7XBZ

Crystal structure of Staphylococcus aureus ClpP in complex with R-ZG197

Summary for 7XBZ

• Entry DOI: 10.2210/pdb7xbz/pdb
• Descriptor: ATP-dependent Clp protease proteolytic subunit, (6S,9aS)-6-[(2S)-butan-2-yl]-8-[(1R)-1-naphthalen-1-ylethyl]-4,7-bis(oxidanylidene)-N-[4,4,4-tris(fluoranyl)butyl]-3,6,9,9a-tetrahydro-2H-pyrazino[1,2-a]pyrimidine-1-carboxamide, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: protease, hydrolase
• Biological source: Staphylococcus aureus
• Total number of polymer chains: 14
• Total formula weight: 309966.88

Authors

Wei, B.Y.,Gan, J.H.,Yang, C.-G. (deposition date: 2022-03-22, release date: 2022-11-16, Last modification date: 2023-11-29)

Primary citation

Wei, B.,Zhang, T.,Wang, P.,Pan, Y.,Li, J.,Chen, W.,Zhang, M.,Ji, Q.,Wu, W.,Lan, L.,Gan, J.,Yang, C.G.
Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP.
Nat Commun, 13:6909-6909, 2022

PubMed Abstract: The emergence of methicillin-resistant Staphylococcus aureus isolates highlights the urgent need to develop more antibiotics. ClpP is a highly conserved protease regulated by ATPases in bacteria and in mitochondria. Aberrant activation of  bacterial ClpP is an alternative method of discovering antibiotics, while it remains difficult to develop selective  Staphylococcus aureus ClpP activators that can avoid disturbing Homo sapiens ClpP functions. Here, we use a structure-based design to identify (R)- and (S)-ZG197 as highly selective Staphylococcus aureus ClpP activators. The key structural elements in Homo sapiens ClpP, particularly W146 and its joint action with the C-terminal motif, significantly contribute to the discrimination of the activators. Our selective activators display wide antibiotic properties towards an array of multidrug-resistant staphylococcal strains in vitro, and demonstrate promising antibiotic efficacy in zebrafish and murine skin infection models. Our findings indicate that the species-specific activators of Staphylococcus aureus ClpP are exciting therapeutic agents to treat staphylococcal infections.

PubMed: 36376309
DOI: 10.1038/s41467-022-34753-0

Experimental method

X-RAY DIFFRACTION (2.15 Å)