5IJK

Crystal structure of anti-gliadin 1002-1E03 Fab fragment in complex of peptide PLQPEQPFP

5IJK の概要

• エントリーDOI: 10.2210/pdb5ijk/pdb
• 関連するPDBエントリー: 5IFJ 5IG7 5IHZ
• 分子名称: peptide PRO-LEU-GLN-PRO-GLU-GLN-PRO-PHE-PRO, 1E03 Fab fragment heavy chain, 1E03 Fab fragment light chain, ... (5 entities in total)
• 機能のキーワード: anti-gliadin antibody, celiac disease, immune system
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 100087.15

構造登録者

Snir, O.,Chen, X.,Gidoni, M.,du Pre, M.F.,Zhao, Y.,Steinsbo, O.,Lundin, K.E.,Yaari, G.,Sollid, L.M. (登録日: 2016-03-02, 公開日: 2017-03-15, 最終更新日: 2024-10-16)

主引用文献

Snir, O.,Chen, X.,Gidoni, M.,du Pre, M.F.,Zhao, Y.,Steinsbo, O.,Lundin, K.E.,Yaari, G.,Sollid, L.M.
Stereotyped antibody responses target posttranslationally modified gluten in celiac disease.
JCI Insight, 2:-, 2017

PubMed Abstract: The role of B cells and posttranslational modifications in pathogenesis of organ-specific immune diseases is increasingly envisioned but remains poorly understood, particularly in human disorders. In celiac disease, transglutaminase 2-modified (TG2-modified; deamidated) gluten peptides drive disease-specific T cell and B cell responses, and antibodies to deamidated gluten peptides are excellent diagnostic markers. Here, we substantiate by high-throughput sequencing of IGHV genes that antibodies to a disease-specific, deamidated, and immunodominant B cell epitope of gluten (PLQPEQPFP) have biased and stereotyped usage of IGHV3-23 and IGHV3-15 gene segments with modest somatic mutations. X-ray crystal structures of 2 prototype IGHV3-15/IGKV4-1 and IGHV3-23/IGLV4-69 antibodies reveal peptide interaction mainly via germline-encoded residues. In-depth mutational analysis showed restricted selection and substitution patterns at positions involved in antigen binding. While the IGHV3-15/IGKV4-1 antibody interacts with Glu5 and Gln6, the IGHV3-23/IGLV4-69 antibody interacts with Gln3, Pro4, Pro7, and Phe8 - residues involved in substrate recognition by TG2. Hence, both antibodies, despite different interaction with the epitope, recognize signatures of TG2 processing that facilitates B cell presentation of deamidated gluten peptides to T cells, thereby providing a molecular framework for the generation of these clinically important antibodies. The study provides essential insight into the pathogenic mechanism of celiac disease.

PubMed: 28878138
DOI: 10.1172/jci.insight.93961

実験手法

X-RAY DIFFRACTION (2.5 Å)