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-A(g7) in nonobese diabetic (NOD) mice are the major risk factors for increased susceptibility to type 1 diabetes. Using X-ray crystallography, we have determined the three-dimensional structure of DQ8 complexed with an immunodominant peptide from insulin. The similarity of the DQ8, DQ2 and I-A(g7) peptide-binding pockets suggests that diabetes is caused by the same antigen-presentation event(s) in humans and NOD mice. Correlating type 1 diabetes epidemiology and MHC sequences with the DQ8 structure suggests that other structural features of the P9 pocket in addition to position 57 contribute to susceptibility to type 1 diabetes.
Lee
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KH
Laboratory of Molecular Medicine, The Department of Medicine, The Children's Hospital, 320 Longwood Avenue, Boston, MA 02115, USA.
Wucherpfennig
K W
KW
Wiley
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DC
D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D006239:Haplotypes; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000235:genetics; D007328:Insulin / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D046911:Macromolecular Substances; D051379:Mice; D016688:Mice, Inbred NOD; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D011487:Protein Conformation
D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; C109756:HLA-DQ8 antigen; D000949:Histocompatibility Antigens Class II; C407099:I-A g7 antigen; D016056:Immunodominant Epitopes; D007328:Insulin; D046911:Macromolecular Substances; D010446:Peptide Fragments; C097877:insulin B (9-23)