6W9T

Crystal structure of Neisseria meningitidis ClpP protease complex with small molecule activator ACP1-06

6W9T の概要

• エントリーDOI: 10.2210/pdb6w9t/pdb
• 分子名称: ATP-dependent Clp protease proteolytic subunit, POTASSIUM ION, N-{2-[(2-chlorophenyl)sulfanyl]ethyl}-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]sulfonyl}propanamide, ... (4 entities in total)
• 機能のキーワード: serine protease, proteostasis, activator, complex, antibacterial drugs, hydrolase
• 由来する生物種: Neisseria meningitidis
• タンパク質・核酸の鎖数: 7
• 化学式量合計: 155687.88

構造登録者

Mabanglo, M.F.,Houry, W.A. (登録日: 2020-03-23, 公開日: 2020-12-09, 最終更新日: 2023-10-18)

主引用文献

Binepal, G.,Mabanglo, M.F.,Goodreid, J.D.,Leung, E.,Barghash, M.M.,Wong, K.S.,Lin, F.,Cossette, M.,Bansagi, J.,Song, B.,Balasco Serrao, V.H.,Pai, E.F.,Batey, R.A.,Gray-Owen, S.D.,Houry, W.A.
Development of Antibiotics That Dysregulate the Neisserial ClpP Protease.
Acs Infect Dis., 6:3224-3236, 2020

PubMed Abstract: Evolving antimicrobial resistance has motivated the search for novel targets and alternative therapies. Caseinolytic protease (ClpP) has emerged as an enticing new target since its function is conserved and essential for bacterial fitness, and because its inhibition or dysregulation leads to bacterial cell death. ClpP protease function controls global protein homeostasis and is, therefore, crucial for the maintenance of the bacterial proteome during growth and infection. Previously, acyldepsipeptides (ADEPs) were discovered to dysregulate ClpP, leading to bactericidal activity against both actively growing and dormant Gram-positive pathogens. Unfortunately, these compounds had very low efficacy against Gram-negative bacteria. Hence, we sought to develop non-ADEP ClpP-targeting compounds with activity against Gram-negative species and called these activators of self-compartmentalizing proteases (ACPs). These ACPs bind and dysregulate ClpP in a manner similar to ADEPs, effectively digesting bacteria from the inside out. Here, we performed further ACP derivatization and testing to improve the efficacy and breadth of coverage of selected ACPs against Gram-negative bacteria. We observed that a diverse collection of and clinical isolates were exquisitely sensitive to these ACP analogues. Furthermore, based on the ACP-ClpP cocrystal structure solved here, we demonstrate that ACPs could be designed to be species specific. This validates the feasibility of drug-based targeting of ClpP in Gram-negative bacteria.

PubMed: 33237740
DOI: 10.1021/acsinfecdis.0c00599

実験手法

X-RAY DIFFRACTION (1.64 Å)