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

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. IMAGES:

本研究对人类白细胞抗原（HLA）A*6801、HLA-A*0201及HLA-B*2705的X射线晶体结构（X-ray structures）坐标展开分析，以探究这三类亚型在肽结合过程中选择性的分子基础。结合肽段第二位氨基酸残基（P2残基，P2 residue）侧链的结合口袋，在上述三种HLA亚型中分别偏好识别缬氨酸（Val）、亮氨酸（Leu）与精氨酸（Arg）。HLA-B*2705的精氨酸特异性结合口袋与HLA-A*0201、HLA-A*6801存在显著差异，该差异源于构成口袋表面的侧链存在多处序列差异。HLA-A*0201与HLA-A*6801之间的结合特异性差异则更为微妙，既取决于口袋残基缬氨酸-67（Val-67）的构象变化，也与第9位残基的序列差异相关。缬氨酸-67的构象变化似乎由α1结构域α螺旋（alpha 1-domain alpha-helix）相对于抗原结合裂缝内β折叠片层（beta-sheet）的位移所引发，事实上其可能还依赖于P2口袋远端的氨基酸差异。对P2侧链与其结合口袋相互作用的立体化学特征进行分析，可估算其对肽结合自由能变化（free-energy change）的贡献。IMAGES: