Alternative conformations of a major antigenic site on RSV F

Jones, Harrison G.; Battles, Michael B.; Lin, Chun-Chi; Bianchi, Siro; Corti, Davide; McLellan, Jason S.

https://doi.org/10.1371/journal.ppat.1007944.g004 conformationally heterogeneous as indicated by the lack of electron density. However, site Ø cavity-filling mutations introduced in the Cav1 (PDB ID: 4MMS) or DS-Cav1 (PDB ID: 4MMU) variants stabilized the prefusion RSV F structure and showed clear electron density extending from the fusion peptide through site Ø. Taken together, this suggests that movement of the fusion peptide is conditional upon prior rearrangement of site Ø. The only discrepancy between the crystal structures of wild-type prefusion RSV F when bound to D25 and the prefusion-stabilized variant DS-Cav1 is the kinked-open conformation of α4 in the DS-Cav1 model, which was attributed to the cavity-filling V207L mutation being unable to fully stabilize the α4-helix [40] . However, the structure reported here of DS-Cav1 in complex with the human antibody AM22 matches the unbound DS-Cav1 structure and demonstrates that this conformation is a naturally sampled alternative conformation of prefusion RSV F.