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Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding

View ORCID ProfileTyler N. Starr, View ORCID ProfileAllison J. Greaney, View ORCID ProfileSarah K. Hilton, View ORCID ProfileKatharine H.D. Crawford, Mary Jane Navarro, John E. Bowen, View ORCID ProfileM. Alejandra Tortorici, View ORCID ProfileAlexandra C. Walls, View ORCID ProfileDavid Veesler, View ORCID ProfileJesse D. Bloom
doi: https://doi.org/10.1101/2020.06.17.157982
Tyler N. Starr
1Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
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  • ORCID record for Tyler N. Starr
Allison J. Greaney
1Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
2Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
3Medical Scientist Training Program, University of Washington, Seattle, WA 98195, USA
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Sarah K. Hilton
1Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
2Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
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Katharine H.D. Crawford
1Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
2Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
3Medical Scientist Training Program, University of Washington, Seattle, WA 98195, USA
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Mary Jane Navarro
4Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
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John E. Bowen
4Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
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M. Alejandra Tortorici
4Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
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  • ORCID record for M. Alejandra Tortorici
Alexandra C. Walls
4Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
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David Veesler
4Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
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Jesse D. Bloom
1Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
2Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
5Howard Hughes Medical Institute, Seattle, WA 98109, USA
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  • For correspondence: jbloom@fredhutch.org
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Abstract

The receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein mediates viral attachment to ACE2 receptor, and is a major determinant of host range and a dominant target of neutralizing antibodies. Here we experimentally measure how all amino-acid mutations to the RBD affect expression of folded protein and its affinity for ACE2. Most mutations are deleterious for RBD expression and ACE2 binding, and we identify constrained regions on the RBD’s surface that may be desirable targets for vaccines and antibody-based therapeutics. But a substantial number of mutations are well tolerated or even enhance ACE2 binding, including at ACE2 interface residues that vary across SARS-related coronaviruses. However, we find no evidence that these ACE2-affinity enhancing mutations have been selected in current SARS-CoV-2 pandemic isolates. We present an interactive visualization and open analysis pipeline to facilitate use of our dataset for vaccine design and functional annotation of mutations observed during viral surveillance.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵6 Co-first authors

  • ↵7 Lead Contact

  • https://jbloomlab.github.io/SARS-CoV-2-RBD_DMS/

  • https://jbloomlab.github.io/SARS-CoV-2-RBD_DMS/structures/

  • https://github.com/jbloomlab/SARS-CoV-2-RBD_DMS

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 17, 2020.
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Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding
Tyler N. Starr, Allison J. Greaney, Sarah K. Hilton, Katharine H.D. Crawford, Mary Jane Navarro, John E. Bowen, M. Alejandra Tortorici, Alexandra C. Walls, David Veesler, Jesse D. Bloom
bioRxiv 2020.06.17.157982; doi: https://doi.org/10.1101/2020.06.17.157982
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Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding
Tyler N. Starr, Allison J. Greaney, Sarah K. Hilton, Katharine H.D. Crawford, Mary Jane Navarro, John E. Bowen, M. Alejandra Tortorici, Alexandra C. Walls, David Veesler, Jesse D. Bloom
bioRxiv 2020.06.17.157982; doi: https://doi.org/10.1101/2020.06.17.157982

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