Members of the killer cell immunoglobulin-like receptor (KIR) family, a large group of polymorphic receptors expressed on natural killer (NK) cells, recognize particular peptide-laden human leukocyte antigen (pHLA) class I molecules and have a pivotal role in innate immune responses1. Allelic variation and extensive polymorphism within the three-domain KIR family (KIR3D, domains D0–D1–D2) affects pHLA binding specificity and is linked to the control of viral replication and the treatment outcome of certain haematological malignancies1,2,3. Here we describe the structure of a human KIR3DL1 receptor bound to HLA-B*5701 complexed with a self-peptide. KIR3DL1 clamped around the carboxy-terminal end of the HLA-B*5701 antigen-binding cleft, resulting in two discontinuous footprints on the pHLA. First, the D0 domain, a distinguishing feature of the KIR3D family, extended towards β2-microglobulin and abutted a region of the HLA molecule with limited polymorphism, thereby acting as an ‘innate HLA sensor’ domain. Second, whereas the D2–HLA-B*5701 interface exhibited a high degree of complementarity, the D1–pHLA-B*5701 contacts were suboptimal and accommodated a degree of sequence variation both within the peptide and the polymorphic region of the HLA molecule. Although the two-domain KIR (KIR2D) and KIR3DL1 docked similarly onto HLA-C4,5 and HLA-B respectively, the corresponding D1-mediated interactions differed markedly, thereby providing insight into the specificity of KIR3DL1 for discrete HLA-A and HLA-B allotypes. Collectively, in association with extensive mutagenesis studies at the KIR3DL1–pHLA-B*5701 interface, we provide a framework for understanding the intricate interplay between peptide variability, KIR3D and HLA polymorphism in determining the specificity requirements of this essential innate interaction that is conserved across primate species.
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Protein Data Bank
The atomic coordinates and structure factors for the KIR3DL*001–pHLA-B*5701 complex were deposited in the Protein Data Bank under accession code 3VH8.
We thank the staff at the MX2 beamline of the Australian synchrotron for assistance with data collection. We thank A. Radu Aricescu for the gift of the pHLsec vector. This research was supported by the National Health and Medical Research Council of Australia (NHMRC), the Australian Research Council (ARC) and the Intramural Research Programs of the National Cancer Institute and the National Institute of Allergy and Infectious Diseases, National Institutes of Health. D.W.M. and G.M.O'C. were supported by the Intramural AIDS Targeted Antiviral Program of the National Institutes of Health. J.P.V. is supported by an NHMRC Peter Doherty Research Fellowship; D.A.P. is supported by a Medical Research Council (UK) Senior Clinical Fellowship; B.A.P.L. is supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; C.S.C. is supported by an ARC QEII Fellowship; J.R. is supported by an ARC Federation Fellowship.
The file contains Supplementary Figures 1-7 with legends and Supplementary Tables 1-3.