The function of natural killer (NK) and myeloid cells depends on the balance of a number of activating and inhibitory receptors. Natural cytotoxicity receptors (NCR) are the major receptors responsible for NK cell-mediated lysis of tumor and viral-infected cells. Recent cloning of three NCRs, NKp46, NKp44, and NKp30, prompted studies by a number of investigators to elucidate their function as well as to identify their ligands. In the past few years, we have characterized the structure and function of several inhibitory as well as activating NK cell receptors. These include the crystal structures of CD94, KIR2DL2 and its complex with HLA-Cw3, NKG2D and its complex with ULBP3, NKp46 and TREM-1. Despite the progress made in understanding the function of NK receptors in the past few years, the ligands recognized by NCR remain unknown. Our effort of understanding the function of NCR has led a structural solution for NKp46. The structure revealed striking resemblence between NKp46 and KIR receptors and enabled us to propose a potential ligand binding site. To search for the potential ligands of NCR, we designed a high throughput binding assay that enables us to systematically evaluate the binding of NCR to known cell surface antigens.? ? In an effort to understand the mechanism of a virulence factor, mac-1, from Group A Streptococcus, we have revealed that the protein functions as a cysteine protease specific for IgG. The structure shows that it adopts a cysteine protease fold with a unique dimer formation and that the mutations at the dimer interface drastically reduced the catalytic activity.
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