{"citation":{"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>.","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).","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>","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.","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>","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>.","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."},"publication":"Science Advances","volume":5,"article_number":"eaaw3818","type":"journal_article","status":"public","_id":"8406","article_processing_charge":"No","author":[{"first_name":"Jan","full_name":"Felix, Jan","last_name":"Felix"},{"last_name":"Weinhäupl","full_name":"Weinhäupl, Katharina","first_name":"Katharina"},{"last_name":"Chipot","first_name":"Christophe","full_name":"Chipot, Christophe"},{"last_name":"Dehez","first_name":"François","full_name":"Dehez, François"},{"first_name":"Audrey","full_name":"Hessel, Audrey","last_name":"Hessel"},{"full_name":"Gauto, Diego F.","first_name":"Diego F.","last_name":"Gauto"},{"full_name":"Morlot, Cecile","first_name":"Cecile","last_name":"Morlot"},{"full_name":"Abian, Olga","first_name":"Olga","last_name":"Abian"},{"first_name":"Irina","full_name":"Gutsche, Irina","last_name":"Gutsche"},{"last_name":"Velazquez-Campoy","full_name":"Velazquez-Campoy, Adrian","first_name":"Adrian"},{"first_name":"Paul","full_name":"Schanda, Paul","orcid":"0000-0002-9350-7606","last_name":"Schanda","id":"7B541462-FAF6-11E9-A490-E8DFE5697425"},{"last_name":"Fraga","first_name":"Hugo","full_name":"Fraga, Hugo"}],"day":"04","doi":"10.1126/sciadv.aaw3818","oa":1,"oa_version":"Published Version","year":"2019","main_file_link":[{"open_access":"1","url":" https://doi.org/10.1126/sciadv.aaw3818"}],"publication_identifier":{"issn":["2375-2548"]},"article_type":"original","month":"09","extern":"1","abstract":[{"lang":"eng","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."}],"quality_controlled":"1","date_updated":"2021-01-12T08:19:03Z","publication_status":"published","title":"Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors","publisher":"American Association for the Advancement of Science","intvolume":"         5","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","date_created":"2020-09-17T10:28:36Z","issue":"9","language":[{"iso":"eng"}],"date_published":"2019-09-04T00:00:00Z"}