Crystal structure of the human natural killer cell inhibitory receptor KIR2DL1–HLA-Cw4 complex

Abstract

Inhibitory natural killer (NK) cell receptors down-regulate the cytotoxicity of NK cells upon recognition of specific class I major histocompatibility complex (MHC) molecules on target cells. We report here the crystal structure of the inhibitory human killer cell immunoglobulin-like receptor 2DL1 (KIR2DL1) bound to its class I MHC ligand, HLA-Cw4. The KIR2DL1–HLA-Cw4 interface exhibits charge and shape complementarity. Specificity is mediated by a pocket in KIR2DL1 that hosts the Lys80 residue of HLA-Cw4. Many residues conserved in HLA-C and in KIR2DL receptors make different interactions in KIR2DL1–HLA-Cw4 and in a previously reported KIR2DL2–HLA-Cw3 complex. A dimeric aggregate of KIR–HLA-C complexes was observed in one KIR2DL1–HLA-Cw4 crystal. Most of the amino acids that differ between human and chimpanzee KIRs with HLA-C specificities form solvent-accessible clusters outside the KIR-HLA interface, which suggests undiscovered interactions by KIRs.

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Figure 1: Ribbon diagram of the crystal structure of KIR2DL1 bound to HLA-Cw4.
Figure 2: Recognition of HLA-Cw4 by KIR2DL1.
Figure 3: The interactions at the KIR2DL1–HLA-Cw4 interface.
Figure 4: The KIR2DL1 specificity pocket for Lys80 of HLA-Cw4.
Figure 5: Different peptide conformations in HLA-Cw4 and HLA-Cw3.
Figure 6: A common HLA-C binding mode for KIR2DL1 and KIR2DL2.
Figure 7: Ribbon diagram of a crystallographic dimer of the KIR2DL1–HLA-Cw4 complex.

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Acknowledgements

We thank Y. Tao for help with data collection, D. N. Garboczi for helpful advice, A. Haykov for inclusion body preparation, N. Siniskaya for peptide and DNA synthesis, D. J. Stauber and W. A. Hendrickson for the program TOSS, C. Watzl for the Lig.1 antibody, I. Vakser for molecular modeling studies, P. Sun for the coordinates of KIR2DL2–HLA-Cw3 complex structure and a preprint of the manuscript, R. Mariuzza for discussion of the Ly49A–H-2Dd complex structure before publication, R. Rajalingam for a preprint of the manuscript on Pygmy Chimpanzee KIR, P. Sliz, K. Mahan, B. Harris and R. Crouse for technical assistance and staff at the X25 beamline of NSLS and F-1 beamline at CHESS for help with data collection. Supported by the Howard Hughes Medical Institute, National Institute of Health and the National Science Foundation (Q. R. F.). D. C. W. is supported by HHMI.

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Correspondence to Don C. Wiley.

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Fan, Q., Long, E. & Wiley, D. Crystal structure of the human natural killer cell inhibitory receptor KIR2DL1–HLA-Cw4 complex. Nat Immunol 2, 452–460 (2001). https://doi.org/10.1038/87766

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