6PMD

Structure of ClpP from Staphylococcus aureus in complex with Acyldepsipeptide

Summary for 6PMD

• Entry DOI: 10.2210/pdb6pmd/pdb
• Related: 5VZ2 5W18 6PKA
• Related PRD ID: PRD_002357
• Descriptor: ATP-dependent Clp protease proteolytic subunit, SHV-WFP-SER-PRO-YCP-ALA-MP8 Acyldepsipeptide, (4S)-2-METHYL-2,4-PENTANEDIOL, ... (4 entities in total)
• Functional Keywords: clpp adep, antibiotic, hydrolase-antibiotic complex, hydrolase/antibiotic
• Biological source: Staphylococcus aureus (strain NCTC 8325); More
• Total number of polymer chains: 25
• Total formula weight: 326861.87

Authors

Griffith, E.C.,Lee, R.E. (deposition date: 2019-07-01, release date: 2019-11-06, Last modification date: 2023-11-15)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.21 Å)