Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease
Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease
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DOI：
10.1073/pnas.0306885101
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发表时间：
2004-03-23
影响因子：
11.1
通讯作者：
Sollid, LM
中科院分区：
文献类型：
--
作者：
Kim, CY;Quarsten, H;Sollid, LM
乳糜泻，也称为乳糜泻，是一种麸质诱导的小肠自身免疫样疾病，与HLA-DQ 2密切相关。与来自谷蛋白的免疫原性表位QLQPFPQPELPY复合的DQ 2的结构已经通过X射线晶体学确定为2.2埃分辨率。P6处的谷氨酸通过组织转氨酶催化的脱酰胺作用形成，是重要的锚残基，因为它参与了涉及DQ 2的Lys-β 71的广泛氢键网络。谷蛋白肽-DQ 2复合物保留了MHC和肽骨架之间的关键氢键，尽管肽中存在许多不能参与酰胺介导的氢键的脯氨酸残基。脯氨酸残基的定位使得它们不干扰骨架氢键导致可用于谷蛋白肽与MHC II类分子结合的寄存器数量减少，并且可能损害建立有利的侧链相互作用的可能性。乳糜泻中的HLA相关性可以通过DQ 2结合富含脯氨酸的谷蛋白肽的偏向性库的上级能力来解释，所述谷蛋白肽已经在胃肠道消化中存活并且已经被组织转氨酶脱酰胺。最后，表面暴露的脯氨酸残基的蛋白水解抗性配体被取代的功能化类似物，从而提供了一个起点的口服活性剂的设计，用于阻断谷蛋白诱导的毒性。
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-Angstrom 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.