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J. Biol. Chem., Vol. 280, Issue 23, 21791-21796, June 10, 2005

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Main Chain Hydrogen Bond Interactions in the Binding of Proline-rich Gluten Peptides to the Celiac Disease-associated HLA-DQ2 Molecule^*

Elin Bergseng, Jiang Xia¶, Chu-Young Kim¶||, Chaitan Khosla¶||**, and Ludvig M. Sollid

From the Institute of Immunology, University of Oslo, Rikshospitalet University Hospital, N-0027 Oslo, Norway and Departments of ^¶Chemistry, ^||Chemical Engineering, and ^**Biochemistry, Stanford University, Stanford, California 94305-5080

Binding of peptide epitopes to major histocompatibility complex proteins involves multiple hydrogen bond interactions between the peptide main chain and major histocompatibility complex residues. The crystal structure of HLA-DQ2 complexed with the I-gliadin epitope (LQPFPQPELPY) revealed four hydrogen bonds between DQ2 and peptide main chain amides. This is remarkable, given that four of the nine core residues in this peptide are proline residues that cannot engage in amide hydrogen bonding. Preserving main chain hydrogen bond interactions despite the presence of multiple proline residues in gluten peptides is a key element for the HLA-DQ2 association of celiac disease. We have investigated the relative contribution of each main chain hydrogen bond interaction by preparing a series of N-methylated I epitope analogues and measuring their binding affinity and off-rate constants to DQ2. Additionally, we measured the binding of I-gliadin peptide analogues in which norvaline, which contains a backbone amide hydrogen bond donor, was substituted for each proline. Our results demonstrate that hydrogen bonds at P4 and P2 positions are most important for binding, whereas the hydrogen bonds at P9 and P6 make smaller contributions to the overall binding affinity. There is no evidence for a hydrogen bond between DQ2 and the P1 amide nitrogen in peptides without proline at this position. This is a unique feature of DQ2 and is likely a key parameter for preferential binding of proline-rich gluten peptides and development of celiac disease.

Received for publication, February 10, 2005 , and in revised form, April 12, 2005.

^* This work was supported by grants from the Research Council of Norway and by National Institutes of Health Grants DK65965 and DK63158. 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. Tel.: 47-23073815; Fax: 47-23073510; E-mail: elin.bergseng{at}medisin.uio.no.

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