computer modeling in molecular biology.pdf

198 Christopher .l Thorpe and David S. Moss7.7 Modelling of an Epstein Barr Virus NuclearAntigen Peptide with HLA-B27 Sub-TypeMoleculesHLA-B27 is an enigma in the field of immunology, in both its disease associations,and the primary structure of the peptides which it presents. It is to date the onlyhuman class I molecule to have a strong genetic linkage to an autoimmune disease,in its well known, but poorly characterised, association with ankylosing spondylitis(AS) [43, 441. In contrast to the link between HLA-B27 and AS the majority oforgan specific T-cell mediated autoimmune diseases display a strong association tothe class I1 genes of the MHC and a weak association to class I genes via linkagedisequilibria (see Table 7-1).Table 7-1. The MHC class I associations to autoimmune diseases known to date.Disorder HLA allele Relative riskHodgkin’s diseaseIdiopathic hemochromatosisBechet’s diseaseCongenital adrenal hyperplasiaAnkylosing spondylitisReiter’s diseaseAcute anterior uveitisSubacute thyroiditisPsoriasis vugarisHLA-A1HLA-A3HLA-B14HLA-B5HLA-B47HLA-B27HLA-B27HLA-B27HLA-B35HLA-Cw61.48.24.26.315.487.437.010.413.713.3In addition to these associations HLA-B7, HLA-A3 and HLA-Cw7 have been demonstratedto be linked to narcolepsy, probably through their linkage disequilibrium with haplotypes containingthe class I1 HLA-DR2 alleles that have been observed in all narcoleptics typed to date.Another class I allele HLA-BlS has been weaklv linked to C2 comulement deficiencv.The structure of the HLA-B27 molecule determined by X-ray crystallography isvirtually identical to that of HLA-A2. However the initial structure of HLA-B*2705was the first to define the shape of the peptide in the cleft. In the structures of HLA-A2 and HLA-Aw68 with collections of endogenous peptides, electron density for thepeptide was visible but was not interpretable. This feature was suggested to be causedby the vast diversity of peptides bound; diverse both in length and sequence. All ofthe peptides eluted from HLA-B*2705 were nonamers and had an identical residueat position P2. It was considered to be these features which allowed the visualisationof an average backbone peptide conformation in the 3.0 A structure. However octamerand decamer HLA-B27 epitopes have been characterised but all have arginine