8OLR

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

Summary for 8OLR

• Entry DOI: 10.2210/pdb8olr/pdb
• Related: 6G7F
• Descriptor: Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (18 entities in total)
• Functional Keywords: anti-virulence, proteasome, inhibitor, natural product, mode of action, hydrolase
• Biological source: Saccharomyces cerevisiae (baker's yeast); More
• Total number of polymer chains: 28
• Total formula weight: 733526.55

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: 2024-10-16)

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

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: 38029352
DOI: 10.1002/anie.202314028

Experimental method

X-RAY DIFFRACTION (2.8 Å)