Comparison of the P2 specificity pocket in three human histocompatibility antigens: HLA-A*6801, HLA-A*0201, and HLA-B*2705.

Abstract

Coordinates from x-ray structures of HLA-A*6801, HLA-A*0201, and HLA-B*2705 were analyzed to examine the basis for their selectivity in peptide binding. The pocket that binds the side chain of the peptide's second amino acid residue (P2 residue) shows a preference for Val, Leu, and Arg in these three HLA subtypes, respectively. The Arg-specific pocket of HLA-B*2705 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 between HLA-A*0201 and HLA-A*6801 is more subtle and depends both on a change in conformation of pocket residue Val-67 and on a sequence difference at residue 9. The Val-67 conformational change appears to be caused by a shift in the position of the alpha 1-domain alpha-helix relative to the beta-sheet in the cleft and may, in fact, depend on amino acid differences remote from the P2 pocket. Analysis of the stereochemistry of the P2 side chain interacting with its binding pocket permits an estimate to be made of its contribution to the free-energy change of peptide binding.

Motif Inference Reveals Optimal CTL Epitopes Presented by HLA Class I Alleles Highly Prevalent in Southern Africa

“…This may be inferred from knowledge of the amino acid sequence of the alleles and of the residues that, from crystallographic studies, characteristically form these binding pockets (7)(8)(9)(10). We hypothesized that the motif may then be successfully inferred by comparison of these pocket-forming HLA residues in uncharacterized alleles, such as HLA-B*4201, with those equivalent HLA residues that form the same pockets in related alleles, such as HLA-B*0702, for which the peptide-binding motif has been determined.…”

Conformational changes within the HLA‐A1:MAGE‐A1 complex induced by binding of a recombinant antibody fragment with TCR‐like specificity

“…Its side chain apex (CZ atom) is separated by 5.54 Å in the two structures. Lys146 contacts the CDR-L3 residues Ser93 and Asp95A, the MAGE-A1 residue pTyr 9 and HLA-A1 HC residue Tyr84 through direct hydrogen-bonds. Its NZ apex is separated by 3.60 Å in the two structures.…”

“…1(E)]. The solvent accessibility of the MAGE-A1 peptide residues demonstrates varying degrees of solvent exposure for peptide residues, with pPro 4 , pThr 5 , pGly 6 , and pSer 8 being the most ''exposed'' residues (solvent accessible surface area (SASA) values per residue: 89.6, 39.7, 43.5, and 52.4 Å 2 , respectively) and pAla 2 , as well as the anchor residues pAsp 3 and pTyr 9 being the most ''occluded'' residues (SASA values per residue: 3.9, 10.2, and 7.0 Å 2 , respectively). .…”

“…Arg145 engages also in a hydrogen bond with a symmetry-related molecule (not shown). Lys146NZ forms indirect, water-mediated contacts with pTyr 9 , pSer 8 On the other hand, Lys146 forms direct hydrogen bonds with the CDR-L3 residues Ser93 and Asp95A, as well as with the HLA-A1 HC residue Tyr84 and with the C-terminal peptide residue pTyr 9 [ Fig. 5(D)].…”

“…These peptides are anchored in the peptide binding groove that is formed by HC residues through specific interactions between side chains of the peptide and residues shaping the peptide-binding pockets of an MHC molecule. 1,8 The specificity of peptide presentation is usually determined by only one or two of such pockets that accommodate primary anchor residues of a peptide, 9 with one or more secondary anchors that fine tune the binding motifs for a given MHC class I antigen. 10 For example, HLA-A*010101 is a human MHC class I allele whose product preferentially binds nonapeptides with the anchor residues Asp or Glu at position 3 and Tyr at position 9.…”