puc-header

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

46 Pages Posted: 10 Aug 2020 Publication Status: Published

See all articles by Leonid Yurkovetskiy

Leonid Yurkovetskiy

University of Massachusetts Worcester - Program in Molecular Medicine

Xue Wang

Thermo Fisher Scientific

Kristen E. Pascal

​Regeneron Pharmaceutical, Inc.

Christopher Tomkins-Tinch

Harvard University

Thomas Nyalile

University of Massachusetts Worcester - Program in Molecular Medicine

Yetao Wang

University of Massachusetts Medical School - Program in Molecular Medicine

Alina Baum

​Regeneron Pharmaceutical, Inc.

William E. Diehl

University of Massachusetts Worcester - Program in Molecular Medicine

Ann Dauphin

University of Massachusetts Worcester - Program in Molecular Medicine

Claudia Carbone

University of Massachusetts Worcester - Program in Molecular Medicine

Kristen Veinotte

University of Massachusetts Worcester - Program in Molecular Medicine

Shawn Egri

University of Massachusetts Worcester - Program in Molecular Medicine

Stephen Schaffner

Harvard University

Jacob E. Lemieux

Masssachusetts Institute of Technology and Harvard University - Broad Institute

James Munro

University of Massachusetts Worcester - Department of Microbiology and Physiological Systems

Ashique Rafique

​Regeneron Pharmaceutical, Inc.

Abhi Barve

Thermo Fisher Scientific

Pardis C. Sabeti

Masssachusetts Institute of Technology and Harvard University - Broad Institute

Christos A. Kyratsous

​Regeneron Pharmaceutical, Inc.

Natalya Dudkina

Thermo Fisher Scientific

Kuang Shen

University of Massachusetts Worcester - Program in Molecular Medicine

Jeremy Luban

University of Massachusetts Worcester - Program in Molecular Medicine

More...

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.

Suggested Citation

Yurkovetskiy, Leonid and Wang, Xue and Pascal, Kristen E. and Tomkins-Tinch, Christopher and Nyalile, Thomas and Wang, Yetao and Baum, Alina and Diehl, William E. and Dauphin, Ann and Carbone, Claudia and Veinotte, Kristen and Egri, Shawn and Schaffner, Stephen and Lemieux, Jacob E. and Munro, James and Rafique, Ashique and Barve, Abhi and Sabeti, Pardis C. and Kyratsous, Christos A. and Dudkina, Natalya and Shen, Kuang and Luban, Jeremy, Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant. Available at SSRN: https://ssrn.com/abstract=3657338 or http://dx.doi.org/10.2139/ssrn.3657338
This version of the paper has not been formally peer reviewed.

Leonid Yurkovetskiy

University of Massachusetts Worcester - Program in Molecular Medicine ( email )

Program in Molecular Medicine
Worcester, MA 01605
United States

Xue Wang

Thermo Fisher Scientific

Kristen E. Pascal

​Regeneron Pharmaceutical, Inc. ( email )

United States

Christopher Tomkins-Tinch

Harvard University

Thomas Nyalile

University of Massachusetts Worcester - Program in Molecular Medicine ( email )

Program in Molecular Medicine
Worcester, MA 01605
United States

Yetao Wang

University of Massachusetts Medical School - Program in Molecular Medicine ( email )

Program in Molecular Medicine
Worcester, MA 01605
United States

Alina Baum

​Regeneron Pharmaceutical, Inc. ( email )

United States

William E. Diehl

University of Massachusetts Worcester - Program in Molecular Medicine ( email )

Program in Molecular Medicine
Worcester, MA 01605
United States

Ann Dauphin

University of Massachusetts Worcester - Program in Molecular Medicine ( email )

Program in Molecular Medicine
Worcester, MA 01605
United States

Claudia Carbone

University of Massachusetts Worcester - Program in Molecular Medicine ( email )

Program in Molecular Medicine
Worcester, MA 01605
United States

Kristen Veinotte

University of Massachusetts Worcester - Program in Molecular Medicine ( email )

Program in Molecular Medicine
Worcester, MA 01605
United States

Shawn Egri

University of Massachusetts Worcester - Program in Molecular Medicine ( email )

Program in Molecular Medicine
Worcester, MA 01605
United States

Stephen Schaffner

Harvard University

Jacob E. Lemieux

Masssachusetts Institute of Technology and Harvard University - Broad Institute

James Munro

University of Massachusetts Worcester - Department of Microbiology and Physiological Systems ( email )

United States

Ashique Rafique

​Regeneron Pharmaceutical, Inc. ( email )

United States

Abhi Barve

Thermo Fisher Scientific

Pardis C. Sabeti

Masssachusetts Institute of Technology and Harvard University - Broad Institute

Christos A. Kyratsous

​Regeneron Pharmaceutical, Inc. ( email )

United States

Natalya Dudkina

Thermo Fisher Scientific

Kuang Shen

University of Massachusetts Worcester - Program in Molecular Medicine ( email )

Program in Molecular Medicine
Worcester, MA 01605
United States

Jeremy Luban (Contact Author)

University of Massachusetts Worcester - Program in Molecular Medicine

Program in Molecular Medicine
Worcester, MA 01605
United States

Click here to go to Cell.com

Paper statistics

Abstract Views
997
Downloads
10
PlumX Metrics