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Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant.
Yurkovetskiy, Leonid; Wang, Xue; Pascal, Kristen E; Tomkins-Tinch, Christopher; Nyalile, Thomas; Wang, Yetao; Baum, Alina; Diehl, William E; Dauphin, Ann; Carbone, Claudia; Veinotte, Kristen; Egri, Shawn B; Schaffner, Stephen F; Lemieux, Jacob E; Munro, James; Rafique, Ashique; Barve, Abhi; Sabeti, Pardis C; Kyratsous, Christos A; Dudkina, Natalya; Shen, Kuang; Luban, Jeremy.
  • Yurkovetskiy L; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • Wang X; These authors contributed equally to this work.
  • Pascal KE; Thermo Fisher Scientific, Achtseweg Noord 5, 5651 GG Eindhoven, Netherlands.
  • Tomkins-Tinch C; These authors contributed equally to this work.
  • Nyalile T; Regeneron Pharmaceutical, Inc., 777 Old Saw Mill River Rd, Tarrytown, NY 10591.
  • Wang Y; Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, MA 02142, USA.
  • Baum A; Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA.
  • Diehl WE; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • Dauphin A; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • Carbone C; Regeneron Pharmaceutical, Inc., 777 Old Saw Mill River Rd, Tarrytown, NY 10591.
  • Veinotte K; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • Egri SB; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • Schaffner SF; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • Lemieux JE; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • Munro J; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • Rafique A; Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, MA 02142, USA.
  • Barve A; Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA.
  • Sabeti PC; Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, MA 02142, USA.
  • Kyratsous CA; Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114.
  • Dudkina N; D epartment of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • Shen K; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • Luban J; Regeneron Pharmaceutical, Inc., 777 Old Saw Mill River Rd, Tarrytown, NY 10591.
bioRxiv ; 2020 Jul 15.
Article in English | MEDLINE | ID: covidwho-637849
ABSTRACT
The SARS-CoV-2 spike (S) protein variant D614G supplanted the ancestral virus worldwide in a matter of months. Here we show that D614G was more infectious than the ancestral form on human lung cells, colon cells, and cells rendered permissive by ectopic expression of various mammalian ACE2 orthologs. Nonetheless, 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 a critical interprotomer contact and that this dramatically shifts the S protein trimer conformation toward an ACE2-binding and fusion-competent state. Consistent with the more open conformation, neutralization potency of antibodies targeting the S protein receptor-binding domain was not attenuated. These results indicate that D614G adopts conformations that make virion membrane fusion with the target cell membrane more probable but that D614G retains susceptibility to therapies that disrupt interaction of the SARS-CoV-2 S protein with the ACE2 receptor.

Full text: Available Collection: International databases Database: MEDLINE Topics: Variants Language: English Year: 2020 Document Type: Article Affiliation country: 2020.07.04.187757

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Full text: Available Collection: International databases Database: MEDLINE Topics: Variants Language: English Year: 2020 Document Type: Article Affiliation country: 2020.07.04.187757