ArticleNature communications2025
Structural Insights into Bortezomib-Induced Activation of the Caseinolytic Chaperone-Protease System in Mycobacterium tuberculosis.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
What it found
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Who cites it
9 citing papers in PubMed.
- Bortezomib exhibited bacteriostatic activity and pro-inflammatory effect against Mycoplasma pneumoniae.The Journal of antibiotics · 2026Article
- ClpC1-dependent iron homeostasis underlies mycobacterial defense against oxygen-driven Fenton reaction during reactivation.Microbiology spectrum · 2026Article
- Repurposing approved drugs as potential inhibitors of Mycobacterium tuberculosis ClpP: Structure-based virtual screening, molecular dynamics, and in vitro evaluation.Molecular diversity · 2026Article
- ClpC1-targeting peptide natural products differentially dysregulate the proteome of Mycobacterium tuberculosis.Nature communications · 2026Article
- Structure of the central Staphylococcus aureus AAA+ protease MecA/ClpC/ClpP.Communications biology · 2025Article
- Allosteric regulation of proteolytic machines unveiled by the synergy between cryo-EM and solution NMR spectroscopy.The Biochemical journal · 2025Review
- Mutations in ClpC1 or ClpX subunit of caseinolytic protease confer resistance to ilamycins in mycobacteria.Communications biology · 2025Article
- The Identification of Novel Mutations in ATP-Dependent Protease ClpC1 Assists in the Molecular Diagnosis of Obscured Pyrazinamide-Resistant Tuberculosis Clinical Isolates.Microorganisms · 2025Article
- Host-Directed Therapies Based on Protease Inhibitors to ControlMicroorganisms · 2025Review
Corrections and comments
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Authors and funding
22 authors.
Funding
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.
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