7UBX

Structure of a pore forming fragment of Clostridium difficile toxin A in complex with VHH AA6

7UBX の概要

• エントリーDOI: 10.2210/pdb7ubx/pdb
• 分子名称: Toxin A, Nanobody VHH AA6 (3 entities in total)
• 機能のキーワード: pore forming, neutralizing antibody, toxin
• 由来する生物種: Clostridioides difficile; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 113484.44

構造登録者

Chen, B.,Rongsheng, J.,Kay, P. (登録日: 2022-03-15, 公開日: 2022-11-16, 最終更新日: 2023-10-25)

主引用文献

Chen, B.,Perry, K.,Jin, R.
Neutralizing epitopes on Clostridioides difficile toxin A revealed by the structures of two camelid VHH antibodies.
Front Immunol, 13:978858-978858, 2022

PubMed Abstract: Toxin A (TcdA) and toxin B (TcdB) are two key virulence factors secreted by , which is listed as an urgent threat by the CDC. These two large homologous exotoxins are mainly responsible for diseases associated with infection (CDI) with symptoms ranging from diarrhea to life threatening pseudomembranous colitis. Single-domain camelid antibodies (VHHs) AH3 and AA6 are two potent antitoxins against TcdA, which when combined with two TcdB-targeting VHHs showed effective protection against both primary and recurrent CDI in animal models. Here, we report the co-crystal structures of AH3 and AA6 when they form complexes with the glucosyltransferase domain (GTD) and a fragment of the delivery and receptor-binding domain (DRBD) of TcdA, respectively. Based on these structures, we find that AH3 binding enhances the overall stability of the GTD and interferes with its unfolding at acidic pH, and AA6 may inhibit the pH-dependent conformational changes in the DRBD that is necessary for pore formation of TcdA. These studies reveal two functionally critical epitopes on TcdA and shed new insights into neutralizing mechanisms and potential development of epitope-focused vaccines against TcdA.

PubMed: 36466927
DOI: 10.3389/fimmu.2022.978858

実験手法

X-RAY DIFFRACTION (1.81 Å)