Structures of vesicular stomatitis virus glycoprotein G alone and bound to a neutralizing antibody

TL;DR

This study reveals the structure of a key viral protein and its interaction with a neutralizing antibody, offering insights for vaccine and therapy development.

Contribution

The first complete cryo-EM structures of VSV G alone and in complex with a broadly neutralizing antibody are presented.

Findings

The post-fusion structure of VSV G shows a novel C-terminal rearrangement that stabilizes the trimer.

The antibody 8G5F1 binds a conserved epitope accessible across all G conformations, explaining its broad neutralization.

Structural insights could guide the design of vaccines and oncolytic virotherapy vectors.

Abstract

VSV G mediates viral entry via endocytosis. In the endosome, G undergoes a pH-dependent conformational change from pre- to post-fusion state, catalyzing membrane fusion. No complete structure of G has been reported so far. We present cryo-EM structures of G, isolated from virions using detergent, alone and in complex with the broadly neutralizing antibody 8G5F1 that binds all G conformations. The post-fusion structure reveals a novel rearrangement of the C-terminal part of the G ectodomain, showing that it undergoes a conformational rearrangement and stabilizes the post-fusion trimer by nesting into a groove between adjacent fusion domains. Structures of G-Fab complex show that the epitope belongs to a conserved antigenic site, explaining the broad neutralization capacity of the antibody. This work provides insights into the molecular basis of VSV G mediated fusion and antibody recognition, with potential implications for vaccine development, oncolytic virotherapy.

Vesicular stomatitis virus (VSV) enters host cells via endocytosis During this process, its surface glycoprotein G undergoes a low pH-triggered conformational change that drives fusion of the cellular and viral membranes. Although central to infection, a complete high-resolution structure of VSV G has long been missing. Using cryo-electron microscopy, we determined the structure of purified VSV G, both alone and in complex with a broadly neutralizing antibody that recognizes several conformations of VSV G. Our results reveal that in the post-fusion state, the C-terminal part of the ectodomain folds back and inserts between neighboring protomers, stabilizing the trimeric post-fusion assembly. The antibody-bound structures further identify a conserved epitope that remains accessible across conformations, explaining how it can neutralize vesiculoviruses so broadly.

Together, these findings expand our understanding of how VSV G mediates membrane fusion and how antibodies can block it, offering structural clues that could guide the design of vaccines and oncolytic vectors.

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