COMPARISON OF THE P2 SPECIFICITY POCKET IN 3 HUMAN HISTOCOMPATIBILITYANTIGENS - HLA-A-ASTERISK-6801, HLA-A-ASTERISK-0201, AND HLA-B-ASTERISK-2705

Coordinates from x-ray structures of HLA-A6801, HLA-A*0201, and HLA-B 2705 were analyzed to examine the basis for their selectivity in pept ide binding. The pocket that binds the side chain of the peptide's sec ond amino acid residue (P2 residue) shows a preference for Val, Leu, a nd Arg in these three HLA subtypes, respectively. The Arg-specific poc ket of HLA-B2705 differs markedly from those of HLA-A*0201 and HLA-A* 6801, as a result of numerous differences in the side chains that form the pocket's surface. The cause of the specificity differences betwee n HLA-A0201 and HLA-A*6801 is more subtle and depends both on a chang e in conformation of pocket residue Val-67 and on a sequence differenc e at residue 9. The Val-67 conformational change appears to be caused by a shift in the position of the alpha1-domain alpha-helix relative t o the beta-sheet in the cleft and may, in fact, depend on amino add di fferences remote from the P2 pocket. Analysis of the stereochemistry o f the P2 side chain interacting with its binding pocket permits an est imate to be made of its contribution to the free-energy change of pept ide binding.