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-Structure paper
Title | Stabilizing the closed SARS-CoV-2 spike trimer. |
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Journal, issue, pages | Nat Commun, Vol. 12, Issue 1, Page 244, Year 2021 |
Publish date | Jan 11, 2021 |
Authors | Jarek Juraszek / Lucy Rutten / Sven Blokland / Pascale Bouchier / Richard Voorzaat / Tina Ritschel / Mark J G Bakkers / Ludovic L R Renault / Johannes P M Langedijk / |
PubMed Abstract | The trimeric spike (S) protein of SARS-CoV-2 is the primary focus of most vaccine design and development efforts. Due to intrinsic instability typical of class I fusion proteins, S tends to ...The trimeric spike (S) protein of SARS-CoV-2 is the primary focus of most vaccine design and development efforts. Due to intrinsic instability typical of class I fusion proteins, S tends to prematurely refold to the post-fusion conformation, compromising immunogenic properties and prefusion trimer yields. To support ongoing vaccine development efforts, we report the structure-based design of soluble S trimers with increased yields and stabilities, based on introduction of single point mutations and disulfide-bridges. We identify regions critical for stability: the heptad repeat region 1, the SD1 domain and position 614 in SD2. We combine a minimal selection of mostly interprotomeric mutations to create a stable S-closed variant with a 6.4-fold higher expression than the parental construct while no longer containing a heterologous trimerization domain. The cryo-EM structure reveals a correctly folded, predominantly closed pre-fusion conformation. Highly stable and well producing S protein and the increased understanding of S protein structure will support vaccine development and serological diagnostics. |
External links | Nat Commun / PubMed:33431842 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.75 - 2.92 Å |
Structure data | EMDB-11639, PDB-7a4n: EMDB-11719, PDB-7ad1: |
Chemicals | ChemComp-NAG: |
Source |
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Keywords | VIRAL PROTEIN / SARS-CoV-2 / virology / COVID-19 / class I fusion proteins / S glycoprotein / cryo-EM / prefusion / corona |