title: Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease.
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.
authors.affiliation: Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.
authors.forename: Chu-Young
authors.initials: CY
authors.lastname: Kim
authors.forename: Hanne
authors.initials: H
authors.lastname: Quarsten
authors.forename: Elin
authors.initials: E
authors.lastname: Bergseng
authors.forename: Chaitan
authors.initials: C
authors.lastname: Khosla
authors.forename: Ludvig M
authors.initials: LM
authors.lastname: Sollid
mesh_terms: D002446:Celiac Disease / Q000276:immunology*; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D005903:Gliadin / Q000737:chemistry / Q000276:immunology; D005983:Glutens / Q000737:chemistry* / Q000276:immunology; D006683:HLA-DQ Antigens / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D008024:Ligands; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011392:Proline / Q000737:chemistry; D017434:Protein Structure, Tertiary
chemical_list: D000939:Epitopes; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D008024:Ligands; D010455:Peptides; D005983:Glutens; D005903:Gliadin; D011392:Proline