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Structural and biochemical rationale for enhanced spike protein fitness in delta and kappa SARS-CoV-2 variants

The Delta and Kappa variants of SARS-CoV-2 co-emerged in India in late 2020, with the Delta variant underlying the resurgence of COVID-19, even in countries with high vaccination rates. In this study, we assess structural and biochemical aspects of viral fitness for these two variants using cryo-ele...

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Autores principales: Saville, James W., Mannar, Dhiraj, Zhu, Xing, Srivastava, Shanti S., Berezuk, Alison M., Demers, Jean-Philippe, Zhou, Steven, Tuttle, Katharine S., Sekirov, Inna, Kim, Andrew, Li, Wei, Dimitrov, Dimiter S., Subramaniam, Sriram
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8826856/
https://www.ncbi.nlm.nih.gov/pubmed/35136050
http://dx.doi.org/10.1038/s41467-022-28324-6
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author Saville, James W.
Mannar, Dhiraj
Zhu, Xing
Srivastava, Shanti S.
Berezuk, Alison M.
Demers, Jean-Philippe
Zhou, Steven
Tuttle, Katharine S.
Sekirov, Inna
Kim, Andrew
Li, Wei
Dimitrov, Dimiter S.
Subramaniam, Sriram
author_facet Saville, James W.
Mannar, Dhiraj
Zhu, Xing
Srivastava, Shanti S.
Berezuk, Alison M.
Demers, Jean-Philippe
Zhou, Steven
Tuttle, Katharine S.
Sekirov, Inna
Kim, Andrew
Li, Wei
Dimitrov, Dimiter S.
Subramaniam, Sriram
author_sort Saville, James W.
collection PubMed
description The Delta and Kappa variants of SARS-CoV-2 co-emerged in India in late 2020, with the Delta variant underlying the resurgence of COVID-19, even in countries with high vaccination rates. In this study, we assess structural and biochemical aspects of viral fitness for these two variants using cryo-electron microscopy (cryo-EM), ACE2-binding and antibody neutralization analyses. Both variants demonstrate escape of antibodies targeting the N-terminal domain, an important immune hotspot for neutralizing epitopes. Compared to wild-type and Kappa lineages, Delta variant spike proteins show modest increase in ACE2 affinity, likely due to enhanced electrostatic complementarity at the RBD-ACE2 interface, which we characterize by cryo-EM. Unexpectedly, Kappa variant spike trimers form a structural head-to-head dimer-of-trimers assembly, which we demonstrate is a result of the E484Q mutation and with unknown biological implications. The combination of increased antibody escape and enhanced ACE2 binding provides an explanation, in part, for the rapid global dominance of the Delta variant.
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spelling pubmed-88268562022-02-18 Structural and biochemical rationale for enhanced spike protein fitness in delta and kappa SARS-CoV-2 variants Saville, James W. Mannar, Dhiraj Zhu, Xing Srivastava, Shanti S. Berezuk, Alison M. Demers, Jean-Philippe Zhou, Steven Tuttle, Katharine S. Sekirov, Inna Kim, Andrew Li, Wei Dimitrov, Dimiter S. Subramaniam, Sriram Nat Commun Article The Delta and Kappa variants of SARS-CoV-2 co-emerged in India in late 2020, with the Delta variant underlying the resurgence of COVID-19, even in countries with high vaccination rates. In this study, we assess structural and biochemical aspects of viral fitness for these two variants using cryo-electron microscopy (cryo-EM), ACE2-binding and antibody neutralization analyses. Both variants demonstrate escape of antibodies targeting the N-terminal domain, an important immune hotspot for neutralizing epitopes. Compared to wild-type and Kappa lineages, Delta variant spike proteins show modest increase in ACE2 affinity, likely due to enhanced electrostatic complementarity at the RBD-ACE2 interface, which we characterize by cryo-EM. Unexpectedly, Kappa variant spike trimers form a structural head-to-head dimer-of-trimers assembly, which we demonstrate is a result of the E484Q mutation and with unknown biological implications. The combination of increased antibody escape and enhanced ACE2 binding provides an explanation, in part, for the rapid global dominance of the Delta variant. Nature Publishing Group UK 2022-02-08 /pmc/articles/PMC8826856/ /pubmed/35136050 http://dx.doi.org/10.1038/s41467-022-28324-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Saville, James W.
Mannar, Dhiraj
Zhu, Xing
Srivastava, Shanti S.
Berezuk, Alison M.
Demers, Jean-Philippe
Zhou, Steven
Tuttle, Katharine S.
Sekirov, Inna
Kim, Andrew
Li, Wei
Dimitrov, Dimiter S.
Subramaniam, Sriram
Structural and biochemical rationale for enhanced spike protein fitness in delta and kappa SARS-CoV-2 variants
title Structural and biochemical rationale for enhanced spike protein fitness in delta and kappa SARS-CoV-2 variants
title_full Structural and biochemical rationale for enhanced spike protein fitness in delta and kappa SARS-CoV-2 variants
title_fullStr Structural and biochemical rationale for enhanced spike protein fitness in delta and kappa SARS-CoV-2 variants
title_full_unstemmed Structural and biochemical rationale for enhanced spike protein fitness in delta and kappa SARS-CoV-2 variants
title_short Structural and biochemical rationale for enhanced spike protein fitness in delta and kappa SARS-CoV-2 variants
title_sort structural and biochemical rationale for enhanced spike protein fitness in delta and kappa sars-cov-2 variants
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8826856/
https://www.ncbi.nlm.nih.gov/pubmed/35136050
http://dx.doi.org/10.1038/s41467-022-28324-6
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