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.g002 (Fig 5) . The structure of DS-Cav1 in complex with AM22 shows a more open conformation of this site, with the α4-helix kinked out and away from α5, resulting in a stretched α4-α5 loop and a larger angle between the α4 and α5 helices. This structure closely matches the unbound prefusion-stabilized RSV F variants DS-Cav1 (PDB ID: 4MMU) and PR-DM (PDB ID: 5C69 [41] ), specifically the kink in the α4-helix and greater angle between α4 and α5. In contrast, the prefusion RSV F-D25 structure has a more closed conformation of site Ø, where α4 does not kink out and there is a smaller angle between α4 and α5. The structure of DS-Cav1 bound to RSD5-GL reveals an intermediate site Ø conformation, with the α4-helix only slightly kinked out and away from α5, but not to the same degree as seen in the AM22 complex. Because all three of these antibodies were isolated from humans who had experienced natural RSV infection, these structures indicate that site Ø is naturally flexible and adopts at least three states that can be recognized by the human immune system. It is also possible, and perhaps more likely, that site Ø exists as an ensemble of many conformations, three of which were trapped by these antibodies.