Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648.
Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2662-7. doi: 10.1073/pnas.1322052111. Epub 2014 Feb 3.
Inhibitory killer cell Ig-like receptors (KIRs) are known to recognize HLA ligands mainly of the HLA-C and Bw4 groups, but the ligands for KIRs are poorly understood. We report here the identification of the cognate ligand for the activating KIR 2DS2 as HLA-A11:01. The crystal structure of the KIR2DS2-HLA-A11:01 complex was solved at 2.5-Å resolution and revealed residue-binding characteristics distinct from those of inhibitory KIRs with HLA-C and the critical role of residues Tyr45 and Asp72 in shaping binding specificity to HLA-A11:01. Using KIR2DS2 tetramers, binding to surface HLA-A11:01 on live cells was demonstrated and, furthermore, that binding can be altered by residue changes at p8 of the peptide, indicating the influence of peptide sequence on KIR-HLA association. In addition, heteronuclear single quantum coherence NMR was used to map the involvement of critical residues in HLA binding at the interface of KIR and HLA, and validates the data observed in the crystal structure. Our data provide structural evidence of the recognition of A*11:01 by the activating KIR2DS2 and extend our understanding of the KIR-HLA binding spectrum.
抑制性杀伤细胞免疫球蛋白样受体（KIRs）已知可识别主要来自 HLA-C 和 Bw4 组的 HLA 配体，但对 KIR 配体的了解甚少。我们在此报告鉴定出激活型 KIR2DS2 的同源配体为 HLA-A11:01。KIR2DS2-HLA-A11:01 复合物的晶体结构在 2.5 Å 分辨率下得到解决，揭示了与具有 HLA-C 的抑制性 KIR 不同的残基结合特征，以及 Tyr45 和 Asp72 残基在塑造与 HLA-A11:01 的结合特异性方面的关键作用。使用 KIR2DS2 四聚体，在活细胞表面上证明了与 HLA-A11:01 的结合，并且，肽的 p8 残基的变化可以改变结合，表明肽序列对 KIR-HLA 结合的影响。此外，异核单量子相干 NMR 用于映射 KIR 和 HLA 界面处 HLA 结合中关键残基的参与，并验证了晶体结构中观察到的数据。我们的数据提供了激活型 KIR2DS2 识别 A*11:01 的结构证据，并扩展了我们对 KIR-HLA 结合谱的理解。
