86317 20240614091132.0 doi 10.1126/sciadv.aaw3818 sideral 114962 ART-2019-114962 eng Felix, Jan Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors 2019 Access copy available to the general public Unrestricted Coordinated 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. info:eu-repo/grantAgreement/EUR/ERC-2012-StG-311318 info:eu-repo/grantAgreement/ES/FIS/PI15-00663 info:eu-repo/grantAgreement/ES/ISCIII-FIS/PI18-00349 info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P info:eu-repo/semantics/openAccess by-nc http://creativecommons.org/licenses/by-nc/3.0/es/ 41.845 2019 MULTIDISCIPLINARY SCIENCES 2 / 70 = 0.029 2019 Q1 T1 13.11 2019 Multidisciplinary 2019 Q1 History and Philosophy of Science 2019 Q1 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Weinhäupl K. Chipot C. Dehez F. Hessel A. Gauto D.F. Morlot C. Abian, Olga Universidad de Zaragoza (orcid)0000-0001-5664-1729 Gutsche I. Velazquez-Campoy A. Universidad de Zaragoza (orcid)0000-0001-5702-4538 Schanda P. Fraga H. 1002 060 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Bioquímica y Biolog.Mole. 5, 9 (2019), [18 pp.] Sci. Science 0036-8075 6378559 http://zaguan.unizar.es/record/86317/files/texto_completo.pdf Versión publicada 142034 http://zaguan.unizar.es/record/86317/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:86317 articulos driver 2024-06-14-09:07:20 ARTICLE