Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors.

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2019
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Abstract
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.
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Authors Felix, Jan;Weinhäupl, Katharina;Chipot, Christophe;Dehez, François;Hessel, Audrey;Gauto, Diego F;Morlot, Cecile;Abian, Olga;Gutsche, Irina;Velazquez-Campoy, Adrian;Schanda, Paul;Fraga, Hugo;
Journal Science advances
Year 2019
DOI 10.1126/sciadv.aaw3818
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Keywords
computational fluid dynamics mechanical engineering hydrodynamics fink's guide vane fluid mechanics hydrodynamic instability reversible francis turbine unsteady cfd

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