Subnanometer structure of an enveloped virus fusion complex on viral surface reveals new entry mechanisms

Paramyxoviruses-including important pathogens like parainfluenza, measles, and Nipah viruses-use a recep-tor binding protein [hemagglutinin-neuraminidase (HN) for parainfluenza] and a fusion protein (F), acting in a complex, to enter cells. We use cryo-electron tomography to visualize the fusion complex of human parainflu-enza virus 3 (HN/F) on the surface of authentic clinical viruses at a subnanometer resolution sufficient to answer mechanistic questions. An HN loop inserts in a pocket on F, showing how the fusion complex remains in a ready but quiescent state until activation. The globular HN heads are rotated with respect to each other: one down-ward to contact F, and the other upward to grapple cellular receptors, demonstrating how HN/F performs dis-tinct steps before F activation. This depiction of viral fusion illuminates potentially druggable targets for paramyxoviruses and sheds light on fusion processes that underpin wide-ranging biological processes but have not been visualized in situ or at the present resolution.