Structural highlights
FunctionCLPP_STAAR 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. Publication Abstract from PubMedThe caseinolytic protease is a highly conserved serine protease, crucial to prokaryotic and eukaryotic protein homeostasis, and a promising antibacterial and anticancer drug target. Here, we describe the potent cystargolides as the first natural beta-lactone inhibitors of the proteolytic core ClpP. Based on the discovery of two clpP genes next to the cystargolide biosynthetic gene cluster in Kitasatospora cystarginea, we explored ClpP as a potential cystargolide target. We show the inhibition of Staphylococcus aureus ClpP by cystargolide A and B by different biochemical methods in vitro. Synthesis of semi-synthetic derivatives and probes with improved cell penetration allowed us to confirm ClpP as a specific target in S. aureus cells and to demonstrate the anti-virulence activity of this natural product class. Crystal structures show cystargolide A covalently bound to all 14 active sites of ClpP from S. aureus, Aquifex aeolicus, as well as Photorhabdus laumondii, and reveal the molecular mechanism of ClpP inhibition by beta-lactones, the pioneering group of ClpP inhibitors. Structure of Staphylococcus aureus ClpP Bound to the Covalent Active Site Inhibitor Cystargolide A.,Illigmann A, Vielberg MT, Lakemeyer M, Wolf F, Dema T, Stange P, Kuttenlochner W, Liebhart E, Kulik A, Staudt N, Malik I, Grond S, Sieber SA, Kaysser L, Groll M, Brotz-Oesterhelt H Angew Chem Int Ed Engl. 2023 Nov 29:e202314028. doi: 10.1002/anie.202314028. PMID:38029352[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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This page was last modified 08:02, 6 December 2023.