8qyf
From Proteopedia
Crystal structure of ClpP from Staphylococcus epidermidis in complex with ixazomib
Structural highlights
FunctionA0A0N1MQL5_STAEP 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.[HAMAP-Rule:MF_00444][RuleBase:RU000550] Publication Abstract from PubMedCaseinolytic protease P (ClpP) is considered as a promising target for the treatment of Staphylococcus aureus infections. In an unbiased screen of 2632 molecules, a peptidomimetic boronate, MLN9708, was found to be a potent suppressor of SaClpP function. A time-saving and cost-efficient strategy integrating in silico position scanning, multistep miniaturized synthesis, and bioactivity testing was deployed for optimization of this hit compound and led to fast exploration of structure-activity relationships. Five of 150 compounds from the miniaturized synthesis exhibited improved inhibitory activity. Compound 43Hf was the most active inhibitor and showed reversible covalent binding to SaClpP while did not destabilize the tetradecameric structure of SaClpP. The crystal structure of 43Hf-SaClpP complex provided mechanistic insight into the covalent binding mode of peptidomimetic boronate and SaClpP. Furthermore, 43Hf could bind endogenous ClpP in S. aureus cells and exhibited significant efficacy in attenuating S. aureus virulence in vitro and in vivo. Discovery of Novel Peptidomimetic Boronate ClpP Inhibitors with Noncanonical Enzyme Mechanism as Potent Virulence Blockers in Vitro and in Vivo.,Ju Y, He L, Zhou Y, Yang T, Sun K, Song R, Yang Y, Li C, Sang Z, Bao R, Luo Y J Med Chem. 2020 Mar 26;63(6):3104-3119. doi: 10.1021/acs.jmedchem.9b01746. Epub , 2020 Feb 20. PMID:32031798[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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