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In vitro evolution predicts emerging SARS-CoV-2 mutations with high affinity for ACE2 and cross-species binding.
PLoS Pathog. 2022 Jul; 18(7):e1010733.PP

Abstract

Emerging SARS-CoV-2 variants are creating major challenges in the ongoing COVID-19 pandemic. Being able to predict mutations that could arise in SARS-CoV-2 leading to increased transmissibility or immune evasion would be extremely valuable in development of broad-acting therapeutics and vaccines, and prioritising viral monitoring and containment. Here we use in vitro evolution to seek mutations in SARS-CoV-2 receptor binding domain (RBD) that would substantially increase binding to ACE2. We find a double mutation, S477N and Q498H, that increases affinity of RBD for ACE2 by 6.5-fold. This affinity gain is largely driven by the Q498H mutation. We determine the structure of the mutant-RBD:ACE2 complex by cryo-electron microscopy to reveal the mechanism for increased affinity. Addition of Q498H to SARS-CoV-2 RBD variants is found to boost binding affinity of the variants for human ACE2 and confer a new ability to bind rat ACE2 with high affinity. Surprisingly however, in the presence of the common N501Y mutation, Q498H inhibits binding, due to a clash between H498 and Y501 side chains. To achieve an intermolecular bonding network, affinity gain and cross-species binding similar to Q498H alone, RBD variants with the N501Y mutation must acquire instead the related Q498R mutation. Thus, SARS-CoV-2 RBD can access large affinity gains and cross-species binding via two alternative mutational routes involving Q498, with route selection determined by whether a variant already has the N501Y mutation. These mutations are now appearing in emerging SARS-CoV-2 variants where they have the potential to influence human-to-human and cross-species transmission.

Authors+Show Affiliations

Department of Molecular & Cell Biology, University of Leicester, Leicester, Leicester United Kingdom. Department of Cardiovascular Sciences, University of Leicester, Leicester, Leicester United Kingdom.Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cellular Biology, University of Leicester, Leicester, United Kingdom.Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cellular Biology, University of Leicester, Leicester, United Kingdom.Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cellular Biology, University of Leicester, Leicester, United Kingdom.Department of Molecular & Cell Biology, University of Leicester, Leicester, Leicester United Kingdom.School of Life Sciences, The University of Nottingham, Nottingham United Kingdom.Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cellular Biology, University of Leicester, Leicester, United Kingdom.Division of Protein & Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.Department of Molecular & Cell Biology, University of Leicester, Leicester, Leicester United Kingdom. Department of Cardiovascular Sciences, University of Leicester, Leicester, Leicester United Kingdom.

Pub Type(s)

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

Language

eng

PubMed ID

35849637

Citation

Bate, Neil, et al. "In Vitro Evolution Predicts Emerging SARS-CoV-2 Mutations With High Affinity for ACE2 and Cross-species Binding." PLoS Pathogens, vol. 18, no. 7, 2022, pp. e1010733.
Bate N, Savva CG, Moody PCE, et al. In vitro evolution predicts emerging SARS-CoV-2 mutations with high affinity for ACE2 and cross-species binding. PLoS Pathog. 2022;18(7):e1010733.
Bate, N., Savva, C. G., Moody, P. C. E., Brown, E. A., Evans, S. E., Ball, J. K., Schwabe, J. W. R., Sale, J. E., & Brindle, N. P. J. (2022). In vitro evolution predicts emerging SARS-CoV-2 mutations with high affinity for ACE2 and cross-species binding. PLoS Pathogens, 18(7), e1010733. https://doi.org/10.1371/journal.ppat.1010733
Bate N, et al. In Vitro Evolution Predicts Emerging SARS-CoV-2 Mutations With High Affinity for ACE2 and Cross-species Binding. PLoS Pathog. 2022;18(7):e1010733. PubMed PMID: 35849637.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro evolution predicts emerging SARS-CoV-2 mutations with high affinity for ACE2 and cross-species binding. AU - Bate,Neil, AU - Savva,Christos G, AU - Moody,Peter C E, AU - Brown,Edward A, AU - Evans,Sian E, AU - Ball,Jonathan K, AU - Schwabe,John W R, AU - Sale,Julian E, AU - Brindle,Nicholas P J, Y1 - 2022/07/18/ PY - 2022/2/25/received PY - 2022/7/10/accepted PY - 2022/7/28/revised PY - 2022/7/19/pubmed PY - 2022/8/2/medline PY - 2022/7/18/entrez SP - e1010733 EP - e1010733 JF - PLoS pathogens JO - PLoS Pathog VL - 18 IS - 7 N2 - Emerging SARS-CoV-2 variants are creating major challenges in the ongoing COVID-19 pandemic. Being able to predict mutations that could arise in SARS-CoV-2 leading to increased transmissibility or immune evasion would be extremely valuable in development of broad-acting therapeutics and vaccines, and prioritising viral monitoring and containment. Here we use in vitro evolution to seek mutations in SARS-CoV-2 receptor binding domain (RBD) that would substantially increase binding to ACE2. We find a double mutation, S477N and Q498H, that increases affinity of RBD for ACE2 by 6.5-fold. This affinity gain is largely driven by the Q498H mutation. We determine the structure of the mutant-RBD:ACE2 complex by cryo-electron microscopy to reveal the mechanism for increased affinity. Addition of Q498H to SARS-CoV-2 RBD variants is found to boost binding affinity of the variants for human ACE2 and confer a new ability to bind rat ACE2 with high affinity. Surprisingly however, in the presence of the common N501Y mutation, Q498H inhibits binding, due to a clash between H498 and Y501 side chains. To achieve an intermolecular bonding network, affinity gain and cross-species binding similar to Q498H alone, RBD variants with the N501Y mutation must acquire instead the related Q498R mutation. Thus, SARS-CoV-2 RBD can access large affinity gains and cross-species binding via two alternative mutational routes involving Q498, with route selection determined by whether a variant already has the N501Y mutation. These mutations are now appearing in emerging SARS-CoV-2 variants where they have the potential to influence human-to-human and cross-species transmission. SN - 1553-7374 UR - https://www.unboundmedicine.com/medline/citation/35849637/In_vitro_evolution_predicts_emerging_SARS_CoV_2_mutations_with_high_affinity_for_ACE2_and_cross_species_binding_ DB - PRIME DP - Unbound Medicine ER -