STRUCTURAL COMPARISON OF MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I MOLECULES AND HOMOLOGY MODELING OF 5 DISTINCT HUMAN-LEUKOCYTE ANTIGEN-A ALLELES

The peptide complexes of 19 major histocompatibility complex class I a lpha 1 and alpha 2 domains have been compared to identify similarities that can be interpreted as constraints necessary for the function or stability of the molecule. It was found that nearly half of the residu es maintained their side-chain conformations (or had no side chain), w ith the remaining residues being highly solvent exposed and/or polymor phic. Seven hydrogen bonds between the molecule and peptide are conser ved in all the structures and serve to orientate the ends of the pepti de in the binding groove. Furthermore, the general orientations of mos t residue side chains in the peptide are similar. Based on these const raints, homology models for the distinct human leukocyte antigen-A all eles A0302, A*2403, A*2603, A*3101 and A*8001 have been constructed a nd the implications for peptide binding discussed. The models provide a useful framework from,which to engineer allele-specific peptides wit h a high binding affinity.