8B9O

Structure of the C-terminal domain of ClpC2 from Mycobacterium smegmatis

8B9O の概要

• エントリーDOI: 10.2210/pdb8b9o/pdb
• 分子名称: Clp amino terminal domain protein, phospho-arginine (3 entities in total)
• 機能のキーワード: stress resistance protein, cytosolic protein
• 由来する生物種: Mycolicibacterium smegmatis
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 17072.22

構造登録者

Meinhart, A.,Hoi, D.M.,Clausen, T. (登録日: 2022-10-06, 公開日: 2023-07-05, 最終更新日: 2024-02-07)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2 Å)