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Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant.

Leonid Yurkovetskiy1 Xue Wang2 Kristen E Pascal3 Christopher Tomkins-Tinch4,5 Thomas P Nyalile1 Yetao Wang1 Alina Baum3 William E Diehl1 Ann Dauphin1 Claudia Carbone1 Kristen Veinotte1 Shawn B Egri1 Stephen F Schaffner4,5 Jacob E Lemieux4,6 James B Munro7,8 Ashique Rafique3 Abhi Barve2 Pardis C Sabeti4,9,10,11,12 Christos A Kyratsous13 Natalya V Dudkina14 Kuang Shen15 Jeremy Luban16,4,17,18
Affiliations 18 institutions
  1. Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA.
  2. Thermo Fisher Scientific, Achtseweg Noord 5, 5651 GG Eindhoven, Netherlands.
  3. Regeneron Pharmaceutical, Inc., 777 Old Saw Mill River Rd, Tarrytown, NY 10591, USA.
  4. Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, MA 02142, USA
  5. Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA.
  6. Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA.
  7. Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 55 Lake Avenue, Worcester, MA 01605, USA
  8. Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St, Worcester, MA 01605, USA.
  9. Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA
  10. Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, 02115 Boston, MA, USA
  11. Howard Hughes Medical Institute, 4000 Jones Bridge Rd, Chevy Chase, MD 20815, USA
  12. Massachusetts Consortium on Pathogen Readiness, Boston, MA, 02115, USA. Electronic address: [email protected].
  13. Regeneron Pharmaceutical, Inc., 777 Old Saw Mill River Rd, Tarrytown, NY 10591, USA. Electronic address: [email protected].
  14. Thermo Fisher Scientific, Achtseweg Noord 5, 5651 GG Eindhoven, Netherlands. Electronic address: [email protected].
  15. Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA. Electronic address: [email protected].
  16. Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA
  17. Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St, Worcester, MA 01605, USA
  18. Massachusetts Consortium on Pathogen Readiness, Boston, MA, 02115, USA. Electronic address: [email protected].
PMID32991842 DOI10.1016/j.cell.2020.09.032 Year2020 Journal Cell Languageeng Statusppublish

Abstract

The SARS-CoV-2 spike (S) protein variant D614G supplanted the ancestral virus worldwide, reaching near fixation in a matter of months. Here we show that D614G was more infectious than the ancestral form on human lung cells, colon cells, and on cells rendered permissive by ectopic expression of human ACE2 or of ACE2 orthologs from various mammals, including Chinese rufous horseshoe bat and Malayan pangolin. D614G did not alter S protein synthesis, processing, or incorporation into SARS-CoV-2 particles, but D614G affinity for ACE2 was reduced due to a faster dissociation rate. Assessment of the S protein trimer by cryo-electron microscopy showed that D614G disrupts an interprotomer contact and that the conformation is shifted toward an ACE2 binding-competent state, which is modeled to be on pathway for virion membrane fusion with target cells. Consistent with this more open conformation, neutralization potency of antibodies targeting the S protein receptor-binding domain was not attenuated.

ACE2 54 coronavirus 195 COVID-19 467 cryo-electron microscopy 0 infectivity 7 neutralizing antibody 5 pandemic 15 SARS-CoV-2 550 Spike protein 32 Angiotensin-Converting Enzyme 2 177 Animals 1948 Antibodies, Monoclonal 26 Antibodies, Viral 212 Betacoronavirus 78 Cells, Cultured 26 Coronavirus Infections 171 COVID-19 425 Female 289 Genetic Variation 127 HEK293 Cells 61 Humans 1440 Male 224 Models, Molecular 99 Pandemics 108

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