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

Cell, 2020-09, Vol.182 (5), p.1295-1310.e20 [Peer Reviewed Journal]

2020 The Author(s) ;Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved. ;2020. Not withstanding the ProQuest Terms and Conditions, you may use this content in accordance with the associated terms available at https://www.elsevier.com/legal/elsevier-website-terms-and-conditions ;Distributed under a Creative Commons Attribution 4.0 International License ;2020 The Author(s) 2020 ;ISSN: 0092-8674 ;EISSN: 1097-4172 ;DOI: 10.1016/j.cell.2020.08.012 ;PMID: 32841599

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Title:
Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding
Author: Starr, Tyler N. ; Greaney, Allison J. ; Hilton, Sarah K. ; Ellis, Daniel ; Crawford, Katharine H.D. ; Dingens, Adam S. ; Navarro, Mary Jane ; Bowen, John E. ; Tortorici, M. Alejandra ; Walls, Alexandra C. ; King, Neil P. ; Veesler, David ; Bloom, Jesse D.
Subjects: ACE2 ; Angiotensin-Converting Enzyme 2 ; Binding Sites ; deep mutational scanning ; HEK293 Cells ; Humans ; Life Sciences ; Molecular Docking Simulation ; Mutation ; Peptidyl-Dipeptidase A ; Peptidyl-Dipeptidase A - chemistry ; Peptidyl-Dipeptidase A - metabolism ; Phenotype ; Protein Binding ; Protein Folding ; receptor-binding domain ; Resource ; Saccharomyces cerevisiae ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus ; Spike Glycoprotein, Coronavirus - chemistry ; Spike Glycoprotein, Coronavirus - genetics ; Spike Glycoprotein, Coronavirus - metabolism
Is Part Of: Cell, 2020-09, Vol.182 (5), p.1295-1310.e20
Description: 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. [Display omitted] •Measured effects on folding and ACE2 binding of all mutations to the SARS-CoV-2 RBD•Provide open data and interactive visualization for vaccine design and surveillance•Identify constrained surfaces as ideal targets for vaccines and antibody therapeutics•Mutations that enhance ACE2 affinity exist but are not selected in pandemic isolates Starr et al. systematically change every amino acid in the receptor binding domain (RBD) of the SARS-CoV-2 spike protein and determine the effects of the substitutions on RBD expression, folding, and ACE2 binding. The work identifies structurally constrained regions of the spike RBD that would be ideal targets for COVID-19 countermeasures and demonstrates that mutations in the virus that enhance ACE2 affinity can be engineered but have not, to date, been naturally selected during the pandemic.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0092-8674
EISSN: 1097-4172
DOI: 10.1016/j.cell.2020.08.012
PMID: 32841599
Source: Coronavirus Research Database

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

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