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Crystal structure of E. coli ClpP protease in complex with phosphine oxide compound ACP6-12Crystal structure of E. coli ClpP protease in complex with phosphine oxide compound ACP6-12
Structural highlights
FunctionC3TLT2_ECOLX 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 PubMedA series of arylsulfones and heteroarylsulfones have previously been demonstrated to dysregulate the conserved bacterial ClpP protease, causing the unspecific degradation of essential cellular housekeeping proteins and ultimately resulting in cell death. A cocrystal structure of a 2-beta-sulfonylamide analog, ACP1-06, with Escherichia coli ClpP showed that its 2-pyridyl sulfonyl substituent adopts two orientations in the binding site related through a sulfone bond rotation. From this, a new bis-aryl phosphine oxide scaffold, designated as ACP6, was designed based on a "conformation merging" approach of the dual orientation of the ACP1-06 sulfone. One analog, ACP6-12, exhibited over a 10-fold increase in activity over the parent ACP1-06 compound, and a cocrystal X-ray structure with ClpP confirmed its predicted binding conformation. This allowed for a comparative analysis of how different ligand classes bind to the hydrophobic binding site. The study highlights the successful application of structure-based rational design of novel phosphine oxide-based antibiotics. Structure-Based Design and Development of Phosphine Oxides as a Novel Chemotype for Antibiotics that Dysregulate Bacterial ClpP Proteases.,Lin F, Mabanglo MF, Zhou JL, Binepal G, Barghash MM, Wong KS, Gray-Owen SD, Batey RA, Houry WA J Med Chem. 2024 Sep 12;67(17):15131-15147. doi: 10.1021/acs.jmedchem.4c00773. , Epub 2024 Sep 2. PMID:39221504[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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