000086317 001__ 86317
000086317 005__ 20240614091132.0
000086317 0247_ $$2doi$$a10.1126/sciadv.aaw3818
000086317 0248_ $$2sideral$$a114962
000086317 037__ $$aART-2019-114962
000086317 041__ $$aeng
000086317 100__ $$aFelix, Jan
000086317 245__ $$aMechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors
000086317 260__ $$c2019
000086317 5060_ $$aAccess copy available to the general public$$fUnrestricted
000086317 5203_ $$aCoordinated conformational transitions in oligomeric enzymatic complexes modulate function in response to substrates and play a crucial role in enzyme inhibition and activation. Caseinolytic protease (ClpP) is a tetradecameric complex, which has emerged as a drug target against multiple pathogenic bacteria. Activation of different ClpPs by inhibitors has been independently reported from drug development efforts, but no rationale for inhibitor-induced activation has been hitherto proposed. Using an integrated approach that includes x-ray crystallography, solid- and solution-state nuclear magnetic resonance, molecular dynamics simulations, and isothermal titration calorimetry, we show that the proteasome inhibitor bortezomib binds to the ClpP active-site serine, mimicking a peptide substrate, and induces a concerted allosteric activation of the complex. The bortezomib-activated conformation also exhibits a higher affinity for its cognate unfoldase ClpX. We propose a universal allosteric mechanism, where substrate binding to a single subunit locks ClpP into an active conformation optimized for chaperone association and protein processive degradation.
000086317 536__ $$9info:eu-repo/grantAgreement/EUR/ERC-2012-StG-311318$$9info:eu-repo/grantAgreement/ES/FIS/PI15-00663$$9info:eu-repo/grantAgreement/ES/ISCIII-FIS/PI18-00349$$9info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P
000086317 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc$$uhttp://creativecommons.org/licenses/by-nc/3.0/es/
000086317 590__ $$a41.845$$b2019
000086317 591__ $$aMULTIDISCIPLINARY SCIENCES$$b2 / 70 = 0.029$$c2019$$dQ1$$eT1
000086317 592__ $$a13.11$$b2019
000086317 593__ $$aMultidisciplinary$$c2019$$dQ1
000086317 593__ $$aHistory and Philosophy of Science$$c2019$$dQ1
000086317 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000086317 700__ $$aWeinhäupl K.
000086317 700__ $$aChipot C.
000086317 700__ $$aDehez F.
000086317 700__ $$aHessel A.
000086317 700__ $$aGauto D.F.
000086317 700__ $$aMorlot C.
000086317 700__ $$0(orcid)0000-0001-5664-1729$$aAbian, Olga$$uUniversidad de Zaragoza
000086317 700__ $$aGutsche I.
000086317 700__ $$0(orcid)0000-0001-5702-4538$$aVelazquez-Campoy A.$$uUniversidad de Zaragoza
000086317 700__ $$aSchanda P.
000086317 700__ $$aFraga H.
000086317 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000086317 773__ $$g5, 9 (2019), [18 pp.]$$pSci.$$tScience$$x0036-8075
000086317 8564_ $$s6378559$$uhttps://zaguan.unizar.es/record/86317/files/texto_completo.pdf$$yVersión publicada
000086317 8564_ $$s142034$$uhttps://zaguan.unizar.es/record/86317/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000086317 909CO $$ooai:zaguan.unizar.es:86317$$particulos$$pdriver
000086317 951__ $$a2024-06-14-09:07:20
000086317 980__ $$aARTICLE