| Author |
Kohga H, Lertpreedakorn N, Miyazaki R, Wu S, Hosoda K, Tanaka H, Takahashi YS, Yoshikaie K, Kuruma Y, Shigematsu H, Mori T, Tsukazaki T.
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| Abstract |
Many antibiotics target essential cellular processes. To combat multidrug-resistant bacteria, new antibacterial strategies are needed. In the peptidoglycan biogenesis pathway in Escherichia coli, MurJ, the lipid II flippase, is an essential membrane protein. The 37-residue protein M from the Levivirus phage, known as LysM or SglM, targets MurJ and induces cell lysis; however, its molecular mechanism remains unclear. Here, we present the cryo-EM structure of the MurJ/LysM (JM) complex at 3.09-angstrom resolution, revealing that LysM interacts with the crevasse between TM2 and TM7 of MurJ, locking MurJ in an outward-facing conformation, with LysM acting like a wedge. Alanine-scanning mutagenesis and pull-down assays revealed key residues responsible for LysM function, and molecular dynamics simulations showed that LysM stabilizes MurJ's outward-facing state. These findings demonstrate an unprecedented phage-derived mechanism for blocking lipid II transport, providing a structural framework for designing MurJ-targeted antimicrobial agents.
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