Structure of the rabies virus glycoprotein trimer bound to a prefusion-specific neutralizing antibody

Heather Callaway (1) , Dawid Zyla (1) , Florence Larrous (2, 3) , Guilherme Dias de Melo (3) , Kathryn Hastie (1) , Ruben Diaz Avalos (1) , Alyssa Agarwal (1) , Davide Corti (4) , Hervé Bourhy (3) , Erica Ollmann Saphire (1, 5)

1 La Jolla Institute for Immunology [La Jolla, CA, États-Unis]
2 IP - Institut Pasteur [Paris]
3 Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology
4 Humabs BioMed SA
5 UC San Diego - University of California [San Diego]

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.

Domains: Life Sciences [q-bio]

Heather Callaway, Dawid Zyla, Florence Larrous, Guilherme Dias de Melo, Kathryn Hastie, et al.. Structure of the rabies virus glycoprotein trimer bound to a prefusion-specific neutralizing antibody. Science Advances , 2022, 8 (24), ⟨10.1126/sciadv.abp9151⟩. ⟨pasteur-03698942⟩