doi:10.1126/sciadv.aaw3818engFelix, JanWeinhäupl K.Chipot C.Dehez F.Hessel A.Gauto D.F.Morlot C.Abian, OlgaGutsche I.Velazquez-Campoy A.Schanda P.Fraga H.Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitorsART-2019-114962Coordinated 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.2019http://zaguan.unizar.es/record/8631710.1126/sciadv.aaw3818http://zaguan.unizar.es/record/86317oai:zaguan.unizar.es:86317info:eu-repo/grantAgreement/EUR/ERC-2012-StG-311318info:eu-repo/grantAgreement/ES/FIS/PI15-00663info:eu-repo/grantAgreement/ES/ISCIII-FIS/PI18-00349info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-PScience 5, 9 (2019), [18 pp.]by-nchttp://creativecommons.org/licenses/by-nc/3.0/es/info:eu-repo/semantics/openAccess