computer modeling in molecular biology.pdf

200 Christopher J Thorpe and David S. Mosstients carry the EBV genome, and in patients with immune dysregulation caused byinfection by EBV, sustained B-cell proliferation occurs. Burkitt’s lymphoma mainlyaffects children or young adults and with modern treatment a long term survival rateof 50% can be expected. In African tumors in the areas of the maxilla and mandiblesare prevalent, but in the Northern Americas abdominal tumors are more common.It is unlikely that EBV infection is the sole causative agent for Burkitt’s lymphoma.Nasopharyngeal cancer is endemic in southern China. As in Burkitt’s lymphoma theEBV genome is found in all tumors but is probably not the sole causative agent, actingin concert with other as yet undetermined factors.Recent evidence has suggested that the Epstein-Barr nuclear antigen 3C (EBNA3C) is the major target for a response directed by HLA-B27 specific T-cells [48]. Thepredominant epitope from EBNA 3C has been elucidated by the standard techniqueof synthesising overlapping peptides from the antigen and mapping the immunodominantepitopes [49]. For HLA-B*2702 and HLA-B*2705 restricted CTLthe immunodominant peptide from EBNA 3C was the nonamer RRIYDLIEL. ForHLA-B*2704 restricted CTL populations RRIYDLIEL was one of several peptidesto which a response was elicited and would appear to be a minor determinant. Theexistence of peptides which bind to several HLA-B27 sub-types has an obvious bearingon the pathogenesis of AS. If a spondylitic peptide is the causative agent for ASit must bind to all HLA-B27 sub-types associated with the disease. HLA-B27 subtypesare quite divergent in the ligands for the C-terminal side chain of the peptide.For HLA-B*2706 and HLA-B*2707 it would appear unlikely that these alleles wouldbe capable of binding large charged residues such as lysine and arginine due to theAsp + Tyr substitution at position 116 of the heavy chain. This aspartate residue appearsto be of paramount importance in binding the charged terminal residue of thepeptide and its substitution to a large residue diminishes the size of the PC bindingpocket. Thus although the polar hydroxyl group of the tyrosine could supporthydrogen bonding it would be impossible from pure steric grounds for this to occur.From this line of thinking it would appear to be a necessity for the AS peptide tohave a non-charged hydrophobic side chain at the PC residue in order to bind to allof the sub-type molecules. Therefore studies of peptides such as the EBNA 3Cepitope aid the overall visualisation of any putative AS peptide. The sequence alignmentof all seven HLA-B27 sub-type molecules (Figure 7-16a) and the schematicdiagram of the HLA-B27 polymorphisms displayed on the structure of HLA-B*2705(Figure 7-16 b) clearly demonstrate the clustering of polymorphic residues in theregion of the class I molecule which binds the C-terminal portion of the peptide.Due to the hydrophobic nature of the majority of the side chains in the EBNA3C peptide (RRIYDLIEL) there are very few noteworthy hydrogen bonding contactsbetween the peptide and the MHC molecule. Lists of contacts observed in the modelsof the EBNA 3C peptide with HLA-B*2705, HLA-B*2702 and HLA-B*2704 is givenin Tables 7-2(a-c). The majority of hydrogen bonding contacts apart from thepreviously mentioned planar bonding network around the arginine residue at P2 are