7POL

Crystal structure of profragilysin-3 (proBFT-3) from Bacteroides fragilis in complex with flumequine

7POL の概要

• エントリーDOI: 10.2210/pdb7pol/pdb
• 関連するPDBエントリー: 7PND
• 分子名称: BFT-3, ZINC ION, (12~{R})-7-fluoranyl-12-methyl-4-oxidanylidene-1-azatricyclo[7.3.1.0^{5,13}]trideca-2,5(13),6,8-tetraene-3-carboxylic acid, ... (7 entities in total)
• 機能のキーワード: protease, zymogen, proteolysis, enterotoxin, fragilysin, hydrolase
• 由来する生物種: Bacteroides fragilis
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 92389.24

構造登録者

Eckhard, U.,Guevara, T.,Gomis-Ruth, F.X. (登録日: 2021-09-09, 公開日: 2022-09-14, 最終更新日: 2024-01-31)

主引用文献

Jimenez-Alesanco, A.,Eckhard, U.,Asencio Del Rio, M.,Vega, S.,Guevara, T.,Velazquez-Campoy, A.,Gomis-Ruth, F.X.,Abian, O.
Repositioning small molecule drugs as allosteric inhibitors of the BFT-3 toxin from enterotoxigenic Bacteroides fragilis.
Protein Sci., 31:e4427-e4427, 2022

PubMed Abstract: Bacteroides fragilis is an abundant commensal component of the healthy human colon. However, under dysbiotic conditions, enterotoxigenic B. fragilis (ETBF) may arise and elicit diarrhea, anaerobic bacteremia, inflammatory bowel disease, and colorectal cancer. Most worrisome, ETBF is resistant to many disparate antibiotics. ETBF's only recognized specific virulence factor is a zinc-dependent metallopeptidase (MP) called B. fragilis toxin (BFT) or fragilysin, which damages the intestinal mucosa and triggers disease-related signaling mechanisms. Thus, therapeutic targeting of BFT is expected to limit ETBF pathogenicity and improve the prognosis for patients. We focused on one of the naturally occurring BFT isoforms, BFT-3, and managed to repurpose several approved drugs as BFT-3 inhibitors through a combination of biophysical, biochemical, structural, and cellular techniques. In contrast to canonical MP inhibitors, which target the active site of mature enzymes, these effectors bind to a distal allosteric site in the proBFT-3 zymogen structure, which stabilizes a partially unstructured, zinc-free enzyme conformation by shifting a zinc-dependent disorder-to-order equilibrium. This yields proBTF-3 incompetent for autoactivation, thus ablating hydrolytic activity of the mature toxin. Additionally, a similar destabilizing effect is observed for the activated protease according to biophysical and biochemical data. Our strategy paves a novel way for the development of highly specific inhibitors of ETBF-mediated enteropathogenic conditions.

PubMed: 36173175
DOI: 10.1002/pro.4427

実験手法

X-RAY DIFFRACTION (1.95 Å)