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Structure of a human insulin peptide–HLA-DQ8 complex and susceptibility to type 1 diabetes

A Correction to this article was published on 01 September 2001

Abstract

The class II major histocompatibility complex (MHC) glycoproteins HLA-DQ8 and HLA-DQ2 in humans and I-Ag7 in nonobese diabetic (NOD) mice are the major risk factors for increased suscepti-bility to type 1 diabetes. Using X-ray crystallography, we have determined the three-dimen-sional structure of DQ8 complexed with an immunodominant peptide from insulin. The similarity of the DQ8, DQ2 and I-Ag7 peptide-binding pockets suggests that diabetes is caused by the same antigen-presentation event(s) in humans and NOD mice. Correlating type 1 diabetes epidemio-logy and MHC sequences with the DQ8 structure suggests that other structural features of the P9 pocket in addi-tion to position 57 contribute to susceptibility to type 1 diabetes.

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Figure 1: InsulinB bound to human HLA-DQ8 and pocket P9.
Figure 2: Comparison of P4 pockets with P4 tyrosine in the DQ8-insulinB complex and P4 phenylalanine in the DR2-MBP complex.
Figure 3: Hydrogen bonding network in the DQ8-insulinB P1 pocket and a hypothetical network if insulinB bound to I-Ag7.

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Acknowledgements

We thank M. Pietras and J. Pyrdol for technical assistance; the staff at APS at Argonne National Laboratory beamline BIOCARS 14-BM-C for help with data collection; G. K. Papadopoulous for coordinates of DQ8-Celiac-peptide models and members of the Harrison and Wiley and Wucherpfennig groups for assistance. Supported by the Howard Hughes Medical Institute (D. C. W. and K. H. L.), the National Institutes of Health (PO1 AI39619) (D. C. W. and K. W. W.), the American Diabetes Association (K. W. W.) and the Juvenile Diabetes Foundation International (K. H. L.).

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Correspondence to Don C. Wiley.

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Lee, K., Wucherpfennig, K. & Wiley, D. Structure of a human insulin peptide–HLA-DQ8 complex and susceptibility to type 1 diabetes. Nat Immunol 2, 501–507 (2001). https://doi.org/10.1038/88694

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