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| Article Authors: | Chu-Young Kim; Hanne Quarsten; Elin Bergseng; Chaitan Khosla; Ludvig M Sollid |
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| Article Title: | Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease. |
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| Reference ID: | 682 |
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| Abstract: | Celiac disease, also known as celiac sprue, is a gluten-induced autoimmune-like disorder of the small intestine, which is strongly associated with HLA-DQ2. The structure of DQ2 complexed with an immunogenic epitope from gluten, QLQPFPQPELPY, has been determined to 2.2-A resolution by x-ray crystallography. The glutamate at P6, which is formed by tissue transglutaminase-catalyzed deamidation, is an important anchor residue as it participates in an extensive hydrogen-bonding network involving Lys-beta71 of DQ2. The gluten peptide-DQ2 complex retains critical hydrogen bonds between the MHC and the peptide backbone despite the presence of many proline residues in the peptide that are unable to participate in amide-mediated hydrogen bonds. Positioning of proline residues such that they do not interfere with backbone hydrogen bonding results in a reduction in the number of registers available for gluten peptides to bind to MHC class II molecules and presumably impairs the likelihood of establishing favorable side-chain interactions. The HLA association in celiac disease can be explained by a superior ability of DQ2 to bind the biased repertoire of proline-rich gluten peptides that have survived gastrointestinal digestion and that have been deamidated by tissue transglutaminase. Finally, surface-exposed proline residues in the proteolytically resistant ligand were replaced with functionalized analogs, thereby providing a starting point for the design of orally active agents for blocking gluten-induced toxicity. |
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| Affiliations: | Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA. |
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| Date: | 2004 |
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| Reference Type: | Literature |
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| PubMed ID: | 15020763 |
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| Journal: | Proc Natl Acad Sci U S A |
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| Journal Volume: | 101 |
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| Article Pages: | 4175-9 |
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| Journal ISSN: | 1091-6490 |
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| Article Chemical List: | Epitopes;HLA-DQ Antigens;HLA-DQ2 antigen, human;Ligands;Peptides;Proline;Glutens;Gliadin |
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| Article MeSH List: | Celiac Disease(immunology); Crystallography, X-Ray; Epitopes(chemistry; immunology); Gliadin(chemistry; immunology); Glutens(chemistry; immunology); HLA-DQ Antigens(chemistry; immunology); Humans; Ligands; Peptides(chemistry; immunology); Proline(chemistry); Protein Structure, Tertiary |
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| Curation Last Updated: | 2011-08-23 20:10:39 |
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