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

Summary

Cryo-EM structures reveal that sub-stoichiometric bortezomib binding activates M. tuberculosis ClpP1P2, drives chaperone recruitment (ClpC1/ClpX), and uncovers a substrate channel gating mechanism. These insights connect a clinically approved proteasome inhibitor to actionable regulation of a validated TB target.

Key Findings

• Cryo-EM structures of Mtb ClpP1P2, ClpC1P1P2, and ClpXP1P2 bound to bortezomib in multiple conformations were solved.
• Sub-stoichiometric orthosteric binding of bortezomib activates ClpP1P2 and promotes recruitment of ClpC1 or ClpX to form holoenzymes.
• A specialized substrate channel gating mechanism involving the ClpX pore-2 loop and ClpP2 N-termini was identified.

Clinical Implications

While preclinical, the work prioritizes ClpP1P2/ClpC1-ClpX interfaces and activation states as druggable sites; it also cautions about bortezomib’s host toxicity, guiding the search for TB-selective analogs.

Limitations

• Preclinical structural/biochemical work without in vivo efficacy data
• Potential translational toxicity issues with bortezomib require TB-selective derivatives

Future Directions

Design TB-selective Clp modulators guided by binding poses; test efficacy and safety in Mtb infection models; explore resistance liabilities and combination regimens.