SARS-CoV-2 and bat RaTG13 spike glycoprotein structures inform on virus evolution and furin-cleavage effects

Antoni G Wrobel; Donald J Benton; Pengqi Xu; Chloë Roustan; Stephen R Martin; Peter B Rosenthal; John J Skehel; Steven J Gamblin

doi:10.1038/s41594-020-0468-7

SARS-CoV-2 and bat RaTG13 spike glycoprotein structures inform on virus evolution and furin-cleavage effects

Nat Struct Mol Biol. 2020 Aug;27(8):763-767. doi: 10.1038/s41594-020-0468-7. Epub 2020 Jul 9.

Authors

Antoni G Wrobel^#¹, Donald J Benton^#², Pengqi Xu^{3

4}, Chloë Roustan⁵, Stephen R Martin⁵, Peter B Rosenthal⁶, John J Skehel³, Steven J Gamblin⁷

Affiliations

¹ Structural Biology of Disease Processes Laboratory, Francis Crick Institute, London, UK. antoni.wrobel@crick.ac.uk.
² Structural Biology of Disease Processes Laboratory, Francis Crick Institute, London, UK. donald.benton@crick.ac.uk.
³ Structural Biology of Disease Processes Laboratory, Francis Crick Institute, London, UK.
⁴ Precision Medicine Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
⁵ Structural Biology Science Technology Platform, Francis Crick Institute, London, UK.
⁶ Structural Biology of Cells and Viruses Laboratory, Francis Crick Institute, London, UK.
⁷ Structural Biology of Disease Processes Laboratory, Francis Crick Institute, London, UK. steven.gamblin@crick.ac.uk.

^# Contributed equally.

Abstract

SARS-CoV-2 is thought to have emerged from bats, possibly via a secondary host. Here, we investigate the relationship of spike (S) glycoprotein from SARS-CoV-2 with the S protein of a closely related bat virus, RaTG13. We determined cryo-EM structures for RaTG13 S and for both furin-cleaved and uncleaved SARS-CoV-2 S; we compared these with recently reported structures for uncleaved SARS-CoV-2 S. We also biochemically characterized their relative stabilities and affinities for the SARS-CoV-2 receptor ACE2. Although the overall structures of human and bat virus S proteins are similar, there are key differences in their properties, including a more stable precleavage form of human S and about 1,000-fold tighter binding of SARS-CoV-2 to human receptor. These observations suggest that cleavage at the furin-cleavage site decreases the overall stability of SARS-CoV-2 S and facilitates the adoption of the open conformation that is required for S to bind to the ACE2 receptor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin-Converting Enzyme 2
Animals
Betacoronavirus / genetics*
Betacoronavirus / metabolism
Betacoronavirus / ultrastructure
Binding Sites
COVID-19
Chiroptera / virology
Coronavirus Infections / virology
Cryoelectron Microscopy
Evolution, Molecular
Furin / chemistry
Gene Expression
HEK293 Cells
Host-Pathogen Interactions / genetics*
Humans
Models, Molecular
Pandemics
Peptidyl-Dipeptidase A / chemistry*
Peptidyl-Dipeptidase A / genetics
Peptidyl-Dipeptidase A / metabolism
Pneumonia, Viral / virology
Protein Binding
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Interaction Domains and Motifs
Protein Isoforms / chemistry
Protein Isoforms / genetics
Protein Isoforms / metabolism
Protein Stability
Proteolysis
Receptors, Virus / chemistry*
Receptors, Virus / genetics
Receptors, Virus / metabolism
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
SARS-CoV-2
Spike Glycoprotein, Coronavirus / chemistry*
Spike Glycoprotein, Coronavirus / genetics
Spike Glycoprotein, Coronavirus / metabolism
Structural Homology, Protein

Substances

Protein Isoforms
Receptors, Virus
Recombinant Proteins
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2
Peptidyl-Dipeptidase A
ACE2 protein, human
Angiotensin-Converting Enzyme 2
Furin

Abstract

Publication types

MeSH terms

Substances

Grants and funding