Abstract
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.
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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Alleles
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Amino Acid Motifs
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Amino Acid Sequence
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Animals
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Aspartic Acid / chemistry
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Crystallography, X-Ray
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Diabetes Mellitus, Type 1 / immunology*
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Drosophila melanogaster
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Genes, MHC Class II*
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Glutamate Decarboxylase / metabolism
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Histocompatibility Antigens Class II / chemistry*
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Histocompatibility Antigens Class II / genetics
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Histocompatibility Antigens Class II / metabolism
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Humans
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Hydrogen Bonding
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Mice
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Mice, Inbred NOD
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Models, Molecular
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Molecular Sequence Data
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Peptide Library
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Protein Binding
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Protein Conformation
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Protein Structure, Secondary
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Receptors, Antigen, T-Cell / metabolism
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
Substances
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Histocompatibility Antigens Class II
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I-A g7 antigen
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Peptide Library
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Receptors, Antigen, T-Cell
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Recombinant Proteins
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Aspartic Acid
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Glutamate Decarboxylase