                 328 
               
               
                 MD2 
                 29.027824402 
                 28.301166534 
                 80.897590637 
                 PRO 
                 66 b 
                 0.1000 
                 329 
               
               
                 C 
                 25.977466583 
                 27.479314804 
                 77.725341797 
                 PRO 
                 66 c′ 
                 0.3800 
                 330 
               
               
                 O 
                 25.217950821 
                 25.417282104 
                 77.982574463 
                 PRO 
                 66 o′ 
                 −0.3800 
                 331 
               
               
                 CB 
                 27.045602798 
                 26.422634125 
                 79.851196258 
                 PRO 
                 66 c2 
                 −0.2000 
                 332 
               
               
                 MB1 
                 26.132562637 
                 25.797079086 
                 79.827728271 
                 PRO 
                 66 h 
                 0.1000 
                 333 
               
               
                 MB2 
                 27.890687943 
                 25.729280472 
                 80.029365540 
                 PRO 
                 66 h 
                 −0.1000 
                 334 
               
               
                 CG 
                 27.003501892 
                 27.477243423 
                 80.958015442 
                 PRO 
                 66 c2 
                 −0.2000 
                 335 
               
               
                 MG1 
                 25.990892410 
                 27.921483994 
                 81.014678955 
                 PRO 
                 66 h 
                 0.1000 
                 336 
               
               
                 MH2 
                 27.232566833 
                 27.061700821 
                 81.956459045 
                 PRO 
                 66 h 
                 0.1000 
                 337 
               
               
                 N 
                 25.734319687 
                 26.626403809 
                 76.719802856 
                 ARG+ 
                 67 n 
                 −0.5000 
                 335 
               
               
                 CA 
                 24.603988647 
                 26.793025970 
                 75.767257690 
                 ARG+ 
                 67 ca 
                 0.1200 
                 339 
               
               
                 MN 
                 26.386735916 
                 25.841371536 
                 76.649803162 
                 ARG+ 
                 67 hn 
                 0.2800 
                 340 
               
               
                 MA 
                 24.496238708 
                 27.874828339 
                 75.561668396 
                 ARG+ 
                 67 h 
                 0.1000 
                 341 
               
               
                 C 
                 23.227464676 
                 26.224872589 
                 76.267372131 
                 ARG+ 
                 67 c′ 
                 0.2800 
                 342 
               
               
                 O 
                 23.178310394 
                 25.034952164 
                 76.603759766 
                 ARG+ 
                 67 o′ 
                 −0.3800 
                 343 
               
               
                 CB 
                 24.990055899 
                 26.165229797 
                 74.398826599 
                 ARG+ 
                 67 c2 
                 −0.2000 
                 344 
               
               
                 MB1 
                 24.135663986 
                 26.318639755 
                 73.709175110 
                 ARG+ 
                 67 h 
                 0.1100 
                 345 
               
               
                 MB2 
                 25.787433624 
                 26.779323578 
                 73.940032959 
                 ARG+ 
                 67 h 
                 0.1100 
                 346 
               
               
                 CG 
                 25.439929962 
                 24.676465988 
                 74.361564636 
                 ARG+ 
                 67 c2 
                 −0.2000 
                 347 
               
               
                 MG1 
                 26.546255112 
                 24.646316528 
                 74.415458679 
                 ARG+ 
                 67 h 
                 0.1300 
                 348 
               
               
                 MG2 
                 25.092346191 
                 24.131168365 
                 75.261718750 
                 ARG+ 
                 67 h 
                 0.1300 
                 349 
               
               
                 CD 
                 24.934387207 
                 23.941221237 
                 73.112297058 
                 ARG+ 
                 67 c2 
                 −0.0900 
                 350 
               
               
                 MD 
                 23.838283539 
                 23.774566650 
                 73.188652039 
                 ARG+ 
                 67 h 
                 0.1300 
                 351 
               
               
                 MD2 
                 25.070211411 
                 24.585262299 
                 72.220893860 
                 ARG+ 
                 67 h 
                 0.1300 
                 352 
               
               
                 ME 
                 25.665744781 
                 22.657058716 
                 72.968780518 
                 ARG+ 
                 67 n1 
                 −0.5000 
                 353 
               
               
                 ME 
                 26.251846313 
                 22.313375473 
                 73.731925964 
                 ARG+ 
                 67 hn 
                 0.3600 
                 354 
               
               
                 CZ 
                 25.689014435 
                 21.902687073 
                 71.871635437 
                 ARG+ 
                 67 cr 
                 0.4500 
                 355 
               
               
                 MM1 
                 26.493299484 
                 20.879484177 
                 71.859733582 
                 ARG+ 
                 67 n2 
                 −0.5000 
                 356 
               
               
                 M11 
                 27.072875705 
                 20.740955353 
                 72.690315247 
                 ARG+ 
                 67 hn 
                 0.3600 
                 357 
               
               
                 MM12 
                 26.520929337 
                 20.119580078 
                 71.006805420 
                 ARG+ 
                 67 hn 
                 0.3600 
                 358 
               
               
                 MM2 
                 24.956668854 
                 22.117029190 
                 70.805320740 
                 ARG+ 
                 67 n2 
                 −0.5000 
                 359 
               
               
                 MM21 
                 25.030595779 
                 21.456792831 
                 70.033142090 
                 ARG+ 
                 67 hn 
                 0.3600 
                 360 
               
               
                 MM22 
                 24.266489029 
                 22.916227341 
                 70.550784302 
                 ARG+ 
                 67 hn 
                 0.3600 
                 361 
               
               
                 N 
                 22.080270767 
                 26.971176147 
                 76.244255066 
                 ARG+ 
                 68 n 
                 −0.4200 
                 362 
               
               
                 CA 
                 20.743734360 
                 24.358839035 
                 76.485237122 
                 PRO 
                 68 ca 
                 0.0600 
                 363 
               
               
                 MA 
                 20.817556381 
                 25.605155945 
                 77.294357300 
                 PRO 
                 68 h 
                 0.1000 
                 364 
               
               
                 CD 
                 22.076143265 
                 28.448001862 
                 76.342918396 
                 PRO 
                 68 c2 
                 0.0600 
                 365 
               
               
                 MD1 
                 22.539228439 
                 25.949869I56 
                 75.469612122 
                 PRO 
                 68 h 
                 0.1000 
                 366 
               
               
                 MD2 
                 22.632146835 
                 25.776126862 
                 77.244499207 
                 PRO 
                 68 h 
                 0.1000 
                 367 
               
               
                 C 
                 20.182382584 
                 25.586324692 
                 75.240180969 
                 PRO 
                 68 c′ 
                 0.3800 
                 368 
               
               
                 O 
                 20.420539856 
                 24.381649017 
                 75.139877319 
                 PRO 
                 68 o′ 
                 −0.3800 
                 369 
               
               
                 CB 
                 19.948141098 
                 27.549791336 
                 77.062515259 
                 PRO 
                 68 c2 
                 −0.2000 
                 370 
               
               
                 MB1 
                 18.858430862 
                 27.490163803 
                 76.877128601 
                 PRO 
                 68 h 
                 0.1000 
                 371 
               
               
                 MB2 
                 20.066789627 
                 27.567596436 
                 78.163002014 
                 PRO 
                 68 h 
                 0.1000 
                 372 
               
               
                 CG 
                 20.592071533 
                 28.804227829 
                 76.667755179 
                 PRO 
                 68 c2 
                 −0.2000 
                 373 
               
               
                 MG1 
                 20.158363342 
                 29.031393051 
                 75.478172302 
                 PRO 
                 68 h 
                 0.1000 
                 374 
               
               
                 MG2 
                 20.428398132 
                 29.704229355 
                 77.092338562 
                 PRO 
                 68 h 
                 0.1000 
                 375 
               
               
                 N 
                 19.458055496 
                 26.229068756 
                 74.300010681 
                 ARG+ 
                 69 n 
                 −0.5000 
                 376 
               
               
                 CA 
                 18.893756866 
                 25.542047501 
                 73.096710205 
                 ARG+ 
                 69 ca 
                 0.1200 
                 377 
               
               
                 MN 
                 19.221296310 
                 27.198928833 
                 74.529014587 
                 ARG+ 
                 69 hn 
                 0.2800 
                 378 
               
               
                 MA 
                 19.667610168 
                 24.872461319 
                 72.660797119 
                 ARG+ 
                 69 h 
                 0.1000 
                 379 
               
               
                 C 
                 18.514461517 
                 26.608341217 
                 72.012504375 
                 ARG+ 
                 69 c′ 
                 0.3800 
                 380 
               
               
                 O 
                 17.383218765 
                 27.099323273 
                 72.036094666 
                 ARG+ 
                 69 o′ 
                 −0.3800 
                 381 
               
               
                 CB 
                 17.681777954 
                 24.654710770 
                 73.539657593 
                 ARG+ 
                 69 c2 
                 −0.2000 
                 352 
               
               
                 MB1 
                 18.011884689 
                 23.935596466 
                 74.315147400 
                 ARG+ 
                 69 h 
                 0.1100 
                 383 
               
               
                 MB2 
                 16.954420090 
                 25.310214996 
                 74.061965942 
                 ARG+ 
                 69 h 
                 0.100 
                 384 
               
               
                 CG 
                 16.946891785 
                 23.862810135 
                 72.427490234 
                 ARG+ 
                 69 c2 
                 −0.2000 
                 385 
               
               
                 MG1 
                 16.649517059 
                 24.851628113 
                 71.612152100 
                 ARG+ 
                 69 h 
                 0.1300 
                 386 
               
               
                 MG2 
                 17.638776779 
                 23.127803802 
                 71.968805054 
                 ARG+ 
                 69 h 
                 0.1300 
                 387 
               
               
                 CD 
                 15.688191414 
                 23.166488647 
                 72.975959775 
                 ARG+ 
                 69 c2 
                 −0.9000 
                 388 
               
               
                 MD1 
                 15.980383873 
                 22.365550995 
                 73.686569214 
                 ARG+ 
                 69 h 
                 0.1300 
                 389 
               
               
                 MD2 
                 15.090404510 
                 23.898859024 
                 73.554351807 
                 ARG+ 
                 69 h 
                 0.1300 
                 390 
               
               
                 ME 
                 14.889810562 
                 22.612804413 
                 71.848815915 
                 ARG+ 
                 69 n1 
                 −0.5000 
                 391 
               
               
                 ME 
                 15.272388458 
                 22.616128922 
                 70.898582458 
                 ARG+ 
                 69 hn 
                 0.3600 
                 392 
               
               
                 CZ 
                 13.644455910 
                 22.143890381 
                 71.942466736 
                 ARG+ 
                 69 cr 
                 0.4500 
                 393 
               
               
                 MM1 
                 13.048615456 
                 21.755460739 
                 70.850708005 
                 ARG+ 
                 69 n2 
                 −0.5000 
                 394 
               
               
                 MM11 
                 13.576630592 
                 21.832328796 
                 69.979103058 
                 ARG+ 
                 69 hn 
                 0.3600 
                 395 
               
               
                 MM12 
                 12.090744019 
                 21.411947250 
                 70.936050933 
                 ARG+ 
                 69 hn 
                 0.3600 
                 396 
               
               
                 MM2 
                 12.989639282 
                 22.056533813 
                 73.074552507 
                 ARG+ 
                 69 n2 
                 −0.5000 
                 397 
               
               
                 CZ 
                 13.644455910 
                 22.143590381 
                 71.942466736 
                 ARG+ 
                 69 cr 
                 0.4500 
                 393 
               
               
                 MM1 
                 13.048615456 
                 21.755460739 
                 70.850705008 
                 ARG+ 
                 69 n2 
                 −0.500 
                 394 
               
               
                 MM11 
                 13.576630592 
                 21.822325796 
                 69.979103088 
                 ARG+ 
                 69 hn 
                 0.3600 
                 395 
               
               
                 MM12 
                 12.090744019 
                 21.411947250 
                 70.936080933 
                 ARG+ 
                 69 hn 
                 0.3600 
                 396 
               
               
                 MM2 
                 12.989639282 
                 22.056533813 
                 73.074882507 
                 ARG+ 
                 69 n2 
                 −0.5000 
                 397 
               
               
                 MM21 
                 12.033639908 
                 21.696094513 
                 73.066261292 
                 ARG+ 
                 69 hn 
                 0.3600 
                 398 
               
               
                 MM22 
                 13.529273987 
                 22.372974396 
                 73.883934021 
                 ARG+ 
                 69 hn 
                 0.3600 
                 399 
               
               
                 N 
                 19.436628342 
                 26.928932190 
                 71.074501038 
                 ARG+ 
                 70 n 
                 −0.5000 
                 400 
               
               
                 CA 
                 19.223009109 
                 27.811206818 
                 69.878326416 
                 ARG+ 
                 70 ca 
                 0.1200 
                 401 
               
               
                 MN 
                 20.357131958 
                 26.451332092 
                 71.165985107 
                 ARG+ 
                 70 hn 
                 0.2800 
                 402 
               
               
                 MA 
                 19.087514877 
                 27.065124512 
                 69.071128845 
                 ARG+ 
                 70 h 
                 0.1000 
                 403 
               
               
                 C 
                 20.512538910 
                 28.575149536 
                 69.398536682 
                 ARG+ 
                 70 c′ 
                 0.3800 
                 404 
               
               
                 O 
                 20.872812271 
                 25.468791962 
                 68.228363037 
                 ARG+ 
                 70 o′ 
                 −0.3800 
                 405 
               
               
                 CB 
                 17.935552597 
                 28.697717667 
                 69.732887268 
                 ARG+ 
                 70 c2 
                 −0.2000 
                 406 
               
               
                 MB1 
                 17.889257431 
                 29.085472107 
                 68.694030762 
                 ARG+ 
                 70 h 
                 0.1100 
                 407 
               
               
                 MB2 
                 17.053388596 
                 28.033058167 
                 69.807891846 
                 ARG+ 
                 70 h 
                 0.1100 
                 408 
               
               
                 CG 
                 17.775762558 
                 29.883768082 
                 70.717842102 
                 ARG+ 
                 70 c2 
                 −0.2000 
                 409 
               
               
                 MG1 
                 18.004568100 
                 29.946030045 
                 71.747383118 
                 ARG+ 
                 70 h 
                 0.1300 
                 410 
               
               
                 MG2 
                 18.540782928 
                 30.651863098 
                 70.495643616 
                 ARG+ 
                 70 h 
                 0.1300 
                 411 
               
               
                 CD 
                 16.368116379 
                 30.502414703 
                 70.693214417 
                 ARG+ 
                 70 c2 
                 −0.0900 
                 412 
               
               
                 MD1 
                 16.095691681 
                 30.812221527 
                 69.664886475 
                 ARG+ 
                 70 h 
                 0.1300 
                 413 
               
               
                 MD2 
                 15.630161285 
                 29.711160660 
                 70.937812805 
                 ARG+ 
                 70 h 
                 0.1300 
                 414 
               
               
                 ME 
                 16.255954742 
                 31.590759277 
                 71.711013794 
                 ARG+ 
                 70 n1 
                 −0.5000 
                 415 
               
               
                 ME 
                 16.253637314 
                 31.350564957 
                 72.706428528 
                 ARG+ 
                 70 hn 
                 0.3600 
                 416 
               
               
                 CE 
                 16.144437790 
                 32.900745392 
                 71.464561462 
                 ARG+ 
                 70 cr 
                 0.4500 
                 417 
               
               
                 MM1 
                 16.055492401 
                 33.712893625 
                 72.481109619 
                 ARG+ 
                 70 n2 
                 −0.5000 
                 418 
               
               
                 MM11 
                 16.071464539 
                 33.294216156 
                 73.413330078 
                 ARG+ 
                 70 hn 
                 0.3600 
                 419 
               
               
                 MM12 
                 15.975571632 
                 34.708621979 
                 72.277374268 
                 ARG+ 
                 70 hn 
                 0.3600 
                 420 
               
               
                 MM2 
                 16.120351791 
                 33.420074463 
                 70.259872437 
                 ARG+ 
                 70 n2 
                 −0.5000 
                 421 
               
               
                 MM21 
                 16.025018692 
                 34.432674408 
                 70.167800903 
                 ARG+ 
                 70 hn 
                 0.3600 
                 422 
               
               
                 MM22 
                 16.187112808 
                 32.736862183 
                 69.505996704 
                 ARG+ 
                 70 lm 
                 0.3600 
                 423 
               
               
                 N 
                 21.115812302 
                 29.562902451 
                 70.071769714 
                 TYRC 
                 71 n 
                 −0.5000 
                 424 
               
               
                 MN 
                 21.515977859 
                 30.157514572 
                 69.338050842 
                 TYRC 
                 71 hn 
                 0.2800 
                 425 
               
               
                 CA 
                 22.034273148 
                 29.314456940 
                 71.218978882 
                 TYRC 
                 71 ca 
                 0.1200 
                 426 
               
               
                 MA 
                 22.671009064 
                 28.444923401 
                 70.976676941 
                 TYRC 
                 71 h 
                 0.1000 
                 427 
               
               
                 C 
                 21.352920532 
                 25.953493118 
                 72.563385010 
                 TYRC 
                 71 c′ 
                 0.4100 
                 428 
               
               
                 OCT 
                 20.392858505 
                 29.553161621 
                 73.048652649 
                 TYRC 
                 71 o′ 
                 −0.3800 
                 429 
               
               
                 Q 
                 21.928325653 
                 27.853042603 
                 73.145797729 
                 TYRC 
                 71 oh 
                 −0.3800 
                 430 
               
               
                 MO 
                 21.429273605 
                 27.558662415 
                 73.909782410 
                 TYRC 
                 71 ho 
                 0.3500 
                 431 
               
               
                 CB 
                 22.969152451 
                 30.555358887 
                 71.361984253 
                 TYRC 
                 71 c2 
                 −0.2000 
                 432 
               
               
                 MB1 
                 22.368267059 
                 31.487627029 
                 71.355415344 
                 TYRC 
                 71 h 
                 0.1000 
                 433 
               
               
                 MB2 
                 23.401992798 
                 30.559690475 
                 72.381835938 
                 TYRC 
                 71 h 
                 0.1000 
                 434 
               
               
                 CG 
                 24.144546509 
                 30.666173935 
                 70.352111816 
                 TYRC 
                 71 cp 
                 0.0000 
                 435 
               
               
                 CD1 
                 23.927537372 
                 31.126276016 
                 69.044418335 
                 TYRC 
                 71 cp 
                 −0.1000 
                 436 
               
               
                 MD1 
                 22.944635391 
                 31.424587630 
                 68.717597961 
                 TYRC 
                 71 h 
                 0.1000 
                 437 
               
               
                 CE1 
                 24.987041473 
                 31.212265015 
                 68.143028259 
                 TYRC 
                 71 cp 
                 −0.1000 
                 438 
               
               
                 ME1 
                 24.819047928 
                 31.555503845 
                 67.131973267 
                 TYRC 
                 71 h 
                 0.1000 
                 439 
               
               
                 CZ 
                 26.273118973 
                 30.861675262 
                 68.542274475 
                 TYRC 
                 71 cp 
                 0.0300 
                 440 
               
               
                 OM 
                 27.314481735 
                 30.957365036 
                 67.652267456 
                 TYRC 
                 71 oh 
                 −0.3800 
                 441 
               
               
                 MN 
                 26.980180740 
                 31.236070633 
                 66.796859741 
                 TYRC 
                 71 ho 
                 0.3500 
                 442 
               
               
                 CE2 
                 26.504697800 
                 30.422637939 
                 69.841377258 
                 TYRC 
                 71 cp 
                 −0.1000 
                 443 
               
               
                 ME2 
                 27.503232956 
                 30.148866653 
                 70.140815735 
                 TYRC 
                 71 h 
                 0.1000 
                 444 
               
               
                 CD2 
                 25.447391510 
                 30.325349808 
                 70.743820190 
                 TYRC 
                 71 cp 
                 −0.1000 
                 445 
               
               
                 MD2 
                 25.652494431 
                 29.968608856 
                 71.745338440 
                 TYRC 
                 71 h 
                 0.1000 
                 446 
               
               
                   
               
               
                 *The numbering of the amino acids is shifted by minus 6 relative to the sequence SEQ ID No. 1.  
               
             
          
         
       
     
     
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE NO. 2 
               
               
                   
               
               
                   
                   
                   
                   
                 residue 
                 atom type, 
               
               
                 Atom 
                   
                   
                   
                 name and 
                 charge and 
               
               
                 name 
                 x 
                 y 
                 z 
                 no. 
                 no. 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 N 
                 24.753730401 
                 26.435615520 
                 68.246300542 
                 CYSn 
                 40 nj 
                 −0.500 
                 1 
               
               
                 CA 
                 24.503000259 
                 26.336292725 
                 69.707687375 
                 CYSn 
                 40 ca 
                 0.1200 
                 2 
               
               
                 NN1 
                 23.561560822 
                 26.429992676 
                 67.734397888 
                 CYSn 
                 40 hn 
                 0.1400 
                 3 
               
               
                 NN2 
                 25.250690460 
                 25.603437424 
                 67.909477234 
                 CYSn 
                 40 hn 
                 0.1400 
                 4 
               
               
                 NA 
                 23.590571594 
                 27.247760773 
                 69.940755269 
                 CYSn 
                 40 h 
                 0.100 
                 5 
               
               
                 C 
                 25.747190475 
                 26.505004883 
                 70.632949529 
                 CYSn 
                 40 c′ 
                 0.3800 
                 6 
               
               
                 O 
                 25.611124039 
                 27.204542160 
                 71.634971619 
                 CYSn 
                 40 o′ 
                 −0.3800 
                 7 
               
               
                 CB 
                 23.602088928 
                 25.125436783 
                 69.979545593 
                 CYSn 
                 40 c2 
                 −0.3000 
                 8 
               
               
                 HB1 
                 22.555475225 
                 25.378625570 
                 69.716011047 
                 CYSn 
                 40 h 
                 0.1000 
                 9 
               
               
                 HB2 
                 23.565217209 
                 24.277284622 
                 69.317871094 
                 CYSn 
                 40 h 
                 0.1000 
                 10 
               
               
                 SG 
                 23.623842010 
                 24.466741562 
                 71.679084778 
                 CYSn 
                 40 s1 
                 0.1000 
                 11 
               
               
                 N 
                 26.910152435 
                 25.8S1416321 
                 70.350471497 
                 SER 
                 41 n 
                 −0.5000 
                 12 
               
               
                 CA 
                 28.052598953 
                 25.721915930 
                 71.310394287 
                 SET 
                 41 ca 
                 0.1200 
                 13 
               
               
                 HN 
                 26.922674725 
                 25.473436356 
                 69.412322998 
                 SER 
                 41 hn 
                 0.2800 
                 14 
               
               
                 RA 
                 27.761577606 
                 24.886217117 
                 71.978584290 
                 SER 
                 41 h 
                 0.1000 
                 15 
               
               
                 C 
                 28.477056503 
                 26.929338455 
                 72.226699529 
                 SER 
                 41 c′ 
                 0.3800 
                 16 
               
               
                 O 
                 25.412267685 
                 28.097608566 
                 71.829902649 
                 SER 
                 41 o′ 
                 −0.3800 
                 17 
               
               
                 CB 
                 28.257335662 
                 25.212779999 
                 70.480110168 
                 SER 
                 41 c2 
                 −0.1700 
                 18 
               
               
                 KB1 
                 28.957101822 
                 24.401222229 
                 69.786743164 
                 SER 
                 41 h 
                 0.1000 
                 19 
               
               
                 KB2 
                 29.657650511 
                 26.030597657 
                 69.845893860 
                 SER 
                 41 h 
                 0.1000 
                 20 
               
               
                 CG 
                 30.284814825 
                 24.713315964 
                 71.339111328 
                 SER 
                 41 ch 
                 −0.3800 
                 21 
               
               
                 NG 
                 31.027490616 
                 24.448732376 
                 70.755003662 
                 SER 
                 41 hc 
                 0.3500 
                 22 
               
               
                 N 
                 28.904022217 
                 24.617259979 
                 73.466476440 
                 GLY 
                 42 n 
                 −0.5000 
                 23 
               
               
                 CA 
                 29.226711273 
                 27.639400482 
                 74.497131348 
                 GLY 
                 42 cg 
                 0.0200 
                 24 
               
               
                 HX 
                 29.140472412 
                 25.626163483 
                 73.587532043 
                 GLY 
                 42 hn 
                 0.2800 
                 25 
               
               
                 KA1 
                 28.567264557 
                 28.519987106 
                 74.394309988 
                 GLY 
                 42 h 
                 0.1000 
                 26 
               
               
                 KA2 
                 28.949186325 
                 27.229663849 
                 75.483924866 
                 GLY 
                 42 h 
                 0.1000 
                 27 
               
               
                 C 
                 30.728670120 
                 28.040773392 
                 74.587509155 
                 GLY 
                 42 c′ 
                 0.3800 
                 28 
               
               
                 O 
                 31.522300720 
                 27.171119690 
                 74.961143494 
                 GLY 
                 42 o′ 
                 −0.3800 
                 29 
               
               
                 N 
                 31.175983429 
                 29.296203613 
                 74.282577515 
                 PRO 
                 43 n 
                 −0.4200 
                 30 
               
               
                 CA 
                 32.627410889 
                 29.612504959 
                 74.140579224 
                 PRO 
                 43 ca 
                 0.0600 
                 31 
               
               
                 KA 
                 33.153442353 
                 28.711788635 
                 73.723632813 
                 PRO 
                 43 h 
                 0.1000 
                 32 
               
               
                 CO 
                 30.295356750 
                 30.374078751 
                 73.784042358 
                 PRO 
                 43 c2 
                 0.0600 
                 33 
               
               
                 KD1 
                 29.605636597 
                 30.735929489 
                 74.571166992 
                 PRO 
                 43 h 
                 0.1000 
                 34 
               
               
                 KD2 
                 29.653467865 
                 30.826647568 
                 72.928161621 
                 PRO 
                 43 h 
                 0.1000 
                 35 
               
               
                 C 
                 33.389945984 
                 30.112844467 
                 75.429031372 
                 PRO 
                 43 c′ 
                 0.3800 
                 36 
               
               
                 O 
                 32.754360199 
                 30.681560516 
                 76.327354431 
                 PRO 
                 43 o′ 
                 −0.3800 
                 37 
               
               
                 CB 
                 32.565906525 
                 30.710325241 
                 73.057388306 
                 PRO 
                 43 c2 
                 −0.2000 
                 38 
               
               
                 KB1 
                 33.449081421 
                 31.378034592 
                 73.055488586 
                 PRO 
                 43 h 
                 0.1000 
                 39 
               
               
                 KB2 
                 31.524932861 
                 30.247560501 
                 72.051818848 
                 PRO 
                 43 h 
                 0.1000 
                 40 
               
               
                 CG 
                 31.263490677 
                 31.466632843 
                 73.332626343 
                 PRO 
                 43 c2 
                 −0.2000 
                 41 
               
               
                 KG1 
                 31.413110733 
                 32.204200745 
                 74.146759733 
                 PRO 
                 43 h 
                 0.1000 
                 42 
               
               
                 KG2 
                 30.894020081 
                 32.022109985 
                 72.450286865 
                 PRO 
                 43 h 
                 0.1000 
                 43 
               
               
                 N 
                 34.754848480 
                 30.015562057 
                 75.523460388 
                 PRO 
                 44 n 
                 −0.4200 
                 44 
               
               
                 CA 
                 35.553565979 
                 30.763086319 
                 76.536285400 
                 PRO 
                 44 ca 
                 0.6000 
                 45 
               
               
                 KA 
                 35.083564758 
                 30.695350647 
                 77.536567688 
                 PRD 
                 44 h 
                 0.1000 
                 46 
               
               
                 CD 
                 35.574893951 
                 29.325835648 
                 74.665214519 
                 PRO 
                 44 c2 
                 0.0600 
                 47 
               
               
                 KD1 
                 35.471595764 
                 29.373666763 
                 73.588935852 
                 PRO 
                 44 h 
                 0.1000 
                 48 
               
               
                 KD2 
                 35.281650543 
                 28.076414108 
                 74.807395935 
                 PRO 
                 44 h 
                 0.1000 
                 49 
               
               
                 C 
                 35.767509460 
                 32.265411377 
                 76.141123281 
                 PRO 
                 44 c′ 
                 0.3300 
                 50 
               
               
                 O 
                 36.544441223 
                 32.599441528 
                 75.238464355 
                 PRD 
                 44 o′ 
                 0.3800 
                 51 
               
               
                 CB 
                 36.549227905 
                 29.927103043 
                 76.567779541 
                 PRO 
                 44 c2 
                 −0.2000 
                 52 
               
               
                 HB1 
                 37.732776642 
                 30.502979279 
                 76.899909705 
                 PRO 
                 44 h 
                 0.1000 
                 53 
               
               
                 HB2 
                 36.733722657 
                 29.095364598 
                 72.253833069 
                 PRO 
                 44 h 
                 0.1000 
                 54 
               
               
                 CG 
                 37.005489349 
                 29.369808197 
                 75.152618408 
                 PRO 
                 44 c2 
                 −0.2000 
                 55 
               
               
                 MG1 
                 37.502185822 
                 30.119005203 
                 74.504158020 
                 PRO 
                 44 h 
                 0.1000 
                 56 
               
               
                 MG2 
                 37.625408173 
                 28.451385498 
                 75.115615845 
                 PRO 
                 44 h 
                 0.1000 
                 57 
               
               
                 N 
                 35.047088623 
                 33.173435211 
                 76.816978455 
                 ALA 
                 45 n 
                 −0.5000 
                 58 
               
               
                 CA 
                 35.021333466 
                 34.699920502 
                 76.449218750 
                 ALA 
                 45 ca 
                 0.1200 
                 59 
               
               
                 MN 
                 34.471403029 
                 32.798248291 
                 77.590728760 
                 ALA 
                 45 hn 
                 0.2800 
                 60 
               
               
                 HA 
                 35.065380096 
                 34.699813843 
                 75.343650818 
                 ALA 
                 45 h 
                 0.1000 
                 61 
               
               
                 C 
                 36.187728882 
                 35.414947510 
                 77.090148926 
                 ALA 
                 45 c′ 
                 0.3800 
                 62 
               
               
                 O 
                 36.133388519 
                 35.819305420 
                 78.255142212 
                 ALA 
                 45 o′ 
                 −0.3800 
                 63 
               
               
                 CB 
                 33.615478516 
                 35.135440826 
                 76.831176758 
                 ALA 
                 45 c3 
                 −0.3000 
                 64 
               
               
                 HB1 
                 33.490375519 
                 36.157480927 
                 76.517280579 
                 ALA 
                 45 h 
                 0.1000 
                 65 
               
               
                 HB2 
                 32.811222076 
                 34.556259155 
                 76.338432312 
                 ALA 
                 45 h 
                 0.1000 
                 66 
               
               
                 HB3 
                 33.433517456 
                 35.098365784 
                 77.922439575 
                 ALA 
                 45 h 
                 0.1000 
                 67 
               
               
                 N 
                 37.264499664 
                 35.613568713 
                 76.306388855 
                 ALA 
                 46 n 
                 −0.5000 
                 68 
               
               
                 HN 
                 37.248532703 
                 35.072978973 
                 75.433502197 
                 ALA 
                 46 hn 
                 0.2800 
                 69 
               
               
                 CA 
                 38.503662109 
                 36.398694611 
                 76.764076233 
                 ALA 
                 46 ca 
                 0.1200 
                 70 
               
               
                 MA 
                 38.303600311 
                 36.883266449 
                 77.688095093 
                 ALA 
                 46 h 
                 0.1000 
                 71 
               
               
                 C 
                 39.082061765 
                 37.173509979 
                 75.687866211 
                 ALA 
                 46 c′ 
                 0.3800 
                 72 
               
               
                 O 
                 38.951850891 
                 37.052509308 
                 74.481193542 
                 ALA 
                 46 c′ 
                 0.3800 
                 73 
               
               
                 CB 
                 39.509185791 
                 35.179004669 
                 77.103065491 
                 ALA 
                 46 c3 
                 −0.3000 
                 74 
               
               
                 HB1 
                 40.441535950 
                 35.582756042 
                 77.525072327 
                 ALA 
                 46 h 
                 0.1000 
                 75 
               
               
                 HB2 
                 39.106670380 
                 34.460605622 
                 77.839447021 
                 ALA 
                 46 h 
                 0.1000 
                 76 
               
               
                 HB3 
                 39.780502319 
                 34.997728729 
                 76.205062866 
                 ALA 
                 46 h 
                 0.1000 
                 77 
               
               
                 N 
                 39.768814087 
                 38.344066620 
                 76.133750916 
                 ALA 
                 47 n 
                 0.5000 
                 78 
               
               
                 CA 
                 40.322643280 
                 39.391151428 
                 75.225708008 
                 ALA 
                 47 ca 
                 0.1200 
                 79 
               
               
                 MN 
                 39.783836365 
                 38.455593109 
                 77.149337769 
                 ALA 
                 47 hn 
                 0.2800 
                 80 
               
               
                 HA 
                 39.932807922 
                 39.265201569 
                 74.196365356 
                 ALA 
                 47 h 
                 0.1000 
                 81 
               
               
                 C 
                 41.900882721 
                 39.401574817 
                 75.126977349 
                 ALA 
                 47 c′ 
                 0.3800 
                 82 
               
               
                 O 
                 42.538444519 
                 40.171451569 
                 75.854652405 
                 ALA 
                 47 o′ 
                 −0.3800 
                 83 
               
               
                 CB 
                 39.728843659 
                 40.731719971 
                 75.714279175 
                 ALA 
                 47 c3 
                 −0.3000 
                 84 
               
               
                 HB1 
                 40.043342590 
                 41.567916570 
                 75.059875488 
                 ALA 
                 47 h 
                 0.1000 
                 85 
               
               
                 HB2 
                 38.621978760 
                 40.726497630 
                 75.711242676 
                 ALA 
                 47 h 
                 0.1000 
                 86 
               
               
                 HB3 
                 40.062076569 
                 40.987442017 
                 76.739311218 
                 ALA 
                 47 h 
                 0.1000 
                 87 
               
               
                 N 
                 42.578651428 
                 38.603999056 
                 74.242019653 
                 PRO 
                 48 n 
                 −0.4200 
                 88 
               
               
                 CA 
                 44.052674976 
                 38.702857971 
                 74.013595581 
                 PRO 
                 48 ca 
                 0.0600 
                 89 
               
               
                 HA 
                 44.576034546 
                 38.850185394 
                 74.977058411 
                 PRO 
                 48 h 
                 0.1020 
                 90 
               
               
                 CO 
                 41.956359863 
                 37.474979401 
                 73.520225525 
                 PRO 
                 48 c2 
                 0.0600 
                 91 
               
               
                 HD1 
                 41.114963531 
                 37.378272858 
                 72.872795105 
                 PRO 
                 48 h 
                 0.1000 
                 92 
               
               
                 HD2 
                 41.576156616 
                 36.723918915 
                 74.239135742 
                 PRO 
                 48 h 
                 0.1000 
                 93 
               
               
                 C 
                 44.492458344 
                 39.820354462 
                 73.002609253 
                 PRO 
                 48 c′ 
                 0.3800 
                 94 
               
               
                 O 
                 43.782276154 
                 40.131282806 
                 72.040626526 
                 PRO 
                 48 o′ 
                 −0.3800 
                 95 
               
               
                 CB 
                 44.356296539 
                 37.288743516 
                 73.479736328 
                 PRO 
                 48 c2 
                 −0.2000 
                 96 
               
               
                 HB1 
                 45.273612976 
                 37.234390259 
                 72.865592957 
                 PRO 
                 48 h 
                 0.1000 
                 97 
               
               
                 HB2 
                 44.813816833 
                 36.591526031 
                 74.322021484 
                 PRO 
                 48 h 
                 0.1000 
                 98 
               
               
                 CG 
                 43.102409363 
                 36.884414673 
                 72.702988770 
                 PRO 
                 48 c2 
                 −0.2000 
                 99 
               
               
                 HG1 
                 43.119277954 
                 37.331111908 
                 71.685241699 
                 PRO 
                 48 h 
                 0.1000 
                 100 
               
               
                 HG2 
                 43.010280609 
                 35.788948059 
                 72.572326660 
                 PRO 
                 48 h 
                 0.1000 
                 101 
               
               
                 N 
                 45.709655762 
                 40.366821289 
                 73.185493469 
                 GLY 
                 49 n 
                 −0.5000 
                 102 
               
               
                 CA 
                 46.317604065 
                 41.332912445 
                 72.214889526 
                 GLY 
                 49 cg 
                 0.0200 
                 103 
               
               
                 HN 
                 46.169986725 
                 40.089691162 
                 74.058357239 
                 GLY 
                 49 hn 
                 0.2800 
                 104 
               
               
                 HA1 
                 45.654991150 
                 41.537052153 
                 71.351181020 
                 GLY 
                 49 h 
                 0.1000 
                 105 
               
               
                 HA2 
                 46.406318665 
                 42.313266754 
                 72.719123840 
                 GLY 
                 49 b 
                 0.1000 
                 106 
               
               
                 C 
                 47.710880280 
                 40.963481903 
                 71.854037476 
                 GLY 
                 49 c′ 
                 0.3800 
                 107 
               
               
                 O 
                 48.630664825 
                 41.772521973 
                 71.754951477 
                 GLY 
                 49 o′ 
                 −0.3800 
                 108 
               
               
                 N 
                 47.830738068 
                 39.763301849 
                 71.063682556 
                 HIS 
                 50 n 
                 −0.5000 
                 109 
               
               
                 HN 
                 46.918842316 
                 39.310573578 
                 70.943237305 
                 HIS 
                 50 hn 
                 0.2800 
                 110 
               
               
                 CA 
                 49.045799255 
                 39.210880280 
                 70.375061035 
                 HIS 
                 50 ca 
                 0.1200 
                 111 
               
               
                 HA 
                 49.315334220 
                 38.320884705 
                 70.972137451 
                 HIS 
                 50 h 
                 0.1000 
                 112 
               
               
                 C 
                 50.433021545 
                 39.981941223 
                 70.267852783 
                 HIS 
                 50 c′ 
                 0.3800 
                 113 
               
               
                 O 
                 50.773132324 
                 40.456230164 
                 69.178672791 
                 HIS 
                 50 o′ 
                 −0.3800 
                 114 
               
               
                 CB 
                 28.558776855 
                 32.590164165 
                 69.024101257 
                 HIS 
                 50 c2 
                 −0.2000 
                 115 
               
               
                 HB1 
                 49.390335083 
                 32.009521484 
                 68.577232361 
                 HIS 
                 50 h 
                 0.1000 
                 116 
               
               
                 HB2 
                 47.792594910 
                 37.817192078 
                 69.227330181 
                 HIS 
                 50 b 
                 0.1000 
                 117 
               
               
                 CG 
                 47.597627258 
                 39.545143127 
                 67.956726074 
                 HIS 
                 50 c5 
                 0.1000 
                 118 
               
               
                 HD1 
                 46.669281006 
                 39.956676482 
                 67.918121338 
                 HIS 
                 50 np 
                 0.1000 
                 119 
               
               
                 CE1 
                 46.730144501 
                 40.789539337 
                 66.829002380 
                 HIS 
                 50 c5 
                 0.2700 
                 120 
               
               
                 NE2 
                 47.911670685 
                 40.950614929 
                 66.152328491 
                 HIS 
                 50 np 
                 −0.5000 
                 121 
               
               
                 CD2 
                 48.729324341 
                 40.126430511 
                 66.304235840 
                 HIS 
                 50 c5 
                 0.0100 
                 122 
               
               
                 HE1 
                 45.843067169 
                 41.327060699 
                 66.517631531 
                 HIS 
                 50 h 
                 0.1300 
                 123 
               
               
                 HE2 
                 48.138290425 
                 41.548683167 
                 65.349815369 
                 HIS 
                 50 hn 
                 0.2800 
                 124 
               
               
                 HB2 
                 49.789726257 
                 39.981491089 
                 66.738136292 
                 HIS 
                 50 h 
                 0.1300 
                 125 
               
               
                 H 
                 51.307849884 
                 40.071182251 
                 71.317932129 
                 PRO 
                 51 n 
                 −0.4200 
                 126 
               
               
                 CA 
                 52.692558239 
                 40.596851349 
                 71.184913635 
                 PRO 
                 51 ca 
                 0.0600 
                 127 
               
               
                 HA 
                 52.742668152 
                 41.390510559 
                 70.412712097 
                 PRO 
                 51 h 
                 0.1000 
                 128 
               
               
                 CD 
                 50.980678558 
                 39.703777313 
                 72.706970215 
                 PRO 
                 51 c2 
                 0.0600 
                 129 
               
               
                 HD1 
                 50.998199463 
                 38.605384827 
                 72.818397522 
                 PRO 
                 51 h 
                 0.1000 
                 130 
               
               
                 HD2 
                 49.987606049 
                 40.071315765 
                 73.019950867 
                 PRO 
                 51 b 
                 0.1000 
                 131 
               
               
                 C 
                 53.739063263 
                 39.471630096 
                 70.880722046 
                 PRO 
                 51 c′ 
                 0.3800 
                 132 
               
               
                 O 
                 53.708900452 
                 38.294466400 
                 71.488830566 
                 PRO 
                 51 c′ 
                 −0.2800 
                 133 
               
               
                 CB 
                 52.868911743 
                 41.240936279 
                 72.572486877 
                 PRO 
                 51 c2 
                 0.2000 
                 134 
               
               
                 HB1 
                 53.929355621 
                 41.264253998 
                 72.864852905 
                 PRO 
                 51 b 
                 0.1000 
                 135 
               
               
                 HB2 
                 52.429229736 
                 42.258647919 
                 72.365872192 
                 PRO 
                 51 h 
                 0.1000 
                 136 
               
               
                 CG 
                 52.087848663 
                 40.349472046 
                 73.547019958 
                 PRO 
                 51 c2 
                 −0.2000 
                 137 
               
               
                 HG1 
                 51.750400543 
                 39.566276550 
                 73.963310242 
                 PRO 
                 51 h 
                 0.1000 
                 138 
               
               
                 HG2 
                 51.686916351 
                 40.923263550 
                 74.403717041 
                 PRO 
                 51 h 
                 0.1000 
                 139 
               
               
                 H 
                 54.676445007 
                 39.726749420 
                 69.946899414 
                 LEU 
                 52 n 
                 −0.5000 
                 140 
               
               
                 CA 
                 55.768096924 
                 38.764469147 
                 69.270259094 
                 LEU 
                 52 ca 
                 0.1200 
                 141 
               
               
                 HN 
                 54.573589325 
                 40.637012482 
                 69.488586426 
                 LEU 
                 52 hn 
                 0.2800 
                 142 
               
               
                 HA 
                 56.414031982 
                 39.225927734 
                 68.869346619 
                 LEU 
                 52 h 
                 0.1000 
                 143 
               
               
                 C 
                 55.281269073 
                 37.240004730 
                 68.718757629 
                 LEU 
                 52 c′ 
                 0.2800 
                 144 
               
               
                 O 
                 55.654800415 
                 37.411125183 
                 67.550910950 
                 LEU 
                 52 o′ 
                 −0.2800 
                 145 
               
               
                 CB 
                 56.713882446 
                 38.254763031 
                 70.751991272 
                 LEU 
                 52 c2 
                 −0.2000 
                 146 
               
               
                 HB1 
                 56.125553131 
                 37.737205505 
                 71.456863403 
                 LEU 
                 52 h 
                 0.1000 
                 147 
               
               
                 HB2 
                 57.488136292 
                 37.658962250 
                 70.274801636 
                 LEU 
                 52 h 
                 0.1000 
                 148 
               
               
                 CG 
                 57.411731720 
                 39.487998962 
                 71.552589417 
                 LEU 
                 52 c1 
                 −0.1000 
                 149 
               
               
                 HG 
                 56.652648926 
                 40.244640350 
                 71.834617615 
                 LEU 
                 52 h 
                 0.1000 
                 150 
               
               
                 CD1 
                 58.010108948 
                 38.936943054 
                 72.859535217 
                 LEU 
                 52 c3 
                 0.2000 
                 151 
               
               
                 HD11 
                 58.475826263 
                 39.735752106 
                 73.467353821 
                 LEU 
                 52 h 
                 0.1000 
                 152 
               
               
                 HD12 
                 57.236072540 
                 38.469894409 
                 73.497505188 
                 LEU 
                 52 h 
                 0.1000 
                 153 
               
               
                 HD13 
                 38.787303925 
                 38.171112061 
                 72.675750732 
                 LEU 
                 52 h 
                 0.1000 
                 154 
               
               
                 CD2 
                 58.537623901 
                 40.187110901 
                 70.742630205 
                 LEU 
                 52 c1 
                 0.3000 
                 155 
               
               
                 HD21 
                 58.993679047 
                 41.001243591 
                 71.321037292 
                 LEU 
                 52 b 
                 0.1000 
                 156 
               
               
                 HD22 
                 59.321178436 
                 39.487018585 
                 70.445312500 
                 LEU 
                 52 h 
                 0.1000 
                 157 
               
               
                 HD23 
                 58.125030518 
                 40.647811890 
                 69.818283082 
                 LEU 
                 52 b 
                 0.1000 
                 158 
               
               
                 H 
                 54.475013733 
                 36.643035889 
                 69.215246582 
                 ALA 
                 53 n 
                 0.5000 
                 159 
               
               
                 CA 
                 53.896503448 
                 35.451416016 
                 68.639259338 
                 ALA 
                 53 ca 
                 0.1200 
                 160 
               
               
                 HN 
                 54.100524902 
                 37.007503510 
                 70.205250713 
                 ALA 
                 53 hn 
                 0.2800 
                 161 
               
               
                 HA 
                 53.553531647 
                 35.773445129 
                 67.634338379 
                 ALA 
                 53 h 
                 0.1000 
                 162 
               
               
                 C 
                 52.602260590 
                 34.908508301 
                 69.253744507 
                 ALA 
                 53 c′ 
                 0.3800 
                 163 
               
               
                 O 
                 51.589200881 
                 34.828308105 
                 68.650024414 
                 ALA 
                 53 o′ 
                 −0.3800 
                 164 
               
               
                 CB 
                 54.970031738 
                 34.364234924 
                 68.394615173 
                 ALA 
                 53 c3 
                 −0.3000 
                 165 
               
               
                 HB1 
                 54.534633636 
                 33.449993134 
                 67.949513843 
                 ALA 
                 53 h 
                 0.1000 
                 166 
               
               
                 HB2 
                 55.742454529 
                 34.720954895 
                 67.688003540 
                 ALA 
                 53 h 
                 0.1000 
                 167 
               
               
                 HB3 
                 55.500236511 
                 34.068145752 
                 69.316299435 
                 ALA 
                 53 h 
                 0.1000 
                 165 
               
               
                 H 
                 52.528435568 
                 34.519321442 
                 70.670552661 
                 PRO 
                 54 h 
                 −0.4200 
                 169 
               
               
                 CA 
                 51.258402557 
                 33.944232941 
                 71.268875122 
                 PRO 
                 54 ca 
                 0.0600 
                 170 
               
               
                 HA 
                 50.560397339 
                 33.194515228 
                 70.573081970 
                 PRO 
                 54 h 
                 0.1000 
                 171 
               
               
                 CD 
                 53.678298950 
                 34.513732910 
                 71.601514270 
                 PRO 
                 54 c2 
                 0.0600 
                 172 
               
               
                 HD1 
                 54.146690369 
                 35.509193420 
                 71.717323303 
                 PRO 
                 54 h 
                 0.1000 
                 173 
               
               
                 HD2 
                 54.456559589 
                 33.804157775 
                 71.264945954 
                 PRO 
                 54 h 
                 0.1000 
                 174 
               
               
                 C 
                 50.163700104 
                 34.973747253 
                 71.631501244 
                 PRO 
                 54 c′ 
                 0.3800 
                 175 
               
               
                 O 
                 50.381851136 
                 36.156935425 
                 71.709472650 
                 PRO 
                 54 o′ 
                 −0.3800 
                 176 
               
               
                 CB 
                 51.868888855 
                 33.209735870 
                 72.497510364 
                 PRO 
                 54 c2 
                 −0.2000 
                 177 
               
               
                 HB1 
                 51.140216527 
                 33.071922302 
                 73.319641113 
                 PRO 
                 54 h 
                 0.1000 
                 178 
               
               
                 HB2 
                 52.201725006 
                 32.193626404 
                 72.207275391 
                 PRO 
                 43 h 
                 0.1000 
                 179 
               
               
                 CG 
                 53.074722290 
                 34.047100067 
                 72.925216675 
                 PRO 
                 54 c2 
                 −0.2000 
                 180 
               
               
                 HG1 
                 52.742275235 
                 34.920612335 
                 73.520271301 
                 PRO 
                 54 h 
                 0.1000 
                 181 
               
               
                 HG2 
                 53.794158936 
                 33.482940674 
                 73.547462463 
                 PRO 
                 54 h 
                 0.1000 
                 182 
               
               
                 N 
                 48.950717926 
                 34.451953345 
                 71.882225037 
                 GLY 
                 55 h 
                 −0.5000 
                 183 
               
               
                 CA 
                 47.799011230 
                 35.264900208 
                 72.354157012 
                 GLY 
                 55 cg 
                 0.2000 
                 184 
               
               
                 HN 
                 48.913242340 
                 33.427757262 
                 71.533122253 
                 GLY 
                 55 hn 
                 0.2800 
                 185 
               
               
                 HA1 
                 47.529734802 
                 36.291049957 
                 71.943451445 
                 GLY 
                 55 h 
                 0.1000 
                 186 
               
               
                 HA2 
                 46.873668621 
                 34.838525226 
                 71.925056975 
                 GLY 
                 55 h 
                 0.1000 
                 187 
               
               
                 C 
                 47.624210355 
                 35.262092590 
                 73.898422241 
                 GLY 
                 55 c′ 
                 0.3800 
                 188 
               
               
                 O 
                 47.184692353 
                 34.228916165 
                 74.411125183 
                 GLY 
                 55 o′ 
                 −0.3800 
                 189 
               
               
                 N 
                 47.910079956 
                 36.345748901 
                 74.679351507 
                 PRO 
                 56 n 
                 −0.4200 
                 190 
               
               
                 CA 
                 47.789894104 
                 36.319248199 
                 76.162750244 
                 PRO 
                 56 ca 
                 0.0600 
                 191 
               
               
                 HA 
                 48.177116394 
                 35.361667633 
                 76.567420959 
                 PRO 
                 56 h 
                 0.1000 
                 192 
               
               
                 CD 
                 48.602729797 
                 37.547939301 
                 74.184952300 
                 PRO 
                 56 c2 
                 0.0600 
                 193 
               
               
                 HD1 
                 48.046642303 
                 35.065422058 
                 73.380996704 
                 PRO 
                 56 h 
                 0.1000 
                 194 
               
               
                 HD2 
                 49.595470428 
                 37.261715750 
                 73.794556152 
                 PRO 
                 56 h 
                 0.1000 
                 195 
               
               
                 C 
                 46.326736450 
                 36.529109955 
                 76.663719177 
                 PRO 
                 56 c′ 
                 0.3800 
                 196 
               
               
                 O 
                 45.857757568 
                 37.657508850 
                 76.842526843 
                 PRO 
                 56 o′ 
                 4.2800 
                 197 
               
               
                 CB 
                 48.777050018 
                 37.430667577 
                 76.578651428 
                 PRO 
                 56 c2 
                 4.2000 
                 198 
               
               
                 HB1 
                 48.524734497 
                 37.895471832 
                 77.549573352 
                 PRO 
                 56 h 
                 0.1000 
                 199 
               
               
                 HB2 
                 49.795513153 
                 37.009433746 
                 76.691307068 
                 PRO 
                 56 h 
                 0.1000 
                 200 
               
               
                 CG 
                 48.752750397 
                 35.431644440 
                 75.422836304 
                 PRO 
                 56 c2 
                 −0.2000 
                 201 
               
               
                 HG1 
                 47.879917145 
                 39.105595450 
                 75.522354126 
                 PRO 
                 56 h 
                 0.1000 
                 202 
               
               
                 HG2 
                 49.655212402 
                 39.069591522 
                 75.391311646 
                 PRO 
                 56 h 
                 0.1000 
                 203 
               
               
                 N 
                 45.616943359 
                 35.415058136 
                 76.897827148 
                 HIS 
                 57 n 
                 −0.5000 
                 204 
               
               
                 HN 
                 46.014194489 
                 34.579135895 
                 76.450401306 
                 HIS 
                 57 hn 
                 0.2500 
                 205 
               
               
                 CA 
                 44.212440491 
                 35.434158325 
                 77.393567493 
                 HIS 
                 57 ca 
                 0.1100 
                 206 
               
               
                 HA 
                 43.635601044 
                 36.135776520 
                 76.762800753 
                 HIS 
                 57 h 
                 0.1000 
                 207 
               
               
                 C 
                 44.146274567 
                 35.852919312 
                 75.904235540 
                 HIS 
                 57 c′ 
                 0.3800 
                 208 
               
               
                 O 
                 44.715753815 
                 35.174930573 
                 79.742973325 
                 HIS 
                 57 o′ 
                 −0.3800 
                 209 
               
               
                 CB 
                 43.577262578 
                 34.025093079 
                 77.198188782 
                 HIS 
                 57 c2 
                 −0.2000 
                 210 
               
               
                 HB1 
                 44.242053986 
                 33.250709534 
                 77.626457732 
                 HIS 
                 57 h 
                 0.1000 
                 211 
               
               
                 HB2 
                 42.665222165 
                 33.964206696 
                 77.822631536 
                 HIS 
                 57 h 
                 0.1000 
                 212 
               
               
                 CG 
                 43.190551758 
                 33.606594056 
                 75.770996094 
                 HIS 
                 57 c5 
                 0.1000 
                 213 
               
               
                 HD1 
                 44.099815216 
                 33.724720001 
                 74.654500415 
                 HIS 
                 57 np 
                 −0.4200 
                 214 
               
               
                 CE1 
                 43.220783234 
                 33.103317261 
                 73.724327087 
                 HIS 
                 57 c5 
                 0.2700 
                 215 
               
               
                 HE1 
                 42.000507355 
                 32.603566577 
                 74.087806702 
                 HIS 
                 57 np 
                 0.5000 
                 216 
               
               
                 CD2 
                 42.008693695 
                 32.921348572 
                 75.433784485 
                 HIS 
                 57 c5 
                 0.0100 
                 217 
               
               
                 HE1 
                 43.579235077 
                 32.995296475 
                 72.708923340 
                 HIS 
                 57 h 
                 0.1300 
                 218 
               
               
                 HE2 
                 41.324546514 
                 32.061363220 
                 73.538429260 
                 HIS 
                 57 hn 
                 0.2500 
                 219 
               
               
                 HD2 
                 41.238662720 
                 32.635732910 
                 76.138023376 
                 HIS 
                 57 h 
                 0.1300 
                 220 
               
               
                 N 
                 43.493415833 
                 37.014365150 
                 79.314620972 
                 PRO 
                 58 n 
                 −0.4200 
                 221 
               
               
                 CA 
                 43.576023102 
                 37.521991730 
                 80.713310242 
                 PRO 
                 58 ca 
                 0.0600 
                 222 
               
               
                 HA 
                 44.640773772 
                 37.575522258 
                 82.019523621 
                 PRO 
                 58 h 
                 0.1000 
                 233 
               
               
                 CD 
                 42.828823090 
                 37.960189519 
                 75.395561215 
                 PRO 
                 58 c2 
                 0.0600 
                 224 
               
               
                 HD1 
                 42.088195801 
                 37.471439362 
                 77.735352080 
                 PRO 
                 58 h 
                 0.1000 
                 225 
               
               
                 HD2 
                 43.573791504 
                 35.467678070 
                 77.749885559 
                 PRO 
                 58 h 
                 0.1000 
                 226 
               
               
                 C 
                 42.782455444 
                 36.660888672 
                 81.747703552 
                 PRO 
                 55 c′ 
                 0.2500 
                 227 
               
               
                 O 
                 41.546211243 
                 36.662254851 
                 81.766304016 
                 PRO 
                 58 o′ 
                 −0.3800 
                 228 
               
               
                 CB 
                 43.067096710 
                 38.972381592 
                 80.563407898 
                 PRO 
                 58 c2 
                 −0.2000 
                 229 
               
               
                 HB1 
                 42.553604126 
                 39.355644226 
                 81.465919495 
                 PRO 
                 58 h 
                 0.1000 
                 230 
               
               
                 HB2 
                 43.922630310 
                 39.652961731 
                 80.282720947 
                 PRO 
                 58 h 
                 0.1000 
                 231 
               
               
                 CG 
                 42.156223297 
                 35.958541870 
                 79.333923340 
                 PRO 
                 58 c2 
                 −0.0200 
                 232 
               
               
                 HG1 
                 41.146640778 
                 38.599040985 
                 79.611282349 
                 PRO 
                 58 h 
                 0.1000 
                 233 
               
               
                 HG2 
                 42.036239624 
                 39.956802365 
                 75.571780396 
                 PRO 
                 58 h 
                 0.1010 
                 234 
               
               
                 N 
                 43.511478424 
                 35.934525351 
                 82.617271423 
                 ALA 
                 59 n 
                 −0.5000 
                 235 
               
               
                 HN 
                 44.509765625 
                 35.905010233 
                 82.256589050 
                 ALA 
                 59 hn 
                 0.2800 
                 236 
               
               
                 CA 
                 42.913761139 
                 34.928112030 
                 83.544029236 
                 ALA 
                 59 ca 
                 0.1200 
                 237 
               
               
                 HA 
                 42.154701233 
                 34.341350555 
                 82.987930298 
                 ALA 
                 59 h 
                 0.1000 
                 238 
               
               
                 C 
                 42.151308746 
                 35.481468201 
                 84.521502656 
                 ALA 
                 59 c′ 
                 0.2800 
                 239 
               
               
                 O 
                 42.459964752 
                 35.112228394 
                 85.965652466 
                 ALA 
                 59 o′ 
                 −0.3800 
                 240 
               
               
                 CB 
                 44.063701630 
                 33.948829651 
                 83.858291626 
                 ALA 
                 59 c3 
                 −0.3000 
                 241 
               
               
                 HB1 
                 43.708641052 
                 33.104522705 
                 84.478195190 
                 ALA 
                 59 h 
                 0.1000 
                 242 
               
               
                 HB2 
                 44.502014160 
                 33.503505707 
                 82.944122314 
                 ALA 
                 59 h 
                 0.1000 
                 243 
               
               
                 HB3 
                 44.882900238 
                 34.433902740 
                 84.422813416 
                 ALA 
                 59 h 
                 0.1000 
                 244 
               
               
                 N 
                 41.178901672 
                 36.333106995 
                 84.577079773 
                 ALA 
                 60 n 
                 −0.5000 
                 245 
               
               
                 HN 
                 41.112052917 
                 36.562049866 
                 83.573013306 
                 ALA 
                 60 hn 
                 0.2800 
                 246 
               
               
                 CA 
                 40.189502716 
                 36.803413391 
                 85.578857422 
                 ALA 
                 60 ca 
                 0.1200 
                 247 
               
               
                 HA 
                 40.008514404 
                 35.981742559 
                 86.302818298 
                 ALA 
                 60 h 
                 0.1000 
                 248 
               
               
                 C 
                 38.811019597 
                 37.037807465 
                 84.860046387 
                 ALA 
                 60 c′ 
                 0.3800 
                 249 
               
               
                 O 
                 37.881835938 
                 36.301105499 
                 85.205276489 
                 ALA 
                 60 o′ 
                 −0.3800 
                 250 
               
               
                 CB 
                 40.746566772 
                 37.985549927 
                 86.401313782 
                 ALA 
                 60 c3 
                 −0.3000 
                 251 
               
               
                 HB1 
                 39.997776031 
                 38.372333527 
                 87.116531372 
                 ALA 
                 60 h 
                 0.1000 
                 252 
               
               
                 HB2 
                 41.624504089 
                 37.670467377 
                 86.996170044 
                 ALA 
                 60 h 
                 0.1000 
                 253 
               
               
                 HB3 
                 41.079444585 
                 38.830841064 
                 85.774902344 
                 ALA 
                 60 h 
                 0.1000 
                 254 
               
               
                 N 
                 38.609931946 
                 37.922218323 
                 83.826889035 
                 PRO 
                 61 n 
                 −0.4200 
                 255 
               
               
                 CA 
                 37.398490906 
                 37.873073578 
                 82.950836182 
                 PRO 
                 61 ca 
                 0.0600 
                 256 
               
               
                 HA 
                 36.485267638 
                 37.839759827 
                 83.576164246 
                 PRO 
                 61 h 
                 0.1000 
                 257 
               
               
                 CD 
                 39.352070615 
                 39.001556396 
                 83.460945129 
                 PRO 
                 61 c2 
                 0.0600 
                 258 
               
               
                 HD1 
                 40.590957642 
                 38.653537750 
                 83.311111430 
                 PRO 
                 61 h 
                 0.1000 
                 259 
               
               
                 HD2 
                 39.564567512 
                 39.780746460 
                 84.247795105 
                 PRO 
                 61 h 
                 0.1000 
                 260 
               
               
                 C 
                 37.256752532 
                 36.700027466 
                 81.909835515 
                 PRO 
                 61 c′ 
                 0.3800 
                 261 
               
               
                 O 
                 36.243316650 
                 36.657413483 
                 81.209106445 
                 PRO 
                 61 o′ 
                 −0.3800 
                 262 
               
               
                 CB 
                 37.477272034 
                 39.256717652 
                 82.271400452 
                 PRO 
                 61 c2 
                 −0.2000 
                 263 
               
               
                 HB1 
                 36.964195251 
                 39.298637390 
                 81.290786743 
                 PRO 
                 61 h 
                 0.1000 
                 264 
               
               
                 HB2 
                 36.951357574 
                 40.016944885 
                 82.906776425 
                 PRO 
                 61 h 
                 0.1000 
                 265 
               
               
                 CG 
                 38.972518921 
                 39.562160492 
                 82.163795471 
                 PRO 
                 61 c2 
                 −0.2000 
                 266 
               
               
                 HG1 
                 39.409160614 
                 39.034259796 
                 81.293624578 
                 PRO 
                 61 h 
                 0.1000 
                 267 
               
               
                 HG2 
                 39.183399200 
                 40.640045166 
                 82.032295227 
                 PRO 
                 61 h 
                 0.1000 
                 268 
               
               
                 N 
                 38.213741302 
                 35.753643036 
                 81.804443359 
                 SER 
                 62 n 
                 −0.5000 
                 269 
               
               
                 CA 
                 38.144962311 
                 34.600208282 
                 80.863403320 
                 SER 
                 62 ca 
                 0.1200 
                 270 
               
               
                 HN 
                 39.020967804 
                 35.895751953 
                 82.434890747 
                 SER 
                 62 hn 
                 0.2800 
                 271 
               
               
                 HA 
                 37.892318726 
                 34.983673096 
                 79.856529236 
                 SER 
                 62 h 
                 0.1000 
                 272 
               
               
                 C 
                 37.055021973 
                 31.324326324 
                 81.273231506 
                 SER 
                 62 c′ 
                 0.3800 
                 273 
               
               
                 O 
                 37.352454436 
                 32.625560760 
                 82.070343018 
                 SER 
                 62 o′ 
                 0.3800 
                 274 
               
               
                 CB 
                 39.569152532 
                 33.994293213 
                 80.760513306 
                 SER 
                 62 c2 
                 −0.1700 
                 275 
               
               
                 HB1 
                 39.601100922 
                 33.242229462 
                 79.949050903 
                 SER 
                 62 h 
                 0.1000 
                 276 
               
               
                 HB2 
                 40.217050934 
                 34.759819031 
                 80.475799561 
                 SER 
                 62 h 
                 0.1000 
                 277 
               
               
                 CG 
                 39.955038330 
                 33.367904663 
                 81.986091614 
                 SER 
                 62 oh 
                 0.1000 
                 278 
               
               
                 HG 
                 39.157264709 
                 32.925077698 
                 82.316406250 
                 SER 
                 62 ho 
                 0.3500 
                 279 
               
               
                 N 
                 35.853912254 
                 33.643447876 
                 80.748901367 
                 SER 
                 63 n 
                 −0.5000 
                 280 
               
               
                 CA 
                 34.681579590 
                 32.893772125 
                 81.280097961 
                 SER 
                 63 ca 
                 0.1200 
                 251 
               
               
                 HN 
                 35.734226227 
                 34.507610321 
                 80.200576782 
                 SER 
                 63 hn 
                 0.2800 
                 282 
               
               
                 HA 
                 34.978878021 
                 32.281963345 
                 82.158424377 
                 SER 
                 63 h 
                 0.1000 
                 283 
               
               
                 C 
                 34.028987885 
                 31.963005066 
                 80.214455165 
                 SER 
                 63 c′ 
                 0.3800 
                 254 
               
               
                 O 
                 33.624385534 
                 32.404701233 
                 79.134857178 
                 SER 
                 63 o′ 
                 −0.3800 
                 285 
               
               
                 CB 
                 33.674541473 
                 33.937455035 
                 81.815757751 
                 SER 
                 63 c2 
                 −0.1700 
                 286 
               
               
                 HB1 
                 34.172107697 
                 34.614356995 
                 82.538948059 
                 SER 
                 63 h 
                 0.1000 
                 287 
               
               
                 HB2 
                 33.303077695 
                 34.594402313 
                 81.003784180 
                 SER 
                 63 h 
                 0.1000 
                 238 
               
               
                 CG 
                 31.576236725 
                 33.301517487 
                 82.471984863 
                 SER 
                 63 oh 
                 −0.3800 
                 289 
               
               
                 HG 
                 32.084590912 
                 32.806625366 
                 81.807708740 
                 SER 
                 63 ho 
                 0.3500 
                 290 
               
               
                 N 
                 33.852622986 
                 30.677625656 
                 80.556045532 
                 TRP 
                 64 n 
                 −0.5000 
                 291 
               
               
                 CA 
                 33.070865631 
                 29.709415436 
                 79.732810974 
                 TRP 
                 64 ca 
                 0.1200 
                 292 
               
               
                 HN 
                 34.153343201 
                 30.435497254 
                 81.506057739 
                 TRP 
                 64 hn 
                 0.2800 
                 293 
               
               
                 HA 
                 33.375720978 
                 29.840501785 
                 78.676765442 
                 TRP 
                 64 h 
                 0.1000 
                 294 
               
               
                 C 
                 31.526346207 
                 29.958730698 
                 79.816452026 
                 TRP 
                 64 c′ 
                 0.3800 
                 295 
               
               
                 O 
                 30.936735153 
                 29.911306351 
                 80.900970459 
                 TRP 
                 64 o′ 
                 −0.3800 
                 296 
               
               
                 CB 
                 33.498536517 
                 25.253648758 
                 80.086425751 
                 TRP 
                 64 c2 
                 −0.2000 
                 297 
               
               
                 HB1 
                 32.936897276 
                 27.550512314 
                 79.442245483 
                 TRP 
                 64 h 
                 0.1000 
                 298 
               
               
                 HB2 
                 34.548812566 
                 28.110004426 
                 79.767990112 
                 TRP 
                 64 h 
                 0.1000 
                 299 
               
               
                 CG 
                 33.372635702 
                 27.788063049 
                 81.551361084 
                 TRP 
                 64 c5 
                 0.0000 
                 300 
               
               
                 CD1 
                 32.236022969 
                 27.198472977 
                 82.145393372 
                 TRP 
                 64 c5 
                 0.0100 
                 301 
               
               
                 HE1 
                 32.442039490 
                 26.926628113 
                 83.513259888 
                 TRP 
                 64 np 
                 −0.5000 
                 302 
               
               
                 CE2 
                 33.734771729 
                 27.365074158 
                 83.750877380 
                 TRP 
                 64 c5 
                 0.1100 
                 303 
               
               
                 CD2 
                 34.313194275 
                 27.855219574 
                 82.565856934 
                 TRP 
                 64 c5 
                 0.0000 
                 304 
               
               
                 HD1 
                 31.305589935 
                 27.011001587 
                 81.622375485 
                 TRP 
                 64 h 
                 0.1000 
                 305 
               
               
                 HE1 
                 31.781488419 
                 26.532098770 
                 84.192108154 
                 TRP 
                 64 hn 
                 0.2800 
                 306 
               
               
                 CE3 
                 35.633460999 
                 28.410655975 
                 85.581642151 
                 TRP 
                 64 cp 
                 −0.1000 
                 307 
               
               
                 HE3 
                 36.086208344 
                 25.812973022 
                 81.656943054 
                 TRP 
                 64 h 
                 0.1000 
                 308 
               
               
                 CZ3 
                 36.338203430 
                 28.401332855 
                 83.786201477 
                 TRP 
                 64 cp 
                 −0.1000 
                 309 
               
               
                 HZ3 
                 37.342418671 
                 28.800062180 
                 83.816750090 
                 TRP 
                 64 h 
                 0.1000 
                 310 
               
               
                 CH2 
                 35.766292572 
                 27.887487411 
                 84.956939697 
                 TRP 
                 64 cp 
                 −0.1000 
                 311 
               
               
                 HH2 
                 36.336753845 
                 27.895225525 
                 85.875114441 
                 TRP 
                 64 h 
                 0.1000 
                 312 
               
               
                 CZ2 
                 34.469055176 
                 27.367534637 
                 84.959693909 
                 TRP 
                 64 cp 
                 −0.1000 
                 313 
               
               
                 HZ2 
                 34.033626556 
                 26.978825430 
                 85.868453979 
                 TRP 
                 64 h 
                 0.1000 
                 314 
               
               
                 N 
                 30.884126663 
                 30.253189087 
                 78.672058105 
                 GLY 
                 65 n 
                 −0.5000 
                 315 
               
               
                 CA 
                 29.433704376 
                 30.522933426 
                 78.625785828 
                 GLY 
                 54 cg 
                 0.0200 
                 316 
               
               
                 HN 
                 31.490442276 
                 30.324731827 
                 77.837860107 
                 GLY 
                 65 hn 
                 0.2800 
                 317 
               
               
                 HA1 
                 29.049486160 
                 30.927183151 
                 79.604759216 
                 GLY 
                 65 h 
                 0.1000 
                 318 
               
               
                 HA2 
                 29.301883698 
                 31.462034225 
                 77.967575073 
                 GLY 
                 65 h 
                 0.1000 
                 319 
               
               
                 C 
                 28.566276550 
                 29.436250687 
                 78.049354553 
                 GLY 
                 65 c′ 
                 0.3800 
                 320 
               
               
                 O 
                 28.476503372 
                 29.383417130 
                 76.820671082 
                 GLY 
                 65 o′ 
                 −0.3800 
                 321 
               
               
                 N 
                 27.919076920 
                 28.520057678 
                 78.830680847 
                 PRO 
                 66 n 
                 −0.4200 
                 322 
               
               
                 CA 
                 27.254582451 
                 27.307062149 
                 78.266265869 
                 PRO 
                 66 ca 
                 0.0600 
                 323 
               
               
                 HA 
                 28.007204056 
                 26.749544144 
                 77.674018860 
                 PRO 
                 66 h 
                 0.1000 
                 324 
               
               
                 CD 
                 27.931732178 
                 28.547025681 
                 80.307373047 
                 PRO 
                 66 c2 
                 0.0600 
                 325 
               
               
                 MD1 
                 27.674114227 
                 29.536535263 
                 80.727989197 
                 PRO 
                 66 h 
                 0.1000 
                 326 
               
               
                 MD2 
                 28.930458069 
                 28.264209747 
                 80.693565369 
                 PRO 
                 66 h 
                 0.1000 
                 327 
               
               
                 C 
                 25.991449356 
                 27.540506363 
                 77.367637634 
                 PRO 
                 66 c′ 
                 0.3800 
                 328 
               
               
                 O 
                 25.234470367 
                 28.498056412 
                 77.550445557 
                 PRO 
                 66 o′ 
                 −0.3800 
                 329 
               
               
                 CB 
                 26.947065353 
                 26.487516403 
                 79.540168762 
                 PRO 
                 66 c2 
                 −0.2000 
                 330 
               
               
                 HB1 
                 26.021696091 
                 25.883453369 
                 79.667781067 
                 PRO 
                 66 h 
                 0.1000 
                 331 
               
               
                 HB2 
                 27.765922546 
                 25.768106561 
                 79.730659485 
                 PRO 
                 66 h 
                 0.1000 
                 332 
               
               
                 CG 
                 26.879997253 
                 27.505201340 
                 80.680580139 
                 PRO 
                 66 c2 
                 −0.2000 
                 333 
               
               
                 HG1 
                 25.878761292 
                 27.974497401 
                 80.712356567 
                 PRO 
                 66 h 
                 0.1000 
                 334 
               
               
                 HG2 
                 27.057765961 
                 27.053478241 
                 81.674545288 
                 PRO 
                 66 h 
                 0.1000 
                 335 
               
               
                 N 
                 25.764133453 
                 26.624628067 
                 76.406608582 
                 CYS 
                 67 n 
                 −0.5000 
                 336 
               
               
                 CA 
                 24.578670502 
                 26.665664673 
                 75.512832642 
                 CYS 
                 67 ca 
                 0.1200 
                 337 
               
               
                 HN 
                 26.474828720 
                 25.893449783 
                 76.320098877 
                 CYS 
                 67 hn 
                 0.2800 
                 338 
               
               
                 HA 
                 24.437746048 
                 27.701400757 
                 75.152099609 
                 CYS 
                 67 h 
                 0.1000 
                 339 
               
               
                 C 
                 23.256376266 
                 26.130277634 
                 76.174392700 
                 CYS 
                 67 c′ 
                 0.3800 
                 340 
               
               
                 O 
                 23.219629288 
                 24.940492630 
                 76.516906738 
                 CYS 
                 67 o′ 
                 −0.3800 
                 341 
               
               
                 CB 
                 24.900175095 
                 25.819908432 
                 74.260444641 
                 CYS 
                 67 c2 
                 −0.3000 
                 342 
               
               
                 HB1 
                 25.807971954 
                 26.178848267 
                 73.749794106 
                 CYS 
                 67 h 
                 0.1000 
                 343 
               
               
                 HB2 
                 25.105169296 
                 24.761932373 
                 74.532623291 
                 CYS 
                 67 h 
                 0.1000 
                 344 
               
               
                 CG 
                 23.472158432 
                 25.844451904 
                 73.133270264 
                 CYS 
                 67 s1 
                 0.1000 
                 345 
               
               
                 N 
                 22.124137878 
                 26.895683289 
                 76.264381409 
                 PRO 
                 68 n 
                 −0.4200 
                 346 
               
               
                 CA 
                 20.786550522 
                 26.297697067 
                 76.829830933 
                 PRO 
                 69 ca 
                 0.0600 
                 347 
               
               
                 HA 
                 20.877141953 
                 25.506265650 
                 77.300582886 
                 PRO 
                 68 h 
                 0.1000 
                 348 
               
               
                 CD 
                 22.161409378 
                 28.364057541 
                 76.432929993 
                 PRO 
                 68 c2 
                 0.0600 
                 349 
               
               
                 HB1 
                 22.628620148 
                 28.901371002 
                 75.585960388 
                 PRO 
                 68 h 
                 0.1000 
                 350 
               
               
                 HB2 
                 22.732339859 
                 28.631174088 
                 77.345329285 
                 PRO 
                 68 h 
                 0.1000 
                 351 
               
               
                 C 
                 20.190311432 
                 25.593938828 
                 75.255737305 
                 PRO 
                 68 c′ 
                 0.3800 
                 352 
               
               
                 O 
                 20.566764832 
                 24.451507568 
                 74.984413147 
                 PRO 
                 68 o′ 
                 −0.3800 
                 353 
               
               
                 CB 
                 20.033475876 
                 27.483673096 
                 77.173645020 
                 PRO 
                 68 c2 
                 −0.2000 
                 354 
               
               
                 HB1 
                 18.940057755 
                 27.449979782 
                 77.017181396 
                 PRO 
                 68 h 
                 0.1000 
                 355 
               
               
                 HB2 
                 20.183664322 
                 27.458950043 
                 78.271354675 
                 PRO 
                 68 h 
                 0.1000 
                 356 
               
               
                 CG 
                 20.687761307 
                 28.746078491 
                 76.604209900 
                 PRO 
                 68 c2 
                 −0.2000 
                 357 
               
               
                 HG1 
                 20.234010696 
                 29.017192841 
                 75.632743835 
                 PRO 
                 68 h 
                 0.1000 
                 358 
               
               
                 HG2 
                 20.559530258 
                 29.623554230 
                 77.265640259 
                 PRO 
                 68 h 
                 0.1000 
                 359 
               
               
                 N 
                 19.297069550 
                 26.226366043 
                 74.460205078 
                 ARG+ 
                 69 n 
                 −0.5000 
                 360 
               
               
                 CA 
                 18.727945328 
                 25.594141006 
                 73.229873657 
                 ARG+ 
                 69 ca 
                 0.1200 
                 361 
               
               
                 HN 
                 18.899488449 
                 27.074655533 
                 74.874603271 
                 ARG+ 
                 69 hn 
                 0.2800 
                 362 
               
               
                 HA 
                 19.468439102 
                 24.889890671 
                 72.798027039 
                 ARG+ 
                 69 h 
                 0.1000 
                 363 
               
               
                 C 
                 18.426181793 
                 26.666866302 
                 72.127845764 
                 ARG+ 
                 69 c′ 
                 0.3800 
                 364 
               
               
                 O 
                 17.302417755 
                 27.170328140 
                 72.057907104 
                 ARG+ 
                 69 o′ 
                 −0.3800 
                 365 
               
               
                 CB 
                 17.487716675 
                 24.741283417 
                 73.645401001 
                 ARG+ 
                 69 c2 
                 −0.2000 
                 366 
               
               
                 HB1 
                 17.790594101 
                 24.038330078 
                 74.447227478 
                 ARG+ 
                 69 h 
                 0.1100 
                 367 
               
               
                 HB2 
                 16.742151260 
                 25.409061432 
                 74.119949341 
                 ARG+ 
                 69 h 
                 0.1100 
                 368 
               
               
                 CG 
                 16.806570053 
                 23.930654526 
                 72.510940552 
                 ARG+ 
                 69 c2 
                 −0.2000 
                 369 
               
               
                 HG1 
                 16.500089645 
                 24.624885559 
                 71.702163696 
                 ARG+ 
                 69 h 
                 0.1300 
                 370 
               
               
                 HG2 
                 17.539186478 
                 23.235509872 
                 72.053100586 
                 ARG+ 
                 69 h 
                 0.1300 
                 371 
               
               
                 CD 
                 15.574314117 
                 23.148860931 
                 73.007453918 
                 ARG+ 
                 69 c2 
                 −0.0900 
                 372 
               
               
                 HD1 
                 15.890284538 
                 27.374292374 
                 73.738624573 
                 ARG+ 
                 69 h 
                 0.1300 
                 373 
               
               
                 HD2 
                 14.902976036 
                 23.843069077 
                 73.554016113 
                 ARG+ 
                 69 h 
                 0.1300 
                 374 
               
               
                 HZ 
                 14.865127563 
                 22.521680832 
                 71.855873108 
                 ARG+ 
                 69 n1 
                 −0.5000 
                 375 
               
               
                 HE 
                 15.293711662 
                 22.507183075 
                 70.926025391 
                 ARG+ 
                 69 hn 
                 0.3600 
                 376 
               
               
                 CZ 
                 13.645489693 
                 21.980854034 
                 71.902374268 
                 ARG+ 
                 69 cr 
                 0.4500 
                 377 
               
               
                 NH1 
                 13.127552986 
                 21.522832870 
                 70.798370361 
                 ARG+ 
                 69 n2 
                 −0.5000 
                 378 
               
               
                 NH11 
                 13.689088821 
                 21.608518620 
                 69.948852539 
                 ARG+ 
                 69 hn 
                 0.3600 
                 379 
               
               
                 NH12 
                 12.188611031 
                 21.122539520 
                 70.853851318 
                 ARG+ 
                 69 hn 
                 0.3600 
                 380 
               
               
                 HN2 
                 12.936479568 
                 21.886768341 
                 73.000465393 
                 ARG+ 
                 69 n2 
                 −0.500 
                 381 
               
               
                 NH21 
                 12.008401871 
                 21.462900162 
                 72.952354431 
                 ARG+ 
                 69 hn 
                 0.3600 
                 382 
               
               
                 NH22 
                 13.405644417 
                 22.251142502 
                 73.831558228 
                 ARG+ 
                 69 hn 
                 0.3600 
                 383 
               
               
                 N 
                 19.430337904 
                 26.966600418 
                 71.273384094 
                 ARG+ 
                 70 n 
                 −0.5000 
                 384 
               
               
                 CA 
                 19.316965103 
                 27.784936905 
                 70.016807556 
                 ARG+ 
                 70 ca 
                 0.1200 
                 385 
               
               
                 HW 
                 20.317523956 
                 26.522159576 
                 71.527793884 
                 ARG+ 
                 70 hn 
                 0.2800 
                 386 
               
               
                 HA 
                 19.139877319 
                 27.013025284 
                 69.241798401 
                 ARG+ 
                 70 h 
                 0.1000 
                 387 
               
               
                 C 
                 20.690151215 
                 28.397680283 
                 69.573341370 
                 ARG+ 
                 70 c′ 
                 0.3800 
                 385 
               
               
                 O 
                 21.267679214 
                 27.963806152 
                 68.579154968 
                 ARG+ 
                 70 o′ 
                 −0.3800 
                 389 
               
               
                 CB 
                 18.103752136 
                 28.753581454 
                 69.796676636 
                 AR0+ 
                 70 c2 
                 −0.2000 
                 390 
               
               
                 HB1 
                 18.134477615 
                 29.133897751 
                 68.754875153 
                 ARG+ 
                 70 h 
                 0.1100 
                 391 
               
               
                 HB2 
                 17.153977127 
                 25.135446545 
                 69.816154480 
                 ARG+ 
                 70 h 
                 0.1100 
                 392 
               
               
                 CG 
                 17.944366455 
                 29.552959061 
                 70.767364502 
                 ARG+ 
                 70 c2 
                 −0.2000 
                 393 
               
               
                 HG1 
                 18.201717377 
                 29.630409241 
                 71.795295715 
                 ARG+ 
                 70 h 
                 0.1300 
                 394 
               
               
                 HG2 
                 18.686578751 
                 30.737569809 
                 70.523498535 
                 ARG+ 
                 70 h 
                 0.1300 
                 395 
               
               
                 CD 
                 16.516407013 
                 30.528032303 
                 70.757499695 
                 ARG+ 
                 70 c2 
                 −0.0900 
                 396 
               
               
                 HD1 
                 16.205293655 
                 30.812314987 
                 69.732495169 
                 ARG+ 
                 70 h 
                 0.1300 
                 397 
               
               
                 HD2 
                 15.804359436 
                 29.724859238 
                 71.041206360 
                 ARG+ 
                 70 h 
                 0.1300 
                 398 
               
               
                 HE 
                 16.396289825 
                 31.632033883 
                 71.751823425 
                 ARG+ 
                 70 n1 
                 −0.5000 
                 399 
               
               
                 NE 
                 16.351929398 
                 31.418577194 
                 72.754444790 
                 ARG+ 
                 70 hn 
                 0.3600 
                 400 
               
               
                 CE 
                 16.270032883 
                 32.931114197 
                 71.475357056 
                 ARG+ 
                 70 cr 
                 0.4500 
                 401 
               
               
                 HN1 
                 16.119342804 
                 33.758121490 
                 72.470024109 
                 ARG+ 
                 70 n2 
                 −0.5000 
                 402 
               
               
                 HN11 
                 16.097789764 
                 33.352241516 
                 73.407394409 
                 ARG+ 
                 70 hn 
                 0.3600 
                 403 
               
               
                 HN12 
                 16.020824432 
                 34.751869202 
                 72.242614746 
                 ARG+ 
                 70 hn 
                 0.3600 
                 404 
               
               
                 NH2 
                 16.295974731 
                 33.427280426 
                 70.262794495 
                 ARG+ 
                 70 n2 
                 −0.5000 
                 405 
               
               
                 HN21 
                 16.192591263 
                 34.436058562 
                 70.142570496 
                 ARG+ 
                 70 hn 
                 0.3600 
                 406 
               
               
                 HN22 
                 16.439620972 
                 32.732715607 
                 69.527351379 
                 ARG+ 
                 70 hn 
                 0.3600 
                 407 
               
               
                 N 
                 21.215826035 
                 29.506198883 
                 70.104598999 
                 TYRC 
                 71 n 
                 −0.5000 
                 408 
               
               
                 HN 
                 21.692993164 
                 29.961484909 
                 69.319816589 
                 TYRC 
                 71 hn 
                 0.2800 
                 409 
               
               
                 CA 
                 21.037544250 
                 29.469150543 
                 71.348726365 
                 TYRC 
                 71 ca 
                 0.1300 
                 410 
               
               
                 HA 
                 22.727062225 
                 28.601654053 
                 71.296867371 
                 TYRC 
                 71 h 
                 0.1000 
                 411 
               
               
                 C 
                 21.230804443 
                 29.295030594 
                 72.663772583 
                 TYRC 
                 71 c′ 
                 0.4100 
                 412 
               
               
                 CKT 
                 20.420524597 
                 30.105148315 
                 73.113685608 
                 TYRC 
                 71 o′ 
                 −0.3800 
                 413 
               
               
                 C 
                 21.522385052 
                 28.107995987 
                 73.273979187 
                 TYRC 
                 71 ch 
                 −0.3800 
                 414 
               
               
                 HO 
                 20.994127274 
                 28.000011444 
                 74.066841125 
                 TYRC 
                 71 ho 
                 0.3500 
                 415 
               
               
                 CE 
                 22.938613892 
                 30.740638733 
                 71.402084351 
                 TYRC 
                 71 c2 
                 0.2000 
                 416 
               
               
                 HB1 
                 22.321226120 
                 31.652799606 
                 71.283157349 
                 TYRC 
                 71 h 
                 0.1000 
                 417 
               
               
                 HB2 
                 23.363500595 
                 30.553305817 
                 72.420455933 
                 TYRC 
                 71 h 
                 0.1000 
                 418 
               
               
                 CG 
                 24.110603333 
                 30.760416031 
                 70.402580261 
                 TYRC 
                 71 cp 
                 0.000 
                 419 
               
               
                 CD1 
                 23.933057785 
                 31.274461746 
                 69.111869512 
                 TYRC 
                 71 cp 
                 −0.1000 
                 420 
               
               
                 HD1 
                 22.977622986 
                 31.679259164 
                 68.509974670 
                 TYRC 
                 71 h 
                 0.1000 
                 421 
               
               
                 CE1 
                 24.985538483 
                 31.264329910 
                 68.201301575 
                 TYRC 
                 71 cp 
                 −0.1000 
                 422 
               
               
                 HE1 
                 24.833002090 
                 31.650396347 
                 67.203536987 
                 TYRC 
                 71 h 
                 0.1000 
                 423 
               
               
                 CZ 
                 26.227394104 
                 30.757091522 
                 68.577156584 
                 TYRC 
                 71 cp 
                 0.0300 
                 424 
               
               
                 OH 
                 27.265548160 
                 30.762763977 
                 67.686424255 
                 TYRC 
                 71 oh 
                 −0.3800 
                 425 
               
               
                 HN 
                 29.966634750 
                 31.154350798 
                 66.863937378 
                 TYRC 
                 71 ho 
                 0.3500 
                 426 
               
               
                 CE2 
                 26.415199280 
                 30.251981735 
                 69.859985352 
                 TYRC 
                 71 cp 
                 −0.1000 
                 427 
               
               
                 HE2 
                 27.377700806 
                 29.852491379 
                 70.147377014 
                 TYRC 
                 71 h 
                 0.1000 
                 428 
               
               
                 CD2 
                 25.360828400 
                 30.253871918 
                 70.770927429 
                 TYRC 
                 71 cp 
                 −0.1000 
                 429 
               
               
                 HD2 
                 25.521846771 
                 29.846044540 
                 71.760574341 
                 TYRC 
                 71 h 
                 0.1000 
                 430 
               
               
                   
               
               
                 *The numbering of the amino acids is shifted by minus 6 relative to the sequence SEQ ID No. 1  
               
             
          
         
       
     
     
       
         
           
             8 
           
           
             
               476 amino acids 
               amino acid 
               single 
               linear 
             
             
               protein 
             
              1
Leu Gln Pro Gly Ala Glu Val Pro Val Val Trp Ala Gln Glu Gly Ala
1               5                   10                  15
Pro Ala Gln Leu Pro Cys Ser Pro Thr Ile Pro Leu Gln Asp Leu Ser
            20                  25                  30
Leu Leu Arg Arg Ala Gly Val Thr Trp Gln His Gln Pro Asp Ser Gly
        35                  40                  45
Pro Pro Ala Ala Ala Pro Gly His Pro Leu Ala Pro Gly Pro His Pro
    50                  55                  60
Ala Ala Pro Ser Ser Trp Gly Pro Arg Pro Arg Arg Tyr Thr Val Leu
65                  70                  75                  80
Ser Val Gly Pro Gly Gly Leu Arg Ser Gly Arg Leu Pro Leu Gln Pro
                85                  90                  95
Arg Val Gln Leu Asp Glu Arg Gly Arg Gln Arg Gly Asp Phe Ser Leu
            100                 105                 110
Trp Leu Arg Pro Ala Arg Arg Ala Asp Ala Gly Glu Tyr Arg Ala Ala
        115                 120                 125
Val His Leu Arg Asp Arg Ala Leu Ser Cys Arg Leu Arg Leu Arg Leu
    130                 135                 140
Gly Gln Ala Ser Met Thr Ala Ser Pro Pro Gly Ser Leu Arg Ala Ser
145                 150                 155                 160
Asp Trp Val Ile Leu Asn Cys Ser Phe Ser Arg Pro Asp Arg Pro Ala
                165                 170                 175
Ser Val His Trp Phe Arg Asn Arg Gly Gln Gly Arg Val Pro Val Arg
            180                 185                 190
Glu Ser Pro His His His Leu Ala Glu Ser Phe Leu Phe Leu Pro Gln
        195                 200                 205
Val Ser Pro Met Asp Ser Gly Pro Trp Gly Cys Ile Leu Thr Tyr Arg
    210                 215                 220
Asp Gly Phe Asn Val Ser Ile Met Tyr Asn Leu Thr Val Leu Gly Leu
225                 230                 235                 240
Glu Pro Pro Thr Pro Leu Thr Val Tyr Ala Gly Ala Gly Ser Arg Val
                245                 250                 255
Gly Leu Pro Cys Arg Leu Pro Ala Gly Val Gly Thr Arg Ser Phe Leu
            260                 265                 270
Thr Ala Lys Trp Thr Pro Pro Gly Gly Gly Pro Asp Leu Leu Val Thr
        275                 280                 285
Gly Asp Asn Gly Asp Phe Thr Leu Arg Leu Glu Asp Val Ser Gln Ala
    290                 295                 300
Gln Ala Gly Thr Tyr Thr Cys His Ile His Leu Gln Glu Gln Gln Leu
305                 310                 315                 320
Asn Ala Thr Val Thr Leu Ala Ile Ile Thr Val Thr Pro Lys Ser Phe
                325                 330                 335
Gly Ser Pro Gly Ser Leu Gly Lys Leu Leu Cys Glu Val Thr Pro Val
            340                 345                 350
Ser Gly Gln Glu Arg Phe Val Trp Ser Ser Leu Asp Thr Pro Ser Gln
        355                 360                 365
Arg Ser Phe Ser Gly Pro Trp Leu Glu Ala Gln Glu Ala Gln Leu Leu
    370                 375                 380
Ser Gln Pro Trp Gln Cys Gln Leu Tyr Gln Gly Glu Arg Leu Leu Gly
385                 390                 395                 400
Ala Ala Val Tyr Phe Thr Glu Leu Ser Ser Pro Gly Ala Gln Arg Ser
                405                 410                 415
Gly Arg Ala Pro Gly Ala Leu Pro Ala Gly His Leu Leu Leu Phe Leu
            420                 425                 430
Thr Leu Gly Val Leu Ser Leu Leu Leu Leu Val Thr Gly Ala Phe Gly
        435                 440                 445
Phe His Leu Trp Arg Arg Gln Trp Arg Pro Arg Arg Phe Ser Ala Leu
    450                 455                 460
Glu Gln Gly Ile His Pro Arg Arg Leu Arg Ala Arg
465                 470                 475
 
           
           
             
               32 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               cDNA 
             
              2
GCGCCTCGAG GCCCAGACCA TAGGAGAGAT GT                                   32
 
           
           
             
               40 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               cDNA 
             
              3
GCGCAGATCT CTCCAGACCC AGAACAGTGA GGTTATACAT                           40
 
           
           
             
               34 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               cDNA 
             
              4
GCGCAGATCT ACCTGGGCTA GACAGCTCTG TGAA                                 34
 
           
           
             
               37 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               cDNA 
             
              5
CGCCGTCGAC CGCTGCCCAG ACCATAGGAG AGATGTG                              37
 
           
           
             
               37 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               cDNA 
             
              6
GCGCGTCGAC TTACATCGAG GCCTGGCCCA GGCGCAG                              37
 
           
           
             
               35 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               cDNA 
             
              7
GCGCGTCGAC TTAACCCAGA ACAGTGAGGT TATAC                                35
 
           
           
             
               35 base pairs 
               nucleic acid 
               single 
               linear 
             
             
               cDNA 
             
              8
GCGCGTCGAC TTAACCTGGG CTAGACAGCT CTGTG                                35