5W18

Staphylococcus aureus ClpP in complex with (S)-N-((2R,6S,8aS,14aS,20S,23aS)-2,6-dimethyl-5,8,14,19,23-pentaoxooctadecahydro-1H,5H,14H,19H-pyrido[2,1-i]dipyrrolo[2,1-c:2',1'-l][1]oxa[4,7,10,13]tetraazacyclohexadecin-20-yl)-3-phenyl-2-(3-phenylureido)propanamide

5W18 の概要

• エントリーDOI: 10.2210/pdb5w18/pdb
• 分子名称: ATP-dependent Clp protease proteolytic subunit, 9V7-PHE-SER-PRO-YCP-ALA-MP8 (3 entities in total)
• 機能のキーワード: clpp, hydrolase-antibiotic complex, udep, hydrolase/antibiotic
• 由来する生物種: Staphylococcus aureus (strain NCTC 8325); 詳細
• タンパク質・核酸の鎖数: 28
• 化学式量合計: 327173.70

構造登録者

Lee, R.E.,Griffith, E.C. (登録日: 2017-06-02, 公開日: 2017-08-09, 最終更新日: 2024-11-06)

主引用文献

Griffith, E.C.,Zhao, Y.,Singh, A.P.,Conlon, B.P.,Tangallapally, R.,Shadrick, W.R.,Liu, J.,Wallace, M.J.,Yang, L.,Elmore, J.M.,Li, Y.,Zheng, Z.,Miller, D.J.,Cheramie, M.N.,Lee, R.B.,LaFleur, M.D.,Lewis, K.,Lee, R.E.
Ureadepsipeptides as ClpP Activators.
Acs Infect Dis., 2019

PubMed Abstract: Acyldepsipeptides are a unique class of antibiotics that act via allosterically dysregulated activation of the bacterial caseinolytic protease (ClpP). The ability of ClpP activators to kill nongrowing bacteria represents a new opportunity to combat deep-seated biofilm infections. However, the acyldepsipeptide scaffold is subject to rapid metabolism. Herein, we explore alteration of the potentially metabolically reactive α,β unsaturated acyl chain. Through targeted synthesis, a new class of phenyl urea substituted depsipeptide ClpP activators with improved metabolic stability is described. The ureadepsipeptides are potent activators of ClpP and show activity against Gram-positive bacteria, including biofilms. These studies demonstrate that a phenyl urea motif can successfully mimic the double bond, maintaining potency equivalent to acyldepsipeptides but with decreased metabolic liability. Although removal of the double bond from acyldepsipeptides generally has a significant negative impact on potency, structural studies revealed that the phenyl ureadepsipeptides can retain potency through the formation of a third hydrogen bond between the urea and the key Tyr63 residue in the ClpP activation domain. Ureadepsipeptides represent a new class of ClpP activators with improved drug-like properties, potent antibacterial activity, and the tractability to be further optimized.

PubMed: 31588734
DOI: 10.1021/acsinfecdis.9b00245

実験手法

X-RAY DIFFRACTION (2.44 Å)