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Science 21 April 2000:
Vol. 288. no. 5465, pp. 505 - 511
DOI: 10.1126/science.288.5465.505
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Reports

A Structural Framework for Deciphering the Link Between I-Ag7 and Autoimmune Diabetes

Adam L. Corper, 1* Thomas Stratmann, 2* Vasso Apostolopoulos, 1 Christopher A. Scott, 1dagger K. Christopher Garcia, 1ddagger Angray S. Kang, 1§ Ian A. Wilson, 1parallel Luc Teyton 2parallel

Susceptibility to murine and human insulin-dependent diabetes mellitus correlates strongly with major histocompatibility complex (MHC) class II I-A or HLA-DQ alleles that lack an aspartic acid at position beta 57. I-Ag7 lacks this aspartate and is the only class II allele expressed by the nonobese diabetic mouse. The crystal structure of I-Ag7 was determined at 2.6 angstrom resolution as a complex with a high-affinity peptide from the autoantigen glutamic acid decarboxylase (GAD) 65. I-Ag7 has a substantially wider peptide-binding groove around beta 57, which accounts for distinct peptide preferences compared with other MHC class II alleles. Loss of Aspbeta 57 leads to an oxyanion hole in I-Ag7 that can be filled by peptide carboxyl residues or, perhaps, through interaction with the T cell receptor.

1 Department of Molecular Biology and Skaggs Institute for Chemical Biology,
2 Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
*   These authors contributed equally to this work.

dagger    Present address: Department of Medicine 0613-C, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92083-0613, USA.

ddagger    Present address: Stanford University School of Medicine, Departments of Microbiology and Immunology and Structural Biology, Fairchild Sciences Building D-319, 299 Campus Drive, Stanford, CA 94305, USA.

§   Present address: Abgenix Inc., 7601 Dumbarton Circle, Fremont, CA 94555, USA.

parallel    To whom correspondence should be addressed. E-mail: wilson{at}scripps.edu; lteyton{at}scripps.edu

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