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J. Biol. Chem., Vol. 281, Issue 15, 10618-10625, April 14, 2006

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Structural Definition of the H-2K^d Peptide-binding Motif^*

Vesselin Mitaksov and Daved H. Fremont¹

From the Department of Pathology and Immunology and Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110

Classic major histocompatibility complex (MHC) proteins associate with antigen- and self-derived peptides in an allele-specific manner. Herein we present the crystal structure of the MHC class I protein H-2K^d (K^d) expressed by BALB/c mice in complex with an antigenic peptide derived from influenza A/PR/8/34 nucleoprotein (Flu, residues 147-155, TYQRTRALV). Analysis of our structure in conjunction with the sequences of naturally processed epitopes provides a comprehensive understanding of the dominant K^d peptide-binding motif. We find that Flu residues Tyr^P2, Thr^P5, and Val^P9 are sequestered into the B, C, and F pockets of the K^d groove, respectively. The shape and chemistry of the polymorphic B pocket make it an optimal binding site for the side chain of Tyr^P2 as the dominant anchoring residue of nonameric peptides. The non-polar F pocket limits the amino acid repertoire at P9 to hydrophobic residues such as Ile, Leu, or Val, whereas the C pocket restricts the size of the P5-anchoring side chain. We also show that Flu is accommodated in the complex through an unfavorable kink in the otherwise extended peptide backbone due to the presence of a prominent ridge in the K^d groove. Surprisingly, this backbone conformation is strikingly similar to D^b-presented peptides despite the fact that these proteins employ distinct motif-anchoring strategies. The results presented in this study provide a solid foundation for the understanding of K^d-restricted antigen presentation and recognition events.

Received for publication, September 26, 2005 , and in revised form, February 2, 2006.

The atomic coordinates and structure factors (code 2FWO) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by National Institutes of Health Grant GM62414-04 (to D. H. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pathology and Immunology, Washington University School of Medicine, Box 8118, 660 South Euclid Ave, St. Louis, MO 63110. Tel.: 314-747-6547; Fax: 314-362-8888; E-mail: fremont{at}immunology.wustl.edu.

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