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J. Biol. Chem., Vol. 278, Issue 45, 44904-44912, November 7, 2003

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Exploration of the P6/P7 Region of the Peptide-binding Site of the Human Class II Major Histocompatability Complex Protein HLA-DR1^*

Zarixia Zavala-Ruiz, Eric J. Sundberg, Jennifer D. Stone, Daniel B. DeOliveira, Iat C. Chan, Jennifer Svendsen, Roy A. Mariuzza, and Lawrence J. Stern¶||

From the Massachusetts Institute of Technology, Department of Chemistry, Cambridge, Massachusetts 02139, ^¶University of Massachusetts School of Medicine, Pathology Department, Worcester, Massachusetts 01655, and Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, Rockville, Maryland 20850

Crystal structures of the class II major histocompatibilty complex (MHC) protein, HLA-DR1, generally show a tight fit between MHC and bound peptide except in the P6/P7 region of the peptide-binding site. In this region, there is a shallow water-filled pocket underneath the peptide and between the pockets that accommodate the P6 and P7 side chains. We investigated the properties of this pocket with the idea of engineering substitutions into the corresponding region of peptide antigens to increase their binding affinity for HLA-DR1. We investigated D-amino acids and N-alkyl modifications at both the P6 and P7 positions of the peptide and found that binding of peptides to HLA-DR1 could be increased by incorporating an N-methyl substitution at position 7 of the peptide. The crystal structure of HLA-DR1 bound to a peptide containing a P7 N-methyl alanine was determined. The N-methyl group orients in the P6/P7 pocket, displacing one of the waters usually bound in this pocket. The structure shows that the substitution does not alter the conformation of the bound peptide, which adopts the usual polyproline type II helix. An antigenic peptide carrying the N-methyl modification is taken up by antigen-presenting cells and loaded onto endogenous class II MHC molecules for presentation, and the resultant MHC-peptide complexes activate antigen-specific T-cells. These results suggest a possible strategy for increasing the affinity of weakly immunogenic peptides that might be applicable to the development of vaccines and diagnostic reagents.

Received for publication, July 16, 2003 , and in revised form, August 27, 2003.

The atomic coordinates and structure factors (code 1PYW) 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 R01-AI38996 (to L. J. S.), National Institutes of Health R01-AI369000 (to R. A. M.), and National Institutes of Health F31-GM64859 (to Z. Z. R.). 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.

^|| To whom correspondence should be addressed: Rm. S2–127, 55 Lake Ave. N., University of Massachusetts School of Medicine, Worcester, MA 01655. Fax: 508-856-0019; E-mail: lawrence.stern{at}umassmed.edu.

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