Structural basis for inhibition of the lipid flippase MurJ by phage lysis protein Sgl^PP7 suggests convergent evolution with other Sgl peptides

<p>by Kaito Hosoda, Hidetaka Kohga, Sixian Wu, Hiroyuki Tanaka, Hideki Shigematsu, Ryoji Miyazaki, Min Fey Chek, Tomoya Tsukazaki</p> 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 <i>Escherichia coli</i> 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.