Structural Insights into Bortezomib-Induced Activation of the Caseinolytic Chaperone-Protease System in Mycobacterium tuberculosis

Biao Zhou, Yamin Gao, Heyu Zhao, Banghui Liu, Han Zhang, Cuiting Fang, Hang Yuan, Jingjing Wang, Zimu Li, Yi Zhao, Xiaodong Huang, Xiyue Wang, A. Sofia. F. Oliveira, James Spencer, Adrian J. Mulholland, Steven G. Burston, Jinxing Hu, Ning Su, Xinwen Chen (), Jun He (), Tianyu Zhang () and Xiaoli Xiong ()
Additional contact information
Biao Zhou: Guangzhou Medical University
Yamin Gao: Chinese Academy of Sciences
Heyu Zhao: Chinese Academy of Sciences
Banghui Liu: Chinese Academy of Sciences
Han Zhang: Chinese Academy of Sciences
Cuiting Fang: Chinese Academy of Sciences
Hang Yuan: Chinese Academy of Sciences
Jingjing Wang: Chinese Academy of Sciences
Zimu Li: Graduate School of Guangzhou Medical University, Guangzhou Medical University-Guangzhou Institutes of Biomedicine and Health Joint School of Life Sciences, Guangzhou Medical University
Yi Zhao: Chinese Academy of Sciences
Xiaodong Huang: Graduate School of Guangzhou Medical University, Guangzhou Medical University-Guangzhou Institutes of Biomedicine and Health Joint School of Life Sciences, Guangzhou Medical University
Xiyue Wang: Guangxi Medical University Laboratory Animal Center
A. Sofia. F. Oliveira: University of Bristol
James Spencer: University of Bristol
Adrian J. Mulholland: University of Bristol
Steven G. Burston: University of Bristol
Jinxing Hu: Guangzhou Medical University
Ning Su: Guangzhou Medical University
Xinwen Chen: Guangzhou National Laboratory
Jun He: Chinese Academy of Sciences
Tianyu Zhang: Chinese Academy of Sciences
Xiaoli Xiong: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract The caseinolytic protease (Clp) system has recently emerged as a promising anti-tuberculosis target. The anti-cancer drug bortezomib exhibits potent anti-mycobacterial activity and binds to Mycobacterium tuberculosis (Mtb) Clp protease complexes. We determine cryo-EM structures of Mtb 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 MtbClpP1P2 complex. Bortezomib activation of MtbClpP1P2 induces structural changes promoting the recruitment of the chaperone-unfoldases, MtbClpC1 or MtbClpX, facilitating holoenzyme formation. The structures of the MtbClpC1P1P2 holoenzyme indicate that MtbClpC1 motion, induced by ATP rebinding at the MtbClpC1 spiral seam, translocates the substrate. In the MtbClpXP1P2 holoenzyme structure, we identify a specialized substrate channel gating mechanism involving the MtbClpX pore-2 loop and MtbClpP2 N-terminal domains. Our results provide insights into the intricate regulation of the Mtb Clp system and suggest that bortezomib can disrupt this regulation by sub-stoichiometric binding at the Mtb Clp protease sites.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-58410-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58410-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-58410-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().