Structural basis for inhibition of the lipid flippase MurJ by phage lysis protein SglPP7 suggests convergent evolution with other Sgl peptides

Some bacteriophages encode lysis proteins that inhibit essential bacterial processes, and elucidating their mechanisms is valuable for developing antibacterial strategies against drug-resistant pathogens. We determined the cryo-EM structure of the complex between the essential Escherichia coli lipid II flippase MurJ and the phage lysis protein Sgl ^PP7 . Structural, mutational, and molecular dynamics (MD) simulation analyses revealed that Sgl ^PP7 binds along the intramembrane cleft of MurJ and inserts its C-terminal tail into the internal cavity, stabilizing MurJ in an outward-facing conformation. Structural comparison with Lys ^M (Sgl ^M ) and Sgl ^CJ3 showed that these sequence-divergent Sgl proteins stabilize MurJ in the outward-facing conformation through distinct binding modes, consistent with the possibility of convergent evolution toward MurJ inhibition.