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

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 alpha 1 and alpha 2 helices of Cw3 and directly contacts positions 7 acid 8 of the peptide. No significant conformational changes in KIR occur on complex formation. The receptor footprint on HCB 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 hip and conserved HLA-C residues. but a hydrogen band 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.