Alternative conformations of a major antigenic site on RSV F.
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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2019-07-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1007944 |
| _version_ | 1818582293711683584 |
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| author | Harrison G Jones Michael B Battles Chun-Chi Lin Siro Bianchi Davide Corti Jason S McLellan |
| author_facet | Harrison G Jones Michael B Battles Chun-Chi Lin Siro Bianchi Davide Corti Jason S McLellan |
| author_sort | Harrison G Jones |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-16T07:47:05Z |
| format | Article |
| id | doaj.art-13a13ead00974b18b39f36bf1cbc471a |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-16T07:47:05Z |
| publishDate | 2019-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-13a13ead00974b18b39f36bf1cbc471a2022-12-21T22:38:56ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742019-07-01157e100794410.1371/journal.ppat.1007944Alternative conformations of a major antigenic site on RSV F.Harrison G JonesMichael B BattlesChun-Chi LinSiro BianchiDavide CortiJason S McLellanThe 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.https://doi.org/10.1371/journal.ppat.1007944 |
| spellingShingle | Harrison G Jones Michael B Battles Chun-Chi Lin Siro Bianchi Davide Corti Jason S McLellan Alternative conformations of a major antigenic site on RSV F. PLoS Pathogens |
| title | Alternative conformations of a major antigenic site on RSV F. |
| title_full | Alternative conformations of a major antigenic site on RSV F. |
| title_fullStr | Alternative conformations of a major antigenic site on RSV F. |
| title_full_unstemmed | Alternative conformations of a major antigenic site on RSV F. |
| title_short | Alternative conformations of a major antigenic site on RSV F. |
| title_sort | alternative conformations of a major antigenic site on rsv f |
| url | https://doi.org/10.1371/journal.ppat.1007944 |
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