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 alpha1 and alpha2 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.
Boyington
J C
JC
Structural Biology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852, USA.
Motyka
S A
SA
Schuck
P
P
Brooks
A G
AG
Sun
P D
PD
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D004563:Electrochemistry; D004926:Escherichia coli; D015236:HLA-C Antigens / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000737:chemistry* / Q000276:immunology; D008024:Ligands; D008285:Major Histocompatibility Complex; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D011940:Receptor Aggregation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000276:immunology; D054340:Receptors, KIR; D054343:Receptors, KIR2DL2; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology
D015236:HLA-C Antigens; C038653:HLA-C*03 antigen; C515077:KIR2DL2 protein, human; D008024:Ligands; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D054343:Receptors, KIR2DL2; D011994:Recombinant Proteins