4NC1

Crystal Structure of TcdA-A2 Bound to A20.1 VHH and A26.8 VHH

4NC1 の概要

• エントリーDOI: 10.2210/pdb4nc1/pdb
• 関連するPDBエントリー: 2G7C 4NBX 4NBY 4NBZ 4NC0 4NC2
• 分子名称: Cell wall-binding repeat protein, A20.1 VHH, A26.8 VHH, ... (4 entities in total)
• 機能のキーワード: antibody-antigen complex, immune system
• 由来する生物種: Clostridium difficile; 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 121938.57

構造登録者

Murase, T.,Eugenio, L.,Schorr, M.,Hussack, G.,Tanha, J.,Kitova, E.N.,Klassen, J.S.,Ng, K.K.S. (登録日: 2013-10-23, 公開日: 2013-12-11, 最終更新日: 2024-10-30)

主引用文献

Murase, T.,Eugenio, L.,Schorr, M.,Hussack, G.,Tanha, J.,Kitova, E.N.,Klassen, J.S.,Ng, K.K.
Structural Basis for Antibody Recognition in the Receptor-binding Domains of Toxins A and B from Clostridium difficile.
J.Biol.Chem., 289:2331-2343, 2014

PubMed Abstract: Clostridium difficile infection is a serious and highly prevalent nosocomial disease in which the two large, Rho-glucosylating toxins TcdA and TcdB are the main virulence factors. We report for the first time crystal structures revealing how neutralizing and non-neutralizing single-domain antibodies (sdAbs) recognize the receptor-binding domains (RBDs) of TcdA and TcdB. Surprisingly, the complexes formed by two neutralizing antibodies recognizing TcdA do not show direct interference with the previously identified carbohydrate-binding sites, suggesting that neutralization of toxin activity may be mediated by mechanisms distinct from steric blockage of receptor binding. A camelid sdAb complex also reveals the molecular structure of the TcdB RBD for the first time, facilitating the crystallization of a strongly negatively charged protein fragment that has resisted previous attempts at crystallization and structure determination. Electrospray ionization mass spectrometry measurements confirm the stoichiometries of sdAbs observed in the crystal structures. These studies indicate how key epitopes in the RBDs from TcdA and TcdB are recognized by sdAbs, providing molecular insights into toxin structure and function and providing for the first time a basis for the design of highly specific toxin-specific therapeutic and diagnostic agents.

PubMed: 24311789
DOI: 10.1074/jbc.M113.505917

実験手法

X-RAY DIFFRACTION (2.61 Å)