000120016 001__ 120016
000120016 005__ 20240319081002.0
000120016 0247_ $$2doi$$a10.1002/pro.4427
000120016 0248_ $$2sideral$$a130894
000120016 037__ $$aART-2022-130894
000120016 041__ $$aeng
000120016 100__ $$0(orcid)0000-0003-4726-7821$$aJimenez-Alesanco, Ana$$uUniversidad de Zaragoza
000120016 245__ $$aRepositioning small molecule drugs as allosteric inhibitors of the BFT-3 toxin from enterotoxigenic Bacteroides fragilis
000120016 260__ $$c2022
000120016 5060_ $$aAccess copy available to the general public$$fUnrestricted
000120016 5203_ $$aBacteroides 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.
000120016 536__ $$9info:eu-repo/grantAgreement/ES/DGA/E25-20R
000120016 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/
000120016 590__ $$a8.0$$b2022
000120016 592__ $$a4.007$$b2022
000120016 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b36 / 285 = 0.126$$c2022$$dQ1$$eT1
000120016 593__ $$aBiochemistry$$c2022$$dQ1
000120016 593__ $$aMolecular Biology$$c2022$$dQ1
000120016 593__ $$aMedicine (miscellaneous)$$c2022$$dQ1
000120016 594__ $$a10.8$$b2022
000120016 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000120016 700__ $$aEckhard, Ulrich
000120016 700__ $$aAsencio del Rio, Marta
000120016 700__ $$0(orcid)0000-0002-1232-6310$$aVega, Sonia
000120016 700__ $$aGuevara, Tibisay
000120016 700__ $$0(orcid)0000-0001-5702-4538$$aVelazquez-Campoy, Adrian$$uUniversidad de Zaragoza
000120016 700__ $$aGomis-Rüth, Francesc Xavier
000120016 700__ $$0(orcid)0000-0001-5664-1729$$aAbian, Olga$$uUniversidad de Zaragoza
000120016 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000120016 773__ $$g31, 10 (2022), [18 pp.]$$pProtein sci.$$tProtein science$$x0961-8368
000120016 8564_ $$s4884677$$uhttps://zaguan.unizar.es/record/120016/files/texto_completo.pdf$$yVersión publicada
000120016 8564_ $$s2642195$$uhttps://zaguan.unizar.es/record/120016/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000120016 909CO $$ooai:zaguan.unizar.es:120016$$particulos$$pdriver
000120016 951__ $$a2024-03-18-14:16:16
000120016 980__ $$aARTICLE