{"author":[{"last_name":"Felix","full_name":"Felix, Jan","first_name":"Jan"},{"last_name":"Weinhäupl","full_name":"Weinhäupl, Katharina","first_name":"Katharina"},{"last_name":"Chipot","full_name":"Chipot, Christophe","first_name":"Christophe"},{"last_name":"Dehez","full_name":"Dehez, François","first_name":"François"},{"first_name":"Audrey","full_name":"Hessel, Audrey","last_name":"Hessel"},{"full_name":"Gauto, Diego F.","last_name":"Gauto","first_name":"Diego F."},{"first_name":"Cecile","full_name":"Morlot, Cecile","last_name":"Morlot"},{"full_name":"Abian, Olga","last_name":"Abian","first_name":"Olga"},{"first_name":"Irina","full_name":"Gutsche, Irina","last_name":"Gutsche"},{"first_name":"Adrian","full_name":"Velazquez-Campoy, Adrian","last_name":"Velazquez-Campoy"},{"orcid":"0000-0002-9350-7606","id":"7B541462-FAF6-11E9-A490-E8DFE5697425","first_name":"Paul","last_name":"Schanda","full_name":"Schanda, Paul"},{"last_name":"Fraga","full_name":"Fraga, Hugo","first_name":"Hugo"}],"citation":{"ama":"Felix J, Weinhäupl K, Chipot C, et al. Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors. <i>Science Advances</i>. 2019;5(9). doi:<a href=\"https://doi.org/10.1126/sciadv.aaw3818\">10.1126/sciadv.aaw3818</a>","short":"J. Felix, K. Weinhäupl, C. Chipot, F. Dehez, A. Hessel, D.F. Gauto, C. Morlot, O. Abian, I. Gutsche, A. Velazquez-Campoy, P. Schanda, H. Fraga, Science Advances 5 (2019).","ista":"Felix J, Weinhäupl K, Chipot C, Dehez F, Hessel A, Gauto DF, Morlot C, Abian O, Gutsche I, Velazquez-Campoy A, Schanda P, Fraga H. 2019. Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors. Science Advances. 5(9), eaaw3818.","mla":"Felix, Jan, et al. “Mechanism of the Allosteric Activation of the ClpP Protease Machinery by Substrates and Active-Site Inhibitors.” <i>Science Advances</i>, vol. 5, no. 9, eaaw3818, American Association for the Advancement of Science, 2019, doi:<a href=\"https://doi.org/10.1126/sciadv.aaw3818\">10.1126/sciadv.aaw3818</a>.","apa":"Felix, J., Weinhäupl, K., Chipot, C., Dehez, F., Hessel, A., Gauto, D. F., … Fraga, H. (2019). Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors. <i>Science Advances</i>. American Association for the Advancement of Science. <a href=\"https://doi.org/10.1126/sciadv.aaw3818\">https://doi.org/10.1126/sciadv.aaw3818</a>","ieee":"J. Felix <i>et al.</i>, “Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors,” <i>Science Advances</i>, vol. 5, no. 9. American Association for the Advancement of Science, 2019.","chicago":"Felix, Jan, Katharina Weinhäupl, Christophe Chipot, François Dehez, Audrey Hessel, Diego F. Gauto, Cecile Morlot, et al. “Mechanism of the Allosteric Activation of the ClpP Protease Machinery by Substrates and Active-Site Inhibitors.” <i>Science Advances</i>. American Association for the Advancement of Science, 2019. <a href=\"https://doi.org/10.1126/sciadv.aaw3818\">https://doi.org/10.1126/sciadv.aaw3818</a>."},"intvolume":"         5","abstract":[{"text":"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.","lang":"eng"}],"quality_controlled":"1","date_created":"2020-09-17T10:28:36Z","oa_version":"Published Version","date_published":"2019-09-04T00:00:00Z","article_processing_charge":"No","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","article_type":"original","type":"journal_article","publication_identifier":{"issn":["2375-2548"]},"month":"09","status":"public","extern":"1","title":"Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors","issue":"9","doi":"10.1126/sciadv.aaw3818","_id":"8406","publication":"Science Advances","date_updated":"2021-01-12T08:19:03Z","main_file_link":[{"url":" https://doi.org/10.1126/sciadv.aaw3818","open_access":"1"}],"article_number":"eaaw3818","language":[{"iso":"eng"}],"oa":1,"publisher":"American Association for the Advancement of Science","volume":5,"year":"2019","day":"04","publication_status":"published"}