9IF4

Structure of the Mycobacterium Tuberculosis ClpC1P1P2 complex bound to the activator Bz-Leu-Leu

Summary for 9IF4

• Entry DOI: 10.2210/pdb9if4/pdb
• EMDB information: 52840
• Descriptor: ATP-dependent Clp protease ATP-binding subunit ClpC1, ATP-dependent Clp protease proteolytic subunit 2, ATP-dependent Clp protease proteolytic subunit 1, ... (7 entities in total)
• Functional Keywords: protein quality control, peptide activator, protease, atpase, chaperone
• Biological source: Mycobacterium tuberculosis; More
• Total number of polymer chains: 28
• Total formula weight: 741768.72

Authors

Weinhaeupl, K.,Semchonok, D.,Gragera, M.,Arranz, R.,Bueno Carrasco, M.T.,Fraga, H. (deposition date: 2025-02-17, release date: 2025-08-27, Last modification date: 2026-09-09)

Primary citation

Weinhaupl, K.,Akopian, T.,Semchonok, D.A.,Krandor, O.,Arranz, R.,Bueno-Carrasco, M.T.,Gragera, M.,Chevreuil, M.,Raynal, B.,Zinga, S.,Liu, Y.,Lai, J.,Wu, W.,Bachovchin, W.,Gauto, D.,Goldberg, A.,Rubin, E.,Fraga, H.
Activation mechanism and structural assembly of the Mycobacterium tuberculosis ClpP1P2 protease and its associated ATPases.
Cell Rep, 45:117400-117400, 2026

PubMed Abstract: Supramolecular assemblies are fundamental to cellular biochemical processes, relying on their dynamic nature to perform essential functions. The protease ClpP1P2, in association with ATPase partners ClpC1 or ClpX, is critical for the survival of Mycobacterium tuberculosis (Mtb). While the ClpP1P2 complex requires activation by specific N-blocked dipeptides to exhibit proteolytic activity in vitro, the mechanism of in vivo activation remains unclear. In this study, we use cryo-electron microscopy (cryo-EM) to determine the structure of the ClpC1P1P2 complex, revealing a highly asymmetric architecture with ClpC1 bound to the ClpP1P2 protease barrel. The activator dipeptide is observed only in the ClpP2 active site, while the ClpP1 entry pore remains closed. Molecular crowding agents promote the formation of larger ClpXP1P2 and ClpC1P1P2 complexes, enhancing structural stability and enzymatic activity. These findings suggest that molecular crowding stabilizes these complexes and promotes their activation, providing new insights into ClpC1P1P2 structural dynamics and function.

PubMed: 42213777
DOI: 10.1016/j.celrep.2026.117400

Experimental method

ELECTRON MICROSCOPY (3.09 Å)