1. Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9,600 Gudelsky Drive, Rockville, Maryland 20850, USA
2. Institut de Biologia Molecular de Barcelona, CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain
3. Molecular Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA

Correspondence to: Correspondence and requests for materials should be addressed to R.A.M. (e-mail: Email: mariuzza@carb.nist.gov). or D.H.M. (e-mail: Email: dhm@nih.gov). Atomic coordinates have been deposited in the Protein Data Bank under accession number 1qo3.

Abstract

Natural killer (NK) cell function is regulated by NK receptors that interact with MHC class I (MHC-I) molecules on target cells. The murine NK receptor Ly49A inhibits NK cell activity by interacting with H-2D^d through its C-type-lectin-like NK receptor domain. Here we report the crystal structure of the complex between the Ly49A NK receptor domain and unglycosylated H-2D^d. The Ly49A dimer interacts extensively with two H-2D^d molecules at distinct sites. At one interface, a single Ly49A subunit contacts one side of the MHC-I peptide-binding platform, presenting an open cavity towards the conserved glycosylation site on the H-2D^d 2 domain. At a second, larger interface, the Ly49A dimer binds in a region overlapping the CD8-binding site. The smaller interface probably represents the interaction between Ly49A on the NK cell and MHC-I on the target cell, whereas the larger one suggests an interaction between Ly49A and MHC-I on the NK cell itself. Both Ly49A binding sites on MHC-I are spatially distinct from that of the T-cell receptor.