8XOP

Cryo-EM structure of ClpP1P2 in complex with ADEP1 from Streptomyces hawaiiensis

8XOP の概要

• エントリーDOI: 10.2210/pdb8xop/pdb
• 関連するPDBエントリー: 8XN4
• EMDBエントリー: 38537
• 関連するBIRD辞書のPRD_ID: PRD_000503
• 分子名称: ATP-dependent Clp protease proteolytic subunit, ADEP1 (3 entities in total)
• 機能のキーワード: protease, protein degradation, proteostasis, proteolysis, hydrolase
• 由来する生物種: Streptomyces hawaiiensis; 詳細
• タンパク質・核酸の鎖数: 28
• 化学式量合計: 337151.89

構造登録者

Xu, X.,Long, F. (登録日: 2024-01-02, 公開日: 2024-03-27, 最終更新日: 2024-05-01)

主引用文献

Xu, X.,Wang, Y.,Huang, W.,Li, D.,Deng, Z.,Long, F.
Structural insights into the Clp protein degradation machinery.
Mbio, 15:e0003124-e0003124, 2024

PubMed Abstract: The Clp protease system is important for maintaining proteostasis in bacteria. It consists of ClpP serine proteases and an AAA+ Clp-ATPase such as ClpC1. The hexameric ATPase ClpC1 utilizes the energy of ATP binding and hydrolysis to engage, unfold, and translocate substrates into the proteolytic chamber of homo- or hetero-tetradecameric ClpP for degradation. The assembly between the hetero-tetradecameric ClpP1P2 chamber and the Clp-ATPases containing tandem ATPase domains from the same species has not been studied in depth. Here, we present cryo-EM structures of the substrate-bound ClpC1:shClpP1P2 from , and shClpP1P2 in complex with ADEP1, a natural compound produced by and known to cause over-activation and dysregulation of the ClpP proteolytic core chamber. Our structures provide detailed information on the shClpP1-shClpP2, shClpP2-ClpC1, and ADEP1-shClpP1/P2 interactions, reveal conformational transition of ClpC1 during the substrate translocation, and capture a rotational ATP hydrolysis mechanism likely dominated by the D1 ATPase activity of chaperones.IMPORTANCEThe Clp-dependent proteolysis plays an important role in bacterial homeostasis and pathogenesis. The ClpP protease system is an effective drug target for antibacterial therapy. can produce a class of potent acyldepsipeptide antibiotics such as ADEP1, which could affect the ClpP protease activity. Although hosts one of the most intricate ClpP systems in nature, very little was known about its Clp protease mechanism and the impact of ADEP molecules on ClpP. The significance of our research is in dissecting the functional mechanism of the assembled Clp degradation machinery, as well as the interaction between ADEP1 and the ClpP proteolytic chamber, by solving high-resolution structures of the substrate-bound Clp system in . The findings shed light on our understanding of the Clp-dependent proteolysis in bacteria, which will enhance the development of antimicrobial drugs targeting the Clp protease system, and help fighting against bacterial multidrug resistance.

PubMed: 38501868
DOI: 10.1128/mbio.00031-24

実験手法

ELECTRON MICROSCOPY (2.8 Å)