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

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.