Crystal structure of the HLA-Cw3 allotype-specific killer cell inhibitory receptor KIR2DL2

Killer cell inhibitory receptors (KIR) protect class I HLAs expressing targ et cells from natural killer (NK) cell-mediated lysis, To understand the mo lecular basis of this receptor-ligand recognition, we have crystallized the extracellular ligand-binding domains of KIR2DL2, a member of the Ig superf amily receptors that recognize HLA-Cw1, 3, 7, and 8 allotypes, The structur e was determined in two different crystal forms, an orthorhombic P2(1)2(1)2 (1) and a trigonal P3(2)21 space group, to resolutions of 3.0 and 2.9 Angst rom, respectively. The overall fold of this structure, like KIR2DL1, exhibi ts K-type Ig topology with cis-proline residues in both domains that define beta-strand switching, which sets KIR apart from the C2-type hematopoietic growth hormone receptor fold, The hinge angle of KIR2DL2 is approximately 80 degrees, 14 degrees larger than that observed in KIR2DL1 despite the exi stence of conserved hydrophobic residues near the hinge region. There is al so a 5 degrees difference in the observed hinge angles in two crystal forms of 2DL2. suggesting that the interdomain hinge angle is not fixed. The put ative ligand-binding site is formed by residues from several variable loops with charge distribution apparently complementary to that of HLA-C, The pa cking of the receptors in the orthorhombic crystal form offers an intriguin g model for receptor aggregation on the cell surface.