8olr | pdb_00008olr

Structure of yeast 20S proteasome in complex with the natural product beta-lactone inhibitor Cystargolide A

spinqualitylabelsall models 8olr, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8olr is a 20 chain structure with sequence from Saccharomyces cerevisiae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.8Å Ligands: CL, MG, VSZ Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PSA2_YEAST The proteasome degrades poly-ubiquitinated proteins in the cytoplasm and in the nucleus. It is essential for the regulated turnover of proteins and for the removal of misfolded proteins. The proteasome is a multicatalytic proteinase complex that is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. It has an ATP-dependent proteolytic activity. Publication Abstract from PubMed The 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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