8OLL

Staphylococcus aureus ClpP in complex with the natural product beta-lactone inhibitor Cystargolide A at 2.7 A resolution

8OLL の概要

• エントリーDOI: 10.2210/pdb8oll/pdb
• 分子名称: ATP-dependent Clp protease proteolytic subunit, Cystargolide A (bound) (3 entities in total)
• 機能のキーワード: anti-virulence, caseinolytic protease, inhibitor, natural product, mode of action, hydrolase
• 由来する生物種: Staphylococcus aureus; 詳細
• タンパク質・核酸の鎖数: 28
• 化学式量合計: 642631.81

構造登録者

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. (登録日: 2023-03-30, 公開日: 2023-12-06, 最終更新日: 2024-11-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.7 Å)