A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes.
Susceptibility to murine and human insulin-dependent diabetes mellitus correlates strongly with major histocompatibility complex (MHC) class II I-A or HLA-DQ alleles that lack an aspartic acid at position beta57. I-Ag7 lacks this aspartate and is the only class II allele expressed by the nonobese diabetic mouse. The crystal structure of I-Ag7 was determined at 2.6 angstrom resolution as a complex with a high-affinity peptide from the autoantigen glutamic acid decarboxylase (GAD) 65. I-Ag7 has a substantially wider peptide-binding groove around beta57, which accounts for distinct peptide preferences compared with other MHC class II alleles. Loss of Asp(beta57) leads to an oxyanion hole in I-Ag7 that can be filled by peptide carboxyl residues or, perhaps, through interaction with the T cell receptor.
Corper
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Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Stratmann
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Apostolopoulos
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Scott
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CA
Garcia
K C
KC
Kang
A S
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Wilson
I A
IA
Teyton
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D000483:Alleles; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry; D018360:Crystallography, X-Ray; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004331:Drosophila melanogaster; D005802:Genes, MHC Class II; D005968:Glutamate Decarboxylase / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D051379:Mice; D016688:Mice, Inbred NOD; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019151:Peptide Library; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
D000949:Histocompatibility Antigens Class II; C407099:I-A g7 antigen; D019151:Peptide Library; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D001224:Aspartic Acid; D005968:Glutamate Decarboxylase