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Effects of common mutations in the SARS-CoV-2 Spike RBD and its ligand, the human ACE2 receptor on binding affinity and kinetics.
Elife. 2021 08 26; 10E

Abstract

The interaction between the SARS-CoV-2 virus Spike protein receptor binding domain (RBD) and the ACE2 cell surface protein is required for viral infection of cells. Mutations in the RBD are present in SARS-CoV-2 variants of concern that have emerged independently worldwide. For example, the B.1.1.7 lineage has a mutation (N501Y) in its Spike RBD that enhances binding to ACE2. There are also ACE2 alleles in humans with mutations in the RBD binding site. Here we perform a detailed affinity and kinetics analysis of the effect of five common RBD mutations (K417N, K417T, N501Y, E484K, and S477N) and two common ACE2 mutations (S19P and K26R) on the RBD/ACE2 interaction. We analysed the effects of individual RBD mutations and combinations found in new SARS-CoV-2 Alpha (B.1.1.7), Beta (B.1.351), and Gamma (P1) variants. Most of these mutations increased the affinity of the RBD/ACE2 interaction. The exceptions were mutations K417N/T, which decreased the affinity. Taken together with other studies, our results suggest that the N501Y and S477N mutations enhance transmission primarily by enhancing binding, the K417N/T mutations facilitate immune escape, and the E484K mutation enhances binding and immune escape.

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Authors+Show Affiliations

Barton MI
Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
MacGowan SA
School of Life Sciences, University of Dundee, Dundee, United Kingdom.
Kutuzov MA
Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
Dushek O
Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
Barton GJ
School of Life Sciences, University of Dundee, Dundee, United Kingdom.
van der Merwe PA
Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.

MeSH

Angiotensin-Converting Enzyme 2Binding SitesCOVID-19HumansKineticsLigandsMolecular Dynamics SimulationMutationProtein BindingProtein DomainsProtein Interaction Domains and MotifsSARS-CoV-2Spike Glycoprotein, Coronavirus

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34435953

Citation

Barton, Michael I., et al. "Effects of Common Mutations in the SARS-CoV-2 Spike RBD and Its Ligand, the Human ACE2 Receptor On Binding Affinity and Kinetics." ELife, vol. 10, 2021.
Barton MI, MacGowan SA, Kutuzov MA, et al. Effects of common mutations in the SARS-CoV-2 Spike RBD and its ligand, the human ACE2 receptor on binding affinity and kinetics. Elife. 2021;10.
Barton, M. I., MacGowan, S. A., Kutuzov, M. A., Dushek, O., Barton, G. J., & van der Merwe, P. A. (2021). Effects of common mutations in the SARS-CoV-2 Spike RBD and its ligand, the human ACE2 receptor on binding affinity and kinetics. ELife, 10. https://doi.org/10.7554/eLife.70658
Barton MI, et al. Effects of Common Mutations in the SARS-CoV-2 Spike RBD and Its Ligand, the Human ACE2 Receptor On Binding Affinity and Kinetics. Elife. 2021 08 26;10 PubMed PMID: 34435953.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of common mutations in the SARS-CoV-2 Spike RBD and its ligand, the human ACE2 receptor on binding affinity and kinetics. AU - Barton,Michael I, AU - MacGowan,Stuart A, AU - Kutuzov,Mikhail A, AU - Dushek,Omer, AU - Barton,Geoffrey John, AU - van der Merwe,P Anton, Y1 - 2021/08/26/ PY - 2021/05/25/received PY - 2021/08/20/accepted PY - 2021/8/27/pubmed PY - 2021/10/6/medline PY - 2021/8/26/entrez KW - ACE2 KW - COVID-19 KW - SARS-CoV-2 KW - affinity KW - biochemistry KW - chemical biology KW - coronavirus KW - human KW - infectious disease KW - microbiology KW - viral receptor JF - eLife JO - Elife VL - 10 N2 - The interaction between the SARS-CoV-2 virus Spike protein receptor binding domain (RBD) and the ACE2 cell surface protein is required for viral infection of cells. Mutations in the RBD are present in SARS-CoV-2 variants of concern that have emerged independently worldwide. For example, the B.1.1.7 lineage has a mutation (N501Y) in its Spike RBD that enhances binding to ACE2. There are also ACE2 alleles in humans with mutations in the RBD binding site. Here we perform a detailed affinity and kinetics analysis of the effect of five common RBD mutations (K417N, K417T, N501Y, E484K, and S477N) and two common ACE2 mutations (S19P and K26R) on the RBD/ACE2 interaction. We analysed the effects of individual RBD mutations and combinations found in new SARS-CoV-2 Alpha (B.1.1.7), Beta (B.1.351), and Gamma (P1) variants. Most of these mutations increased the affinity of the RBD/ACE2 interaction. The exceptions were mutations K417N/T, which decreased the affinity. Taken together with other studies, our results suggest that the N501Y and S477N mutations enhance transmission primarily by enhancing binding, the K417N/T mutations facilitate immune escape, and the E484K mutation enhances binding and immune escape. SN - 2050-084X UR - https://www.unboundmedicine.com/medline/citation/34435953/Effects_of_common_mutations_in_the_SARS_CoV_2_Spike_RBD_and_its_ligand_the_human_ACE2_receptor_on_binding_affinity_and_kinetics_ DB - PRIME DP - Unbound Medicine ER -