Structure and Mechanism of a Two-component Lanthipeptide Toxin

Ryan Moreira; Constantin Giurgiu; Imran R. Rahman; MacKenzie Patterson; Stefan T. Huber; Yi Yang; Kévin Jeanne Dit Fouque; Francisco Alberto Fernandez-Lima; Ge Liu; Ruihan Guo; Payam Kelich; Po‐Chao Wen; Emad Tajkhorshid; Alex G. Johnson; Wilfred A. van der Donk

doi:10.64898/2026.05.13.724966

BiochemistrybioRxivMay 14, 2026

Preprint

Structure and Mechanism of a Two-component Lanthipeptide Toxin

Ryan Moreira iD, Constantin Giurgiu iD, Imran R. Rahman iD, MacKenzie Patterson iD, Stefan T. Huber iD, Yi Yang iD, Kévin Jeanne Dit Fouque iD, Francisco Alberto Fernandez-Lima iD, Ge Liu iD, Ruihan Guo iD, Payam Kelich iD, Po‐Chao Wen iD, Emad Tajkhorshid iD, Alex G. Johnson iD, Wilfred A. van der Donk iD

Abstract

The enterococcal cytolysin is a two-component lanthipeptide natural product that co-operatively kills mammalian cells and bacteria. It is a virulence factor in typically commensal strains of gut-dwelling Enterococcus faecalis and causes a fatal form of alcoholic hepatitis. Despite its clinical significance, little is known about the mechanism of action. We present here the molecular details of cytolysins remarkable bioactivity. A high-resolution cryo-electron microscopy structure revealed highly ordered tubular assemblies comprising the two subunits. We further demonstrate these structures disrupt the membranes of eukaryotic and bacterial cells. These results provide the first high-resolution structure of two distinct lanthipeptides interacting with one another and offer an explanation for the unique bioactivity of the cytolysin toxin.

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