Crystal structure of a lectin-like natural killer cell receptor bound to its MHC class I ligand

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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-2Dd 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-2Dd. The Ly49A dimer interacts extensively with two H-2Dd 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-2Dd α2 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.

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Figure 1: Structure of the Ly49A/H-2Dd complex and the interaction sites.
Figure 2: Structure of Ly49A NKD, and comparison with other members of the C-type lectin-like superfamily.
Figure 3: Structure-based sequence alignment of NKDs for selected NK cell receptors.
Figure 4: Binding of lymphocyte receptors to MHC-I.
Figure 5: The putative carbohydrate-binding pocket at the Ly49A/H-2Dd interface.


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We thank W. Yang and B. A. Fields for their help with data collection, L. Boyd and R. Carey for assistance with protein expression and characterization, M. Garfield for protein sequencing, and J. C. Boyington and P. D. Sun for providing coordinates of the CD94 structure before release. We thank W. Yokoyama for encouragement and for critical comments on the manuscript. We also thank the staff at the Advanced Photon Source, Argonne National Laboratory, which is operated by the Department of Energy, Office of Basic Energy Sciences. This work was supported, in part, by grants from the National Institutes of Health and the National Multiple Sclerosis Society (R.A.M.) and the Spanish “Comision Interministerial de Ciencia y Tecnologia” (J.T.).

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Correspondence to David H. Margulies or Roy A. Mariuzza.

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Tormo, J., Natarajan, K., Margulies, D. et al. Crystal structure of a lectin-like natural killer cell receptor bound to its MHC class I ligand. Nature 402, 623–631 (1999) doi:10.1038/45170

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