8WCI

Cryo-EM structure of the inhibitor-bound Vo complex from Enterococcus hirae

Summary for 8WCI

• Entry DOI: 10.2210/pdb8wci/pdb
• EMDB information: 37440
• Descriptor: V-type sodium ATPase subunit K, V-type sodium ATPase subunit I, CARDIOLIPIN, ... (6 entities in total)
• Functional Keywords: v-atpase, na+-transporting, membrane protein, atp hydrolyses, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Enterococcus hirae ATCC 9790; More
• Total number of polymer chains: 11
• Total formula weight: 244733.13

Authors

Suzuki, K.,Mikuriya, S.,Adachi, N.,Kawasaki, M.,Senda, T.,Moriya, T.,Murata, T. (deposition date: 2023-09-12, release date: 2024-10-09, Last modification date: 2025-04-23)

Primary citation

Suzuki, K.,Goto, Y.,Otomo, A.,Shimizu, K.,Abe, S.,Moriyama, K.,Yasuda, S.,Hashimoto, Y.,Kurushima, J.,Mikuriya, S.,Imai, F.L.,Adachi, N.,Kawasaki, M.,Sato, Y.,Ogasawara, S.,Iwata, S.,Senda, T.,Ikeguchi, M.,Tomita, H.,Iino, R.,Moriya, T.,Murata, T.
Na + -V-ATPase inhibitor curbs VRE growth and unveils Na + pathway structure.
Nat.Struct.Mol.Biol., 32:450-458, 2025

PubMed Abstract: Vancomycin-resistant Enterococcus faecium (VRE) is a major cause of nosocomial infections, particularly endocarditis and sepsis. With the diminishing effectiveness of antibiotics against VRE, new antimicrobial agents are urgently needed. Our previous research demonstrated the crucial role of Na-transporting V-ATPase in Enterococcus hirae for growth under alkaline conditions. In this study, we identified a compound, V-161, from 70,600 compounds, which markedly inhibits E. hirae V-ATPase activity. V-161 not only inhibits VRE growth in alkaline conditions but also significantly suppresses VRE colonization in the mouse small intestine. Furthermore, we unveiled the high-resolution structure of the membrane V part due to V-161 binding. V-161 binds to the interface of the c-ring and a-subunit, constituting the Na transport pathway in the membrane, thereby halting its rotation. This structural insight presents potential avenues for developing therapeutic agents for VRE treatment and elucidates the Na transport pathway and mechanism.

PubMed: 39572733
DOI: 10.1038/s41594-024-01419-y

Experimental method

ELECTRON MICROSCOPY (2.2 Å)