9K2D

Structure of ClpP from Staphylococcus aureus in complex with ZY39

This is a non-PDB format compatible entry.

Summary for 9K2D

• Entry DOI: 10.2210/pdb9k2d/pdb
• Descriptor: ATP-dependent Clp protease proteolytic subunit, (6~{S},9~{a}~{S})-6-[(2~{S})-butan-2-yl]-8-[(4-methoxynaphthalen-1-yl)methyl]-4,7-bis(oxidanylidene)-~{N}-[4,4,4-tris(fluoranyl)butyl]-3,6,9,9~{a}-tetrahydro-2~{H}-pyrazino[1,2-a]pyrimidine-1-carboxamide, (4S)-2-METHYL-2,4-PENTANEDIOL, ... (4 entities in total)
• Functional Keywords: clpp, staphylococcus aureus, activator, protease, hydrolase, antibiotic
• Biological source: Staphylococcus aureus subsp. aureus Mu3
• Total number of polymer chains: 14
• Total formula weight: 322450.59

Authors

Wei, B.Y.,Wang, P.Y.,Wu, W.,Zhang, T.,Yang, C.-G. (deposition date: 2024-10-17, release date: 2025-02-19)

Primary citation

Zhang, T.,Wu, W.,Zhao, Y.,Ding, Z.,Wei, B.,Yang, T.,Li, J.,Wang, P.,Lan, L.,Gan, J.,Yang, C.G.
Structure-Guided Development of ClpP Agonists with Potent Therapeutic Activities against Staphylococcus aureus Infection.
J.Med.Chem., 68:1810-1823, 2025

PubMed Abstract: Peritonitis caused by poses a severe threat to patients with end-stage renal failure. Treating multidrug-resistant infections requires the use of antibiotics with diverse mechanisms of action. Caseinolytic protease P (ClpP) is a promising antibacterial target; however, selective activation of (ClpP) over human ClpP (ClpP) remains challenging. We previously identified as a selective ClpP agonist, but its potency was suboptimal. Herein, we develop analogs through a structure-guided approach and examine their structure-activity relationships. Notably, demonstrates improved activation of ClpP and superior binding affinity. Interestingly, while facilitates the enzymatic hydrolysis of ClpP and ClpP , it does not target ClpP in cellular environments. Furthermore, effectively inhibits the growth of multidrug-resistant strains and shows excellent therapeutic efficacy in a murine model of peritonitis. These findings highlight as a promising ClpP agonist for combating staphylococcal infections.

PubMed: 39760203
DOI: 10.1021/acs.jmedchem.4c02562

Experimental method

X-RAY DIFFRACTION (1.98 Å)