6DC5

RSV prefusion F in complex with AM22 Fab

Summary for 6DC5

• Entry DOI: 10.2210/pdb6dc5/pdb
• Descriptor: RSV fusion glycoprotein, Fab AM22 heavy chain, Fab AM22 light chain, ... (6 entities in total)
• Functional Keywords: viral fusion glycoprotein, human antibody, immune system
• Biological source: Human respiratory syncytial virus A (strain A2); More
• Total number of polymer chains: 9
• Total formula weight: 333484.07

Authors

Jones, H.G.,McLellan, J.S. (deposition date: 2018-05-04, release date: 2019-07-10, Last modification date: 2024-10-16)

Primary citation

Jones, H.G.,Battles, M.B.,Lin, C.C.,Bianchi, S.,Corti, D.,McLellan, J.S.
Alternative conformations of a major antigenic site on RSV F.
Plos Pathog., 15:e1007944-e1007944, 2019

PubMed Abstract: The respiratory syncytial virus (RSV) fusion (F) glycoprotein is a major target of neutralizing antibodies arising from natural infection, and antibodies that specifically bind to the prefusion conformation of RSV F generally demonstrate the greatest neutralization potency. Prefusion-stabilized RSV F variants have been engineered as vaccine antigens, but crystal structures of these variants have revealed conformational differences in a key antigenic site located at the apex of the trimer, referred to as antigenic site Ø. Currently, it is unclear if flexibility in this region is an inherent property of prefusion RSV F or if it is related to inadequate stabilization of site Ø in the engineered variants. Therefore, we set out to investigate the conformational flexibility of antigenic site Ø, as well as the ability of the human immune system to recognize alternative conformations of this site, by determining crystal structures of prefusion RSV F bound to neutralizing human-derived antibodies AM22 and RSD5. Both antibodies bound with high affinity and were specific for the prefusion conformation of RSV F. Crystal structures of the complexes revealed that the antibodies recognized distinct conformations of antigenic site Ø, each diverging at a conserved proline residue located in the middle of an α-helix. These data suggest that antigenic site Ø exists as an ensemble of conformations, with individual antibodies recognizing discrete states. Collectively, these results have implications for the refolding of pneumovirus and paramyxovirus fusion proteins and should inform development of prefusion-stabilized RSV F vaccine candidates.

PubMed: 31306469
DOI: 10.1371/journal.ppat.1007944

Experimental method

X-RAY DIFFRACTION (3.5 Å)