8A8W

Mycobacterium tuberculosis ClpC1 hexamer structure bound to the natural product antibiotic Ecumycin (class 1)

8A8W の概要

• エントリーDOI: 10.2210/pdb8a8w/pdb
• 関連するPDBエントリー: 8A8U
• EMDBエントリー: 15240 15242
• 分子名称: ATP-dependent Clp protease ATP-binding subunit ClpC1, Bound polypeptide, ADENOSINE-5'-DIPHOSPHATE (3 entities in total)
• 機能のキーワード: hexamer, tuberculosis, drug target, protein quality control, chaperone
• 由来する生物種: Mycobacterium tuberculosis; 詳細
• タンパク質・核酸の鎖数: 7
• 化学式量合計: 574969.82

構造登録者

Felix, J.,Fraga, H.,Gragera, M.,Bueno, T.,Weinhaeupl, K. (登録日: 2022-06-24, 公開日: 2022-10-26, 最終更新日: 2024-07-24)

主引用文献

Weinhaupl, K.,Gragera, M.,Bueno-Carrasco, M.T.,Arranz, R.,Krandor, O.,Akopian, T.,Soares, R.,Rubin, E.,Felix, J.,Fraga, H.
Structure of the drug target ClpC1 unfoldase in action provides insights on antibiotic mechanism of action.
J.Biol.Chem., 298:102553-102553, 2022

PubMed Abstract: The unfoldase ClpC1 is one of the most exciting drug targets against tuberculosis. This AAA+ unfoldase works in cooperation with the ClpP1P2 protease and is the target of at least four natural product antibiotics: cyclomarin, ecumicin, lassomycin, and rufomycin. Although these molecules are promising starting points for drug development, their mechanisms of action remain largely unknown. Taking advantage of a middle domain mutant, we determined the first structure of Mycobacterium tuberculosis ClpC1 in its apo, cyclomarin-, and ecumicin-bound states via cryo-EM. The obtained structure displays features observed in other members of the AAA+ family and provides a map for further drug development. While the apo and cyclomarin-bound structures are indistinguishable and have N-terminal domains that are invisible in their respective EM maps, around half of the ecumicin-bound ClpC1 particles display three of their six N-terminal domains in an extended conformation. Our structural observations suggest a mechanism where ecumicin functions by mimicking substrate binding, leading to ATPase activation and changes in protein degradation profile.

PubMed: 36208775
DOI: 10.1016/j.jbc.2022.102553

実験手法

ELECTRON MICROSCOPY (4.29 Å)