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

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

  • Cell. 2020 Oct 29;183(3):739-751.e8. doi: 10.1016/j.cell.2020.09.032.
Leonid Yurkovetskiy 1,  Xue Wang 2,  Kristen E Pascal 3,  Christopher Tomkins-Tinch 4,  Thomas P Nyalile 1,  Yetao Wang 1,  Alina Baum 3,  William E Diehl 1,  Ann Dauphin 1,  Claudia Carbone 1,  Kristen Veinotte 1,  Shawn B Egri 1,  Stephen F Schaffner 4,  Jacob E Lemieux 5,  James B Munro 6,  Ashique Rafique 3,  Abhi Barve 2,  Pardis C Sabeti 7,  Christos A Kyratsous 8,  Natalya V Dudkina 9,  Kuang Shen 10,  Jeremy Luban 11
Affiliations

Affiliations

  • 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; Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA.
  • 5 Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, MA 02142, USA; Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA.
  • 6 Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 55 Lake Avenue, Worcester, MA 01605, USA; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St, Worcester, MA 01605, USA.
  • 7 Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, MA 02142, USA; Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA; Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, 02115 Boston, MA, USA; Howard Hughes Medical Institute, 4000 Jones Bridge Rd, Chevy Chase, MD 20815, USA; Massachusetts Consortium on Pathogen Readiness, Boston, MA, 02115, USA. Electronic address: pardis.sabeti@broadinstitute.org.
  • 8 Regeneron Pharmaceutical, Inc., 777 Old Saw Mill River Rd, Tarrytown, NY 10591, USA. Electronic address: christos.kyratsous@regeneron.com.
  • 9 Thermo Fisher Scientific, Achtseweg Noord 5, 5651 GG Eindhoven, Netherlands. Electronic address: natalya.dudkina@thermofisher.com.
  • 10 Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA. Electronic address: kuang.shen@umassmed.edu.
  • 11 Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA; Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, MA 02142, USA; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St, Worcester, MA 01605, USA; Massachusetts Consortium on Pathogen Readiness, Boston, MA, 02115, USA. Electronic address: jeremy.luban@umassmed.edu.
PMID: 32991842 DOI: 10.1016/j.cell.2020.09.032
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.

Keywords

ACE2; COVID-19; SARS-CoV-2; Spike protein; coronavirus; cryo-electron microscopy; infectivity; neutralizing antibody; pandemic.

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