Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Binding Sites
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Crystallography, X-Ray
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Diabetes Mellitus, Type 1 / genetics*
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Diabetes Mellitus, Type 1 / immunology*
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HLA-DQ Antigens / chemistry*
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HLA-DQ Antigens / genetics
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HLA-DQ Antigens / immunology
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Haplotypes
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Histocompatibility Antigens Class II / chemistry
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Histocompatibility Antigens Class II / immunology
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Humans
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Immunodominant Epitopes / chemistry
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Immunodominant Epitopes / genetics
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Insulin / chemistry*
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Insulin / genetics
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Insulin / immunology*
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Macromolecular Substances
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Mice
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Mice, Inbred NOD
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Models, Molecular
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Peptide Fragments / chemistry*
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Peptide Fragments / genetics
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Peptide Fragments / immunology*
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Protein Conformation
Substances
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HLA-DQ Antigens
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HLA-DQ2 antigen
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HLA-DQ8 antigen
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Histocompatibility Antigens Class II
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I-A g7 antigen
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Immunodominant Epitopes
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Insulin
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Macromolecular Substances
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Peptide Fragments
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insulin B (9-23)