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TitleStructural Insights into Bortezomib-Induced Activation of the Caseinolytic Chaperone-Protease System in Mycobacterium tuberculosis.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 3466, Year 2025
Publish dateApr 11, 2025
AuthorsBiao 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 / Xiaoli Xiong /
PubMed AbstractThe 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 ...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.
External linksNat Commun / PubMed:40216758 / PubMed Central
MethodsEM (single particle)
Resolution2.15 - 2.56 Å
Structure data

61842

9jvp

EMDB-61842, PDB-9jvp:
CryoEM structure of M. tuberculosis ClpC1P1P2 complex bound to bortezomib, conformation 3
Method: EM (single particle) / Resolution: 2.15 Å

61847

9jvz

EMDB-61847, PDB-9jvz:
CryoEM structure of M. tuberculosis ClpP1P2 bound to bortezomib
Method: EM (single particle) / Resolution: 2.56 Å

Chemicals

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-MG:
Unknown entry

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

ChemComp-BO2:
N-[(1R)-1-(DIHYDROXYBORYL)-3-METHYLBUTYL]-N-(PYRAZIN-2-YLCARBONYL)-L-PHENYLALANINAMIDE / medication, anticancer*YM

Source
  • Mycobacterium tuberculosis (bacteria)
  • mycobacterium tuberculosis h37rv (bacteria)
  • bos grunniens (domestic yak)
KeywordsHYDROLASE / Mycobacterium tuberculosis / Caseinolytic protease system / Activation

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