6pmd

Structure of ClpP from Staphylococcus aureus in complex with Acyldepsipeptide

spinqualitylabelsall models 6pmd, resolution 2.21Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6pmd is a 25 chain structure with sequence from Staphylococcus aureus subsp. aureus NCTC 8325 and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.21Å Ligands: MP8, MPD, SHV, WFP, YCP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CLPP_STAA8 Cleaves peptides in various proteins in a process that requires ATP hydrolysis. Has a chymotrypsin-like activity. Plays a major role in the degradation of misfolded proteins (By similarity). Publication Abstract from PubMed 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 alpha,beta 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 Staphylococcus aureus ClpP and show activity against Gram-positive bacteria, including S. aureus 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. Ureadepsipeptides as ClpP Activators.,Griffith EC, Zhao Y, Singh AP, Conlon BP, Tangallapally R, Shadrick WR, Liu J, Wallace MJ, Yang L, Elmore JM, Li Y, Zheng Z, Miller DJ, Cheramie MN, Lee RB, LaFleur MD, Lewis K, Lee RE ACS Infect Dis. 2019 Oct 24. doi: 10.1021/acsinfecdis.9b00245. PMID:31588734 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Clp protease 3D structures

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