6PMD

Structure of ClpP from Staphylococcus aureus in complex with Acyldepsipeptide

6PMD の概要

• エントリーDOI: 10.2210/pdb6pmd/pdb
• 関連するPDBエントリー: 5VZ2 5W18 6PKA
• 関連するBIRD辞書のPRD_ID: PRD_002357
• 分子名称: ATP-dependent Clp protease proteolytic subunit, SHV-WFP-SER-PRO-YCP-ALA-MP8 Acyldepsipeptide, (4S)-2-METHYL-2,4-PENTANEDIOL, ... (4 entities in total)
• 機能のキーワード: clpp adep, antibiotic, hydrolase-antibiotic complex, 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: 25
• 化学式量合計: 326861.87

構造登録者

Griffith, E.C.,Lee, R.E. (登録日: 2019-07-01, 公開日: 2019-11-06, 最終更新日: 2023-11-15)

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., 5:1915-1925, 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 (2.21 Å)