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Cryo-electron microscopy structures of the N501Y SARS-CoV-2 spike protein in complex with ACE2 and 2 potent neutralizing antibodies.
PLoS Biol. 2021 04; 19(4):e3001237.PB

Abstract

The recently reported "UK variant" (B.1.1.7) of SARS-CoV-2 is thought to be more infectious than previously circulating strains as a result of several changes, including the N501Y mutation. We present a 2.9-Å resolution cryo-electron microscopy (cryo-EM) structure of the complex between the ACE2 receptor and N501Y spike protein ectodomains that shows Y501 inserted into a cavity at the binding interface near Y41 of ACE2. This additional interaction provides a structural explanation for the increased ACE2 affinity of the N501Y mutant, and likely contributes to its increased infectivity. However, this mutation does not result in large structural changes, enabling important neutralization epitopes to be retained in the spike receptor binding domain. We confirmed this through biophysical assays and by determining cryo-EM structures of spike protein ectodomains bound to 2 representative potent neutralizing antibody fragments.

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Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.

Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.

Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.

Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.

Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.

Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.

Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.

Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania, United States of America.

Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania, United States of America.

Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.

Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.

Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.

Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.

MeSH

Angiotensin-Converting Enzyme 2Antibodies, NeutralizingBinding SitesCOVID-19Cryoelectron MicroscopyEpitopesHumansModels, MolecularMutationNeutralization TestsProtein BindingProtein ConformationProtein DomainsSARS-CoV-2Spike Glycoprotein, Coronavirus

Pub Type(s)

Journal Article

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

Language

eng

PubMed ID

33914735

Citation

Zhu, Xing, et al. "Cryo-electron Microscopy Structures of the N501Y SARS-CoV-2 Spike Protein in Complex With ACE2 and 2 Potent Neutralizing Antibodies." PLoS Biology, vol. 19, no. 4, 2021, pp. e3001237.

Zhu X, Mannar D, Srivastava SS, et al. Cryo-electron microscopy structures of the N501Y SARS-CoV-2 spike protein in complex with ACE2 and 2 potent neutralizing antibodies. PLoS Biol. 2021;19(4):e3001237.

Zhu, X., Mannar, D., Srivastava, S. S., Berezuk, A. M., Demers, J. P., Saville, J. W., Leopold, K., Li, W., Dimitrov, D. S., Tuttle, K. S., Zhou, S., Chittori, S., & Subramaniam, S. (2021). Cryo-electron microscopy structures of the N501Y SARS-CoV-2 spike protein in complex with ACE2 and 2 potent neutralizing antibodies. PLoS Biology, 19(4), e3001237. https://doi.org/10.1371/journal.pbio.3001237

Zhu X, et al. Cryo-electron Microscopy Structures of the N501Y SARS-CoV-2 Spike Protein in Complex With ACE2 and 2 Potent Neutralizing Antibodies. PLoS Biol. 2021;19(4):e3001237. PubMed PMID: 33914735.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Cryo-electron microscopy structures of the N501Y SARS-CoV-2 spike protein in complex with ACE2 and 2 potent neutralizing antibodies. AU - Zhu,Xing, AU - Mannar,Dhiraj, AU - Srivastava,Shanti S, AU - Berezuk,Alison M, AU - Demers,Jean-Philippe, AU - Saville,James W, AU - Leopold,Karoline, AU - Li,Wei, AU - Dimitrov,Dimiter S, AU - Tuttle,Katharine S, AU - Zhou,Steven, AU - Chittori,Sagar, AU - Subramaniam,Sriram, Y1 - 2021/04/29/ PY - 2021/03/17/received PY - 2021/04/16/accepted PY - 2021/05/11/revised PY - 2021/4/30/pubmed PY - 2021/5/21/medline PY - 2021/4/29/entrez SP - e3001237 EP - e3001237 JF - PLoS biology JO - PLoS Biol VL - 19 IS - 4 N2 - The recently reported "UK variant" (B.1.1.7) of SARS-CoV-2 is thought to be more infectious than previously circulating strains as a result of several changes, including the N501Y mutation. We present a 2.9-Å resolution cryo-electron microscopy (cryo-EM) structure of the complex between the ACE2 receptor and N501Y spike protein ectodomains that shows Y501 inserted into a cavity at the binding interface near Y41 of ACE2. This additional interaction provides a structural explanation for the increased ACE2 affinity of the N501Y mutant, and likely contributes to its increased infectivity. However, this mutation does not result in large structural changes, enabling important neutralization epitopes to be retained in the spike receptor binding domain. We confirmed this through biophysical assays and by determining cryo-EM structures of spike protein ectodomains bound to 2 representative potent neutralizing antibody fragments. SN - 1545-7885 UR - https://www.unboundmedicine.com/medline/citation/33914735/Cryo_electron_microscopy_structures_of_the_N501Y_SARS_CoV_2_spike_protein_in_complex_with_ACE2_and_2_potent_neutralizing_antibodies_ DB - PRIME DP - Unbound Medicine ER -