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Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand

Abstract

Target cell lysis is regulated by natural killer (NK) cell receptors that recognize class I MHC molecules. Here we report the crystal structure of the human immunoglobulin-like NK cell receptor KIR2DL2 in complex with its class I ligand HLA-Cw3 and peptide. KIR binds in a nearly orthogonal orientation across the α1 and α2 helices of Cw3 and directly contacts positions 7 and 8 of the peptide. No significant conformational changes in KIR occur on complex formation. The receptor footprint on HLA overlaps with but is distinct from that of the T-cell receptor. Charge complementarity dominates the KIR/HLA interface and mutations that disrupt interface salt bridges substantially diminish binding. Most contacts in the complex are between KIR and conserved HLA-C residues, but a hydrogen bond between Lys 44 of KIR2DL2 and Asn 80 of Cw3 confers the allotype specificity. KIR contact requires position 8 of the peptide to be a residue smaller than valine. A second KIR/HLA interface produced an ordered receptor–ligand aggregation in the crystal which may resemble receptor clustering during immune synapse formation.

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Figure 1: Ribbon drawing showing two views of HLA-Cw3 bound to KIR2DL2.
Figure 2: The KIR2DL2/HLA-Cw3 interface.
Figure 3: Comparison of KIR/HLA-Cw3 and TCR/MHC interactions.
Figure 4: Coordination of the GAV peptide.
Figure 5: KIR/HLA aggregation.

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Acknowledgements

We thank Z. Dauter and C. Titlow for help with synchrotron data collection; J. Lukszo for peptide synthesis; C. Hammer for mass spectroscopy measurements; M. Garfield for N-terminal amino-acid sequencing; A. Winterhalter and N. Mifsud for assistance with the mutagenesis and DNA sequencing; and D. Margulies for help with BIAcore SPR measurements. This work is supported by intramural research funding from the National Institute of Allergy and Infectious Diseases and an R. D. Wright Fellowship from the National Health and Medical Research Council, Australia.

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Boyington, J., Motyka, S., Schuck, P. et al. Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand. Nature 405, 537–543 (2000). https://doi.org/10.1038/35014520

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