9OHC

CryoEM structure of Toxin B (TcdB) from clostridioides difficile complexed with taurochenodeoxycholic acid (TCDCA)

9OHC の概要

• エントリーDOI: 10.2210/pdb9ohc/pdb
• 関連するPDBエントリー: 9OHD 9OHE 9OHF
• EMDBエントリー: 70486 70487 70488 70489
• 分子名称: Toxin B, TAUROCHENODEOXYCHOLIC ACID (2 entities in total)
• 機能のキーワード: clostridioides difficile, toxin b, tcdb, bile acid, tcdca, toxin
• 由来する生物種: Clostridioides difficile
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 272266.39

構造登録者

Miletic, S.,Li, Z.,Melnyk, R.A. (登録日: 2025-05-04, 公開日: 2026-03-11)

主引用文献

Miletic, S.,Icho, S.,Li, Z.,Tam, J.,Rose, E.C.,Perkins, C.E.,Nakhi, A.,Yang, X.,Hang, H.C.,Rubinstein, J.L.,Dosa, P.I.,Theriot, C.M.,Melnyk, R.A.
Structure-guided design of a synthetic bile acid that inhibits Clostridioides difficile TcdB toxin.
Nat Microbiol, 10:3215-3228, 2025

PubMed Abstract: Intestinal bile acids are a family of host and microbiota metabolites that can directly inhibit toxin B (TcdB), the primary virulence factor of Clostridioides difficile that causes infectious diarrhoea and colitis. However, the mechanism underlying the inhibition is unclear. Here we used cryogenic electron microscopy and determined the structure of TcdB bound to inhibitory bile acids cholic acid (methyl ester) and taurochenodeoxycholic acid at 2.9 Å and 3.3 Å resolution, respectively. These structures revealed that bile acids lock the C-terminal CROP domain of TcdB in a conformation that allosterically masks the two receptor-binding sites and prevents target cell recognition. Guided by the structure, we synthesized gut-restricted bile acid derivatives, designed to evade the bile acid reuptake transporters within the gut. One of the derivatives, sBA-2, was retained within the gut upon oral dosing and protected mice from toxin-induced C. difficile disease pathology. Our study uncovers the structural basis of inhibition of TcdB by bile acids and its analogues, paving the way for the development of orally deliverable therapeutics against C. difficile.

PubMed: 41254394
DOI: 10.1038/s41564-025-02179-1

実験手法

ELECTRON MICROSCOPY (3.28 Å)