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| Main Authors: | , , , , , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Science advances
2025
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/41061077/ |
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Table of Contents:
- Phage lysis protein Lys acts as a wedge to block MurJ conformational changes. Kohga, Hidetaka Lertpreedakorn, Napathip Miyazaki, Ryoji Wu, Sixian Hosoda, Kaito Tanaka, Hiroyuki Takahashi, Yutaro S Yoshikaie, Kunihito Kuruma, Yutetsu Shigematsu, Hideki Mori, Takaharu Tsukazaki, Tomoya Viral Proteins Escherichia coli Escherichia coli Proteins Protein Conformation Molecular Dynamics Simulation Cryoelectron Microscopy Bacteriophages Protein Binding Many antibiotics target essential cellular processes. To combat multidrug-resistant bacteria, new antibacterial strategies are needed. In the peptidoglycan biogenesis pathway in , MurJ, the lipid II flippase, is an essential membrane protein. The 37-residue protein M from the phage, known as Lys or Sgl, targets MurJ and induces cell lysis; however, its molecular mechanism remains unclear. Here, we present the cryo-EM structure of the MurJ/Lys (JM) complex at 3.09-angstrom resolution, revealing that Lys interacts with the crevasse between TM2 and TM7 of MurJ, locking MurJ in an outward-facing conformation, with Lys acting like a wedge. Alanine-scanning mutagenesis and pull-down assays revealed key residues responsible for Lys function, and molecular dynamics simulations showed that Lys 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.