7MK5

Crystal structure of Escherichia coli ClpP covalently inhibited by clipibicyclene

7MK5 の概要

• エントリーDOI: 10.2210/pdb7mk5/pdb
• 分子名称: ATP-dependent Clp protease proteolytic subunit, (4S)-2-METHYL-2,4-PENTANEDIOL, ACETATE ION, ... (5 entities in total)
• 機能のキーワード: inhibitor, complex, protease, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Escherichia coli K-12
• タンパク質・核酸の鎖数: 28
• 化学式量合計: 620629.89

構造登録者

Culp, E.J.,Sychantha, D.,Hobson, C.,Pawlowski, A.J.,Prehna, G.,Wright, G.D. (登録日: 2021-04-21, 公開日: 2022-02-02, 最終更新日: 2024-10-30)

主引用文献

Culp, E.J.,Sychantha, D.,Hobson, C.,Pawlowski, A.C.,Prehna, G.,Wright, G.D.
ClpP inhibitors are produced by a widespread family of bacterial gene clusters.
Nat Microbiol, 7:451-462, 2022

PubMed Abstract: The caseinolytic protease (ClpP) is part of a highly conserved proteolytic complex whose disruption can lead to antibacterial activity but for which few specific inhibitors have been discovered. Specialized metabolites produced by bacteria have been shaped by evolution for specific functions, making them a potential source of selective ClpP inhibitors. Here, we describe a target-directed genome mining strategy for discovering ClpP-interacting compounds by searching for biosynthetic gene clusters that contain duplicated copies of ClpP as putative antibiotic resistance genes. We identify a widespread family of ClpP-associated clusters that are known to produce pyrrolizidine alkaloids but whose connection to ClpP has never been made. We show that previously characterized molecules do not affect ClpP function but are shunt metabolites derived from the genuine product of these gene clusters, a reactive covalent ClpP inhibitor. Focusing on one such cryptic gene cluster from Streptomyces cattleya, we identify the relevant inhibitor, which we name clipibicyclene, and show that it potently and selectively inactivates ClpP. Finally, we solve the crystal structure of clipibicyclene-modified Escherichia coli ClpP. Clipibicyclene's discovery reveals the authentic function of a family of natural products whose specificity for ClpP and abundance in nature illuminate the role of eco-evolutionary forces during bacterial competition.

PubMed: 35246663
DOI: 10.1038/s41564-022-01073-4

実験手法

X-RAY DIFFRACTION (2.95 Å)