5VZ2
Structure of ClpP from Staphylococcus aureus in complex with Acyldepsipeptide
Summary for 5VZ2
| Entry DOI | 10.2210/pdb5vz2/pdb |
| Related PRD ID | PRD_002274 |
| Descriptor | ATP-dependent Clp protease proteolytic subunit, Acyldepsipeptide (3 entities in total) |
| Functional Keywords | clpp adep, hydrolase-antibiotic complex, hydrolase/antibiotic |
| Biological source | Staphylococcus aureus (strain NCTC 8325) More |
| Total number of polymer chains | 28 |
| Total formula weight | 326655.42 |
| Authors | Griffith, E.C.,Lee, R.E. (deposition date: 2017-05-26, release date: 2017-06-21, 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., 2019 Cited by 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: 31588734DOI: 10.1021/acsinfecdis.9b00245 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.26 Å) |
Structure validation
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