Unprecedented spike flexibility revealed by BSL3 Cryo-ET of active SARS-CoV-2 virions
Abstract Understanding the molecular properties of SARS-CoV-2 is crucial to tackle future outbreaks. Current knowledge of the trimeric spike protein relies on truncated recombinant proteins and inactivated full-length forms, which may suffer from overstabilization. Here, we apply cryo-electron tomography (cryo-ET) at a Biosafety level 3 facility to study the virus structure in its native, active state. The virus particles show variable shapes with diffusible spikes, with the majority in typical prefusion conformations. Notably, we also identified unprecedented, atypical open-trimer prefusion states, revealing hidden flexibility. The sub-tomogram averaged structure suggests a loosely packed trimer. The observed dynamics uncover conserved cryptic regions that can be targeted for broadly effective vaccines. Structural analysis of active viruses will have implications on understanding overlooked fusion mechanism and vaccine, antibody/drug design. (124 words)One-Sentence Summary The BSL3 cryo-electron microscopy uncovered significant flexibility of the spike protein on active viruses, which will facilitate the design of broadly effective vaccines and drugs..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 09. Nov. Zur Gesamtaufnahme - year:2023 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Fukuhara, Hideo [VerfasserIn] |
|---|
| Links: |
Volltext [kostenfrei] |
|---|
| Themen: |
|---|
| doi: |
10.1101/2023.10.10.561643 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XBI041156579 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XBI041156579 | ||
| 003 | DE-627 | ||
| 005 | 20231205143951.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231012s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/2023.10.10.561643 |2 doi | |
| 035 | |a (DE-627)XBI041156579 | ||
| 035 | |a (biorXiv)10.1101/2023.10.10.561643 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Fukuhara, Hideo |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Unprecedented spike flexibility revealed by BSL3 Cryo-ET of active SARS-CoV-2 virions |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a Abstract Understanding the molecular properties of SARS-CoV-2 is crucial to tackle future outbreaks. Current knowledge of the trimeric spike protein relies on truncated recombinant proteins and inactivated full-length forms, which may suffer from overstabilization. Here, we apply cryo-electron tomography (cryo-ET) at a Biosafety level 3 facility to study the virus structure in its native, active state. The virus particles show variable shapes with diffusible spikes, with the majority in typical prefusion conformations. Notably, we also identified unprecedented, atypical open-trimer prefusion states, revealing hidden flexibility. The sub-tomogram averaged structure suggests a loosely packed trimer. The observed dynamics uncover conserved cryptic regions that can be targeted for broadly effective vaccines. Structural analysis of active viruses will have implications on understanding overlooked fusion mechanism and vaccine, antibody/drug design. (124 words)One-Sentence Summary The BSL3 cryo-electron microscopy uncovered significant flexibility of the spike protein on active viruses, which will facilitate the design of broadly effective vaccines and drugs. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Dokainish, Hisham M. |0 (orcid)0000-0002-4387-4790 |4 aut | |
| 700 | 1 | |a Kita, Shunsuke |4 aut | |
| 700 | 1 | |a Tabata, Koshiro |4 aut | |
| 700 | 1 | |a Takasu, Akira |4 aut | |
| 700 | 1 | |a Huiskonen, Juha T. |4 aut | |
| 700 | 1 | |a Anraku, Yuki |4 aut | |
| 700 | 1 | |a Senda, Toshiya |4 aut | |
| 700 | 1 | |a Stuart, David I. |4 aut | |
| 700 | 1 | |a Sasaki, Michihito |0 (orcid)0000-0003-1607-2175 |4 aut | |
| 700 | 1 | |a Orba, Yasuko |4 aut | |
| 700 | 1 | |a Suzuki, Yasuhiko |4 aut | |
| 700 | 1 | |a Sawa, Hirofumi |4 aut | |
| 700 | 1 | |a Maenaka, Katsumi |0 (orcid)0000-0002-5459-521X |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2023) vom: 09. Nov. |
| 773 | 1 | 8 | |g year:2023 |g day:09 |g month:11 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/2023.10.10.561643 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XBI | ||
| 951 | |a AR | ||
| 952 | |j 2023 |b 09 |c 11 | ||