The class II major histocompatibility complex (MHC) glycoproteins HLA-DQ8 a
nd HLA-DQ2 in humans and I-A(g7) in nonobese diabetic (NOD) mice are the ma
jor risk factors for increased susceptibility to type I diabetes. using X-r
ay crystallography, we have determined the three-dimen-sional structure of
DQ8 complexed with an immunodominant peptide from insulin. The similarity o
f the DQ8, DQ2 and I-A(g7) peptide-binding pockets suggests that diabetes i
s caused by the same antigen-presentation event(s) in humans and NOD mice.
Correlating type I diabetes epidemiology and MHC sequences with the DQ8 str
ucture suggests that other structural features of the P9 pocket in addition
to position 57 contribute to susceptibility to type I diabetes.