8B9U

Structure of ClpC1 NTD from Mycobacterium tuberculosis

Summary for 8B9U

• Entry DOI: 10.2210/pdb8b9u/pdb
• Descriptor: ATP-dependent Clp protease ATP-binding subunit ClpC1, (MLE)V(MAA)(E9M)G, FORMIC ACID, ... (4 entities in total)
• Functional Keywords: ligand bound state, chaperone
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv); More
• Total number of polymer chains: 3
• Total formula weight: 32587.36

Authors

Meinhart, A.,Hoi, D.M.,Clausen, T. (deposition date: 2022-10-10, release date: 2023-07-05, Last modification date: 2024-10-16)

Primary citation

Hoi, D.M.,Junker, S.,Junk, L.,Schwechel, K.,Fischel, K.,Podlesainski, D.,Hawkins, P.M.E.,van Geelen, L.,Kaschani, F.,Leodolter, J.,Morreale, F.E.,Kleine, S.,Guha, S.,Rumpel, K.,Schmiedel, V.M.,Weinstabl, H.,Meinhart, A.,Payne, R.J.,Kaiser, M.,Hartl, M.,Boehmelt, G.,Kazmaier, U.,Kalscheuer, R.,Clausen, T.
Clp-targeting BacPROTACs impair mycobacterial proteostasis and survival.
Cell, 186:2176-, 2023

PubMed Abstract: The ClpC1:ClpP1P2 protease is a core component of the proteostasis system in mycobacteria. To improve the efficacy of antitubercular agents targeting the Clp protease, we characterized the mechanism of the antibiotics cyclomarin A and ecumicin. Quantitative proteomics revealed that the antibiotics cause massive proteome imbalances, including upregulation of two unannotated yet conserved stress response factors, ClpC2 and ClpC3. These proteins likely protect the Clp protease from excessive amounts of misfolded proteins or from cyclomarin A, which we show to mimic damaged proteins. To overcome the Clp security system, we developed a BacPROTAC that induces degradation of ClpC1 together with its ClpC2 caretaker. The dual Clp degrader, built from linked cyclomarin A heads, was highly efficient in killing pathogenic Mycobacterium tuberculosis, with >100-fold increased potency over the parent antibiotic. Together, our data reveal Clp scavenger proteins as important proteostasis safeguards and highlight the potential of BacPROTACs as future antibiotics.

PubMed: 37137307
DOI: 10.1016/j.cell.2023.04.009

Experimental method

X-RAY DIFFRACTION (2.25 Å)