Structure of the rabies virus glycoprotein trimer bound to a prefusion-specific neutralizing antibody
Heather Callaway, Dawid Zyla, Florence Larrous, Guilherme Dias de Melo, Kathryn M. Hastie, Ruben Diaz Avalos, Alyssa Agarwal, Davide Corti, Hervé Bourhy, Erica Ollmann Saphire
Abstract
Rabies infection is nearly 100% lethal if untreated and kills more than 50,000 people annually, many of them children. Existing rabies vaccines target the rabies virus glycoprotein (RABV-G) but generate short-lived immune responses, likely because the protein is heterogeneous under physiological conditions. Here, we report the 3.39 Å cryo-electron microscopy structure of trimeric, prefusion RABV-G complexed with RVA122, a potently neutralizing human antibody. RVA122 binds to a quaternary epitope at the top of RABV-G, bridging domains and stabilizing RABV-G protomers in a prefusion state. RABV-G trimerization involves side-to-side interactions between the central α helix and adjacent loops, rather than contacts between central helices, and interactions among the fusion loops at the glycoprotein base. These results provide a basis from which to develop improved rabies vaccines based on RABV-G stabilized in the prefusion conformation.