8OLL
Staphylococcus aureus ClpP in complex with the natural product beta-lactone inhibitor Cystargolide A at 2.7 A resolution
Summary for 8OLL
| Entry DOI | 10.2210/pdb8oll/pdb |
| Descriptor | ATP-dependent Clp protease proteolytic subunit, Cystargolide A (bound) (3 entities in total) |
| Functional Keywords | anti-virulence, caseinolytic protease, inhibitor, natural product, mode of action, hydrolase |
| Biological source | Staphylococcus aureus More |
| Total number of polymer chains | 28 |
| Total formula weight | 642631.81 |
| Authors | Illigmann, A.,Vielberg, M.-T.,Lakemeyer, M.,Wolf, F.,Staudt, N.,Dema, T.,Stange, P.,Malik, I.,Grond, S.,Sieber, S.A.,Groll, M.,Kaysser, L.,Broetz-Oesterhelt, H. (deposition date: 2023-03-30, release date: 2023-12-06, Last modification date: 2024-11-13) |
| Primary citation | Illigmann, A.,Vielberg, M.T.,Lakemeyer, M.,Wolf, F.,Dema, T.,Stange, P.,Kuttenlochner, W.,Liebhart, E.,Kulik, A.,Staudt, N.D.,Malik, I.,Grond, S.,Sieber, S.A.,Kaysser, L.,Groll, M.,Brotz-Oesterhelt, H. Structure of Staphylococcus aureus ClpP Bound to the Covalent Active-Site Inhibitor Cystargolide A. Angew.Chem.Int.Ed.Engl., 63:e202314028-e202314028, 2024 Cited by PubMed Abstract: The caseinolytic protease is a highly conserved serine protease, crucial to prokaryotic and eukaryotic protein homeostasis, and a promising antibacterial and anticancer drug target. Herein, we describe the potent cystargolides as the first natural β-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 semisynthetic 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, and Photorhabdus laumondii, and reveal the molecular mechanism of ClpP inhibition by β-lactones, the predominant class of ClpP inhibitors. PubMed: 38029352DOI: 10.1002/anie.202314028 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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