OmniVira

Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding.

Tyler N Starr1 Allison J Greaney2,3,4 Sarah K Hilton2,5 Daniel Ellis6,7,8 Katharine H D Crawford2,3,4 Adam S Dingens1 Mary Jane Navarro9 John E Bowen9 M Alejandra Tortorici9 Alexandra C Walls9 Neil P King6,9 David Veesler9 Jesse D Bloom2,3,10
Affiliations 10 institutions
  1. Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  2. Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
  3. Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
  4. Medical Scientist Training Program, University of Washington, Seattle, WA 98195, USA.
  5. Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
  6. Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
  7. Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
  8. Graduate Program in Molecular and Cellular Biology, University of Washington, Seattle, WA 98195, USA.
  9. Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
  10. Howard Hughes Medical Institute, Seattle, WA 98109, USA. Electronic address: [email protected].
PMID32841599 DOI10.1016/j.cell.2020.08.012 Year2020 Journal Cell Languageeng Statusppublish

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.

ACE2 54 deep mutational scanning 2 receptor-binding domain 10 SARS-CoV-2 550 Molecular Docking Simulation 5 Mutation 209 Angiotensin-Converting Enzyme 2 177 Binding Sites 89 HEK293 Cells 61 Humans 1440 Peptidyl-Dipeptidase A 57 Phenotype 12 Protein Binding 193 Protein Folding 3 Saccharomyces cerevisiae 0 Spike Glycoprotein, Coronavirus 274 ACE2 protein, human 87 spike protein, SARS-CoV-2 157

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