Substrate binding and activation mechanism of the essential bacterial septal cell wall synthase FtsW

Activation of the Escherichia coli FtsWIQLB septal cell wall synthase relieves self-inhibitory gating, stabilizing acceptor-site binding and reorienting donor and acceptor L2 toward D297.

• Why it matters: Substrate-bound structures of FtsWIQLB are missing, limiting understanding of how flexible lipid II substrates are recognized and how the complex becomes catalytically primed.
• What they did: All-atom molecular dynamics of E. coli FtsWIQLB combined with cysteine-based mutagenesis and cell-based assays mapped donor and acceptor L2 binding sites, implicating conserved arginines near membrane-accessible cavities and constraints that block approach to D297.
• The result: FtsN activation or a superfission FtsW variant stabilizes acceptor-site binding and a catalytically primed substrate arrangement; long donor glycan chains further support this state, informing antibiotic targeting of SEDS-class synthases.

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