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TitleConvergent MurJ flippase inhibition by phage lysis proteins.
Journal, issue, pagesNature, Year 2026
Publish dateFeb 25, 2026
AuthorsYancheng E Li / S Francesca Antillon / Grace F Baron / Karthik Chamakura / Ry Young / William M Clemons /
PubMed AbstractAntimicrobial drug resistance poses a global health challenge that necessitates the identification of new druggable targets. The essential lipid II flippase MurJ is a promising yet underexplored ...Antimicrobial drug resistance poses a global health challenge that necessitates the identification of new druggable targets. The essential lipid II flippase MurJ is a promising yet underexplored antimicrobial target in bacterial cell wall biosynthesis. The only known inhibitors of Gram-negative (diderm) MurJ are the single-gene lysis proteins (Sgls) from the lytic single-strand RNA phages M (Sgl) and PP7 (Sgl). Sgl and Sgl have distinct evolutionary origins and share no sequence similarity. Here we describe a common mechanism of MurJ inhibition by these phage-encoded Sgls. We determined the structures of MurJ-bound Sgl and Sgl and discovered a third distinct MurJ-targeting Sgl from the predicted phage Changjiang3 (Sgl) that we also characterized structurally. Our findings demonstrate that all three Sgls evolved convergently to trap MurJ in a periplasm-open conformation through a common MurJ interface, revealing a pathway for drug design.
External linksNature / PubMed:41741639
MethodsEM (single particle)
Resolution3.6 - 3.7 Å
Structure data

49796

9nu4

EMDB-49796, PDB-9nu4:
Structure of MurJ in complex with single gene lysis protein from phage M
Method: EM (single particle) / Resolution: 3.6 Å

49797

9nu5

EMDB-49797, PDB-9nu5:
Structure of MurJ in complex with single gene lysis protein from phage PP7
Method: EM (single particle) / Resolution: 3.7 Å

49798

9nu8

EMDB-49798, PDB-9nu8:
Structure of MurJ in complex with single gene lysis protein from phage Changjiang3
Method: EM (single particle) / Resolution: 3.6 Å

Source
  • escherichia coli k-12 (bacteria)
  • enterobacteria phage m (virus)
  • pseudomonas phage pp7 (virus)
  • changjiang levi-like virus 3
KeywordsTRANSPORT PROTEIN / lipid II flippase / phage single gene lysis proteins / peptidoglycan biosynthesis

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