Epitopes described in "Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease."

Article Authors:Chu-Young Kim; Hanne Quarsten; Elin Bergseng; Chaitan Khosla; Ludvig M Sollid
Article Title:Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease.
Reference Detail
Reference ID:682
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.
Affiliations:Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.
Reference Type:Literature
PubMed ID:15020763
Journal:Proc Natl Acad Sci U S A
Journal Volume:101
Article Pages:4175-9
Journal ISSN:0027-8424
Article Chemical List:gov.nih.nlm.ncbi.www.jaxb.impl.NameOfSubstanceImpl@131b1ac0;gov.nih.nlm.ncbi.www.jaxb.impl.NameOfSubstanceImpl@58793d0c;gov.nih.nlm.ncbi.www.jaxb.impl.NameOfSubstanceImpl@7f970c34;gov.nih.nlm.ncbi.www.jaxb.impl.NameOfSubstanceImpl@15a26b5d;gov.nih.nlm.ncbi.www.jaxb.impl.NameOfSubstanceImpl@5a36b1c3;gov.nih.nlm.ncbi.www.jaxb.impl.NameOfSubstanceImpl@3cd0a77a;gov.nih.nlm.ncbi.www.jaxb.impl.NameOfSubstanceImpl@26a359c7;gov.nih.nlm.ncbi.www.jaxb.impl.NameOfSubstanceImpl@2e5b2ba2
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
Curation Last Updated:2015-01-17 20:51:59