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The anti-cancer drug bortezomib exhibits potent anti-mycobacterial activity and binds to <jats:italic>Mycobacterium tuberculosis<\/jats:italic> (<jats:italic>Mtb<\/jats:italic>) Clp protease complexes. We determine cryo-EM structures of <jats:italic>Mtb<\/jats:italic> ClpP1P2, ClpC1P1P2 and ClpXP1P2 complexes bound to bortezomib in different conformations. Structural and biochemical data indicate that sub-stoichiometric binding by bortezomib to the protease active sites orthosterically activates the <jats:italic>Mtb<\/jats:italic>ClpP1P2 complex. Bortezomib activation of <jats:italic>Mtb<\/jats:italic>ClpP1P2 induces structural changes promoting the recruitment of the chaperone-unfoldases, <jats:italic>Mtb<\/jats:italic>ClpC1 or <jats:italic>Mtb<\/jats:italic>ClpX, facilitating holoenzyme formation. The structures of the <jats:italic>Mtb<\/jats:italic>ClpC1P1P2 holoenzyme indicate that <jats:italic>Mtb<\/jats:italic>ClpC1 motion, induced by ATP rebinding at the <jats:italic>Mtb<\/jats:italic>ClpC1 spiral seam, translocates the substrate. In the <jats:italic>Mtb<\/jats:italic>ClpXP1P2 holoenzyme structure, we identify a specialized substrate channel gating mechanism involving the <jats:italic>Mtb<\/jats:italic>ClpX pore-2 loop and <jats:italic>Mtb<\/jats:italic>ClpP2 N-terminal domains. Our results provide insights into the intricate regulation of the <jats:italic>Mtb<\/jats:italic> Clp system and suggest that bortezomib can disrupt this regulation by sub-stoichiometric binding at the <jats:italic>Mtb<\/jats:italic> Clp protease sites.<\/jats:p>","DOI":"10.1038\/s41467-025-58410-4","type":"journal-article","created":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T14:37:41Z","timestamp":1744382261000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Structural Insights into Bortezomib-Induced Activation of the Caseinolytic Chaperone-Protease System in Mycobacterium tuberculosis"],"prefix":"10.1038","volume":"16","author":[{"given":"Biao","family":"Zhou","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4131-3444","authenticated-orcid":false,"given":"Yamin","family":"Gao","sequence":"additional","affiliation":[]},{"given":"Heyu","family":"Zhao","sequence":"additional","affiliation":[]},{"given":"Banghui","family":"Liu","sequence":"additional","affiliation":[]},{"given":"Han","family":"Zhang","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8045-3098","authenticated-orcid":false,"given":"Cuiting","family":"Fang","sequence":"additional","affiliation":[]},{"given":"Hang","family":"Yuan","sequence":"additional","affiliation":[]},{"given":"Jingjing","family":"Wang","sequence":"additional","affiliation":[]},{"given":"Zimu","family":"Li","sequence":"additional","affiliation":[]},{"given":"Yi","family":"Zhao","sequence":"additional","affiliation":[]},{"given":"Xiaodong","family":"Huang","sequence":"additional","affiliation":[]},{"given":"Xiyue","family":"Wang","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8753-4950","authenticated-orcid":false,"given":"A. 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