Structure of a Human Insulin peptide-HLA-DQ8 Complex and Susceptibility to Type 1 Diabetes

Nat Immunol. 2001 Jun;2(6):501-7. doi: 10.1038/88694.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology*
  • HLA-DQ Antigens / chemistry*
  • HLA-DQ Antigens / genetics
  • HLA-DQ Antigens / immunology
  • Haplotypes
  • Histocompatibility Antigens Class II / chemistry
  • Histocompatibility Antigens Class II / immunology
  • Humans
  • Immunodominant Epitopes / chemistry
  • Immunodominant Epitopes / genetics
  • Insulin / chemistry*
  • Insulin / genetics
  • Insulin / immunology*
  • Macromolecular Substances
  • Mice
  • Mice, Inbred NOD
  • Models, Molecular
  • Peptide Fragments / chemistry*
  • Peptide Fragments / genetics
  • Peptide Fragments / immunology*
  • Protein Conformation

Substances

  • HLA-DQ Antigens
  • HLA-DQ2 antigen
  • HLA-DQ8 antigen
  • Histocompatibility Antigens Class II
  • I-A g7 antigen
  • Immunodominant Epitopes
  • Insulin
  • Macromolecular Substances
  • Peptide Fragments
  • insulin B (9-23)