Cryo-EM structures reveal the molecular basis of receptor-initiated coxsackievirus uncoating

Enterovirus uncoating receptors bind at the surface depression (canyon'') that encircles each capsid vertex causing the release of a host-derived lipid called pocket factor'' that is buried in a hydrophobic pocket formed by the major viral capsid protein, VP1. Coxsackievirus and adenovirus receptor (CAR) is a universal uncoating receptor of group B coxsackieviruses (CVB). Here, we present five high-resolution cryoEM structures of CVB representing different stages of virus infection. Structural comparisons show that the CAR penetrates deeper into the canyon than other uncoating receptors, leading to a cascade of events: collapse of the VP1 hydrophobic pocket, high-efficiency release of the pocket factor and viral uncoating and genome release under neutral pH, as compared with low pH. Furthermore, we identified a potent therapeutic antibody that can neutralize viral infection by interfering with virion-CAR interactions, destabilizing the capsid and inducing virion disruption. Together, these results define the structural basis of CVB cell entry and antibody neutralization.

Automated summary

This study elucidates the structural changes at different stages of Coxsackievirus B infectivity, demonstrating the crucial role of CAR in the process of virus entry and revealing the fundamental structural basis of viral invasion mechanisms.