tetano
Editor, Senior Moderator
Cell Host Microbe
. 2020 Nov 13;S1931-3128(20)30618-1.
doi: 10.1016/j.chom.2020.11.001. Online ahead of print.
Real-Time Conformational Dynamics of SARS-CoV-2 Spikes on Virus Particles
Maolin Lu[SUP] 1 [/SUP], Pradeep D Uchil[SUP] 2 [/SUP], Wenwei Li[SUP] 2 [/SUP], Desheng Zheng[SUP] 2 [/SUP], Daniel S Terry[SUP] 3 [/SUP], Jason Gorman[SUP] 4 [/SUP], Wei Shi[SUP] 4 [/SUP], Baoshan Zhang[SUP] 4 [/SUP], Tongqing Zhou[SUP] 4 [/SUP], Shilei Ding[SUP] 5 [/SUP], Romain Gasser[SUP] 5 [/SUP], J?r?mie Pr?vost[SUP] 5 [/SUP], Guillaume Beaudoin-Bussi?res[SUP] 5 [/SUP], Sai Priya Anand[SUP] 6 [/SUP], Annemarie Laumaea[SUP] 5 [/SUP], Jonathan R Grover[SUP] 2 [/SUP], Lihong Liu[SUP] 7 [/SUP], David D Ho[SUP] 7 [/SUP], John R Mascola[SUP] 4 [/SUP], Andr?s Finzi[SUP] 6 [/SUP], Peter D Kwong[SUP] 4 [/SUP], Scott C Blanchard[SUP] 3 [/SUP], Walther Mothes[SUP] 8 [/SUP]
Affiliations
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) mediates viral entry into cells and is critical for vaccine development against coronavirus disease 2019 (COVID-19). Structural studies have revealed distinct conformations of S, but real-time information that connects these structures is lacking. Here we apply single-molecule fluorescence (F?rster) resonance energy transfer (smFRET) imaging to observe conformational dynamics of S on virus particles. Virus-associated S dynamically samples at least four distinct conformational states. In response to human receptor angiotensin-converting enzyme 2 (hACE2), S opens sequentially into the hACE2-bound S conformation through at least one on-path intermediate. Conformational preferences observed upon exposure to convalescent plasma or antibodies suggest mechanisms of neutralization involving either competition with hACE2 for binding to the receptor-binding domain (RBD) or allosteric interference with conformational changes required for entry. Our findings inform on mechanisms of S recognition and conformations for immunogen design.
Keywords: SARS-CoV-2 spike protein; antibody neutralization; real-time conformational dynamics; receptor ACE2; single-molecule FRET.
. 2020 Nov 13;S1931-3128(20)30618-1.
doi: 10.1016/j.chom.2020.11.001. Online ahead of print.
Real-Time Conformational Dynamics of SARS-CoV-2 Spikes on Virus Particles
Maolin Lu[SUP] 1 [/SUP], Pradeep D Uchil[SUP] 2 [/SUP], Wenwei Li[SUP] 2 [/SUP], Desheng Zheng[SUP] 2 [/SUP], Daniel S Terry[SUP] 3 [/SUP], Jason Gorman[SUP] 4 [/SUP], Wei Shi[SUP] 4 [/SUP], Baoshan Zhang[SUP] 4 [/SUP], Tongqing Zhou[SUP] 4 [/SUP], Shilei Ding[SUP] 5 [/SUP], Romain Gasser[SUP] 5 [/SUP], J?r?mie Pr?vost[SUP] 5 [/SUP], Guillaume Beaudoin-Bussi?res[SUP] 5 [/SUP], Sai Priya Anand[SUP] 6 [/SUP], Annemarie Laumaea[SUP] 5 [/SUP], Jonathan R Grover[SUP] 2 [/SUP], Lihong Liu[SUP] 7 [/SUP], David D Ho[SUP] 7 [/SUP], John R Mascola[SUP] 4 [/SUP], Andr?s Finzi[SUP] 6 [/SUP], Peter D Kwong[SUP] 4 [/SUP], Scott C Blanchard[SUP] 3 [/SUP], Walther Mothes[SUP] 8 [/SUP]
Affiliations
- PMID: 33242391
- PMCID: PMC7664471
- DOI: 10.1016/j.chom.2020.11.001
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) mediates viral entry into cells and is critical for vaccine development against coronavirus disease 2019 (COVID-19). Structural studies have revealed distinct conformations of S, but real-time information that connects these structures is lacking. Here we apply single-molecule fluorescence (F?rster) resonance energy transfer (smFRET) imaging to observe conformational dynamics of S on virus particles. Virus-associated S dynamically samples at least four distinct conformational states. In response to human receptor angiotensin-converting enzyme 2 (hACE2), S opens sequentially into the hACE2-bound S conformation through at least one on-path intermediate. Conformational preferences observed upon exposure to convalescent plasma or antibodies suggest mechanisms of neutralization involving either competition with hACE2 for binding to the receptor-binding domain (RBD) or allosteric interference with conformational changes required for entry. Our findings inform on mechanisms of S recognition and conformations for immunogen design.
Keywords: SARS-CoV-2 spike protein; antibody neutralization; real-time conformational dynamics; receptor ACE2; single-molecule FRET.