9IRP

Structure of ClpP from Staphylococcus aureus in complex with ZG297

Summary for 9IRP

• Entry DOI: 10.2210/pdb9irp/pdb
• Descriptor: ATP-dependent Clp protease proteolytic subunit, (6S,9aS)-6-[(2S)-butan-2-yl]-4,7-bis(oxidanylidene)-8-(phenanthren-9-ylmethyl)-N-[4,4,4-tris(fluoranyl)butyl]-3,6,9,9a-tetrahydro-2H-pyrazino[1,2-a]pyrimidine-1-carboxamide, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: clpp, staphylococcus aureus, activator, protease, hydrolase
• Biological source: Staphylococcus aureus
• Total number of polymer chains: 14
• Total formula weight: 321368.28

Authors

Wei, B.Y.,Wang, P.Y.,Zhang, T.,Yang, C.-G. (deposition date: 2024-07-16, release date: 2024-10-23, Last modification date: 2025-02-19)

Primary citation

Zhang, T.,Wang, P.,Zhou, H.,Wei, B.,Zhao, Y.,Li, J.,Zhang, M.,Wu, W.,Lan, L.,Gan, J.,Yang, C.G.
Structure-guided development of selective caseinolytic protease P agonists as antistaphylococcal agents.
Cell Rep Med, 5:101837-101837, 2024

PubMed Abstract: Methicillin-resistant Staphylococcus aureus is a ubiquitous pathogen, posing a serious threat to human health worldwide. Thus, there is a high demand for antibiotics with distinct targets. Caseinolytic protease P (ClpP) is a promising target for combating staphylococcal infections; however, selectively activating S. aureus ClpP (SaClpP) rather than Homo sapiens ClpP (HsClpP) remains challenging. Herein, we rationally design and identify ZG297 by structure-based strategy. It binds and activates SaClpP instead of HsClpP. This is due to differentiated ligand binding attributed to crossed "tyrosine/histidine" amino acid pairs. ZG297 substantially inhibits the growth of a broad panel of S. aureus strains in vitro, outperforming the selective (R)-ZG197 agonist. ZG297 also functions as a potent antibiotic against multidrug-resistant S. aureus infections in Galleria mellonella larvae, zebrafish, murine skin, and thigh infection models. Collectively, we demonstrate that ZG297 is a safer and more potent antistaphylococcal agent than acyldepsipeptide 4 and (R)-ZG197.

PubMed: 39615486
DOI: 10.1016/j.xcrm.2024.101837

Experimental method

X-RAY DIFFRACTION (1.901 Å)