Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant.
| العنوان: | Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant. |
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| المؤلفون: | Yurkovetskiy L; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.; These authors contributed equally to this work., Wang X; Thermo Fisher Scientific, Achtseweg Noord 5, 5651 GG Eindhoven, Netherlands.; These authors contributed equally to this work., Pascal KE; Regeneron Pharmaceutical, Inc., 777 Old Saw Mill River Rd, Tarrytown, NY 10591., Tomkins-Tinch C; Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, MA 02142, USA.; Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA., Nyalile T; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA., Wang Y; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA., Baum A; Regeneron Pharmaceutical, Inc., 777 Old Saw Mill River Rd, Tarrytown, NY 10591., 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; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA., 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; Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, MA 02142, USA.; Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA., Lemieux JE; Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, MA 02142, USA.; Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114., Munro J; D epartment of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA.; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA., Rafique A; Regeneron Pharmaceutical, Inc., 777 Old Saw Mill River Rd, Tarrytown, NY 10591., Barve A; Thermo Fisher Scientific, Achtseweg Noord 5, 5651 GG Eindhoven, Netherlands., Sabeti PC; 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.; Howard Hughes Medical Institute, 4000 Jones Bridge Rd, Chevy Chase, MD 20815.; Massachusetts Consortium on Pathogen Readiness, Boston, MA, 02115., Kyratsous CA; Regeneron Pharmaceutical, Inc., 777 Old Saw Mill River Rd, Tarrytown, NY 10591., Dudkina N; Thermo Fisher Scientific, Achtseweg Noord 5, 5651 GG Eindhoven, Netherlands., Shen K; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA., Luban J; Program in Molecular Medicine, University of Massachusetts Medical School, 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, Worcester, MA 01605, USA.; Massachusetts Consortium on Pathogen Readiness, Boston, MA, 02115.; Lead contact. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2020 Jul 15. Date of Electronic Publication: 2020 Jul 15. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | 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. Competing Interests: DECLARATION OF INTERESTS P.C.S. is a co-founder and shareholder of Sherlock Biosciences, and a Board member and shareholder of Danaher Corporation. J.E.L. consulted for Sherlock Biosciences. C.A.K., K.E.P., and A.B. are employed by Regeneron Pharmaceuticals and own stock options in the company. C.A.K. is an officer at Regeneron. X.W., A.B., and N.D. are employees of Thermo Fisher Scientific. |
| التعليقات: | Update in: Cell. 2020 Oct 29;183(3):739-751.e8. (PMID: 32991842) |
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| معلومات مُعتمدة: | K22 CA241362 United States CA NCI NIH HHS; R37 AI147868 United States AI NIAID NIH HHS; R01 AI148784 United States AI NIAID NIH HHS; U19 AI110818 United States AI NIAID NIH HHS; DP2 AI124384 United States AI NIAID NIH HHS |
| تواريخ الأحداث: | Date Created: 20200709 Latest Revision: 20240403 |
| رمز التحديث: | 20240403 |
| مُعرف محوري في PubMed: | PMC7337374 |
| DOI: | 10.1101/2020.07.04.187757 |
| PMID: | 32637944 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2020.07.04.187757 |
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