7AA4

Structure of ClpC1-NTD bound to a CymA analogue

7AA4 の概要

• エントリーDOI: 10.2210/pdb7aa4/pdb
• 分子名称: Negative regulator of genetic competence ClpC/mecB, polymer Cyclomarin A analogue (3 entities in total)
• 機能のキーワード: helical receptor domain, cyclomarin a inhibtor, chaperone
• 由来する生物種: Mycobacterium tuberculosis; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 18323.10

構造登録者

Meinhart, A.,Morreale, F.E.,Kaiser, M.,Clausen, T. (登録日: 2020-09-03, 公開日: 2021-08-11, 最終更新日: 2024-01-31)

主引用文献

Morreale, F.E.,Kleine, S.,Leodolter, J.,Junker, S.,Hoi, D.M.,Ovchinnikov, S.,Okun, A.,Kley, J.,Kurzbauer, R.,Junk, L.,Guha, S.,Podlesainski, D.,Kazmaier, U.,Boehmelt, G.,Weinstabl, H.,Rumpel, K.,Schmiedel, V.M.,Hartl, M.,Haselbach, D.,Meinhart, A.,Kaiser, M.,Clausen, T.
BacPROTACs mediate targeted protein degradation in bacteria.
Cell, 185:2338-, 2022

PubMed Abstract: Hijacking the cellular protein degradation system offers unique opportunities for drug discovery, as exemplified by proteolysis-targeting chimeras. Despite their great promise for medical chemistry, so far, it has not been possible to reprogram the bacterial degradation machinery to interfere with microbial infections. Here, we develop small-molecule degraders, so-called BacPROTACs, that bind to the substrate receptor of the ClpC:ClpP protease, priming neo-substrates for degradation. In addition to their targeting function, BacPROTACs activate ClpC, transforming the resting unfoldase into its functional state. The induced higher-order oligomer was visualized by cryo-EM analysis, providing a structural snapshot of activated ClpC unfolding a protein substrate. Finally, drug susceptibility and degradation assays performed in mycobacteria demonstrate in vivo activity of BacPROTACs, allowing selective targeting of endogenous proteins via fusion to an established degron. In addition to guiding antibiotic discovery, the BacPROTAC technology presents a versatile research tool enabling the inducible degradation of bacterial proteins.

PubMed: 35662409
DOI: 10.1016/j.cell.2022.05.009

実験手法

X-RAY DIFFRACTION (1.68 Å)