Structures of the Omicron Spike trimer with ACE2 and an anti-Omicron antibody

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Abstract

The SARS-CoV-2 Omicron variant has become the dominant infective strain. We report the structures of the Omicron spike trimer on its own or in complex with ACE2 or an anti-Omicron antibody. Most Omicron mutations are located on the surface of the spike protein, which change binding epitopes to many current antibodies. In the ACE2 binding site, compensating mutations strengthen RBD binding to ACE2. Both the RBD and the apo form of the Omicron spike trimer are thermodynamically unstable. An unusual RBD-RBD interaction in the ACE2-spike complex supports the open conformation and further reinforces ACE2 binding to the spike trimer. A broad-spectrum therapeutic antibody, JMB2002, which has completed a Phase 1 clinical trial, maintains neutralizing activity against Omicron. JMB2002 binds to RBD differently from other characterized antibodies and inhibits ACE2 binding.

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Most cited references 35

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UCSF Chimera--a visualization system for exploratory research and analysis.

Eric F. Pettersen, Thomas Goddard, Conrad Huang … (2004)

The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/. Copyright 2004 Wiley Periodicals, Inc.

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Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

Daniel Wrapp, Nianshuang Wang, Kizzmekia S. Corbett … (2020)

Structure of the nCoV trimeric spike The World Health Organization has declared the outbreak of a novel coronavirus (2019-nCoV) to be a public health emergency of international concern. The virus binds to host cells through its trimeric spike glycoprotein, making this protein a key target for potential therapies and diagnostics. Wrapp et al. determined a 3.5-angstrom-resolution structure of the 2019-nCoV trimeric spike protein by cryo–electron microscopy. Using biophysical assays, the authors show that this protein binds at least 10 times more tightly than the corresponding spike protein of severe acute respiratory syndrome (SARS)–CoV to their common host cell receptor. They also tested three antibodies known to bind to the SARS-CoV spike protein but did not detect binding to the 2019-nCoV spike protein. These studies provide valuable information to guide the development of medical counter-measures for 2019-nCoV. Science, this issue p. 1260

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Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

Alexandra C Walls, Young-Jun Park, M. Alejandra Tortorici … (2020)

Summary The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.

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Author and article information

Contributors

Wanchao Yin:

ORCID: https://orcid.org/0000-0002-6889-4907

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Youwei Xu:

ORCID: https://orcid.org/0000-0001-8069-7511

Role: Formal analysisRole: InvestigationRole: ValidationRole: VisualizationRole: Writing - original draft

Peiyu Xu:

ORCID: https://orcid.org/0000-0003-3590-4037

Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Xiaodan Cao:

ORCID: https://orcid.org/0000-0002-6458-4805

Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Canrong Wu:

ORCID: https://orcid.org/0000-0002-2272-3838

Role: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: VisualizationRole: Writing - review & editing

Chunyin Gu:

ORCID: https://orcid.org/0000-0001-8571-7411

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: ValidationRole: Writing - original draftRole: Writing - review & editing

Xinheng He:

ORCID: https://orcid.org/0000-0001-7813-5480

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Xiaoxi Wang:

ORCID: https://orcid.org/0000-0002-4274-5698

Role: InvestigationRole: Validation

Sijie Huang:

ORCID: https://orcid.org/0000-0001-5653-0260

Role: Formal analysisRole: InvestigationRole: Validation

Qingning Yuan: Role: InvestigationRole: Visualization

Kai Wu: Role: Formal analysisRole: Investigation

Wen Hu: Role: Investigation

Zifu Huang:

ORCID: https://orcid.org/0000-0001-9436-4590

Role: Data curationRole: ResourcesRole: Software

Jia Liu: Role: Data curationRole: Formal analysisRole: ResourcesRole: Visualization

Zongda Wang:

ORCID: https://orcid.org/0000-0002-1662-2934

Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing - original draftRole: Writing - review & editing

Fangfang Jia: Role: Formal analysisRole: Funding acquisitionRole: InvestigationRole: Writing - original draft

Kaiwen Xia:

ORCID: https://orcid.org/0000-0002-1336-8790

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: ResourcesRole: ValidationRole: Writing - original draftRole: Writing - review & editing

Peipei Liu: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Xueping Wang:

ORCID: https://orcid.org/0000-0002-2564-8714

Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Bin Song:

ORCID: https://orcid.org/0000-0002-5327-5839

Role: Formal analysisRole: InvestigationRole: Validation

Jie Zheng:

ORCID: https://orcid.org/0000-0001-7932-5753

Role: Data curationRole: Formal analysisRole: InvestigationRole: ResourcesRole: ValidationRole: Visualization

Hualiang Jiang:

ORCID: https://orcid.org/0000-0003-0656-6315

Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: Validation

Xi Cheng:

ORCID: https://orcid.org/0000-0003-3081-3750

Role: Formal analysisRole: InvestigationRole: Project administrationRole: ResourcesRole: Visualization

Yi Jiang:

ORCID: https://orcid.org/0000-0002-0723-1413

Role: Funding acquisitionRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Su-Jun Deng:

ORCID: https://orcid.org/0000-0001-9266-0644

Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

H. Eric Xu:

ORCID: https://orcid.org/0000-0002-6829-8144

Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Journal

Journal ID (nlm-ta): Science

Journal ID (iso-abbrev): Science

Journal ID (publisher-id): science

Title: Science (New York, N.y.)

Publisher: American Association for the Advancement of Science

ISSN (Print): 0036-8075

ISSN (Electronic): 1095-9203

Publication date (Electronic, pub): 08 February 2022

Publication date PMC-release: 08 February 2022

Electronic Location Identifier: eabn8863

Affiliations

[ ¹ ]The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

[ ² ]Shanghai Jemincare Pharmaceuticals Co., Ltd., Shanghai 201203, China.

[ ³ ]University of Chinese Academy of Sciences, Beijing 100049, China.

[ ⁴ ]The Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

[ ⁵ ]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

[ ⁶ ]Immunological Disease Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, .Shanghai 201203, China.

[ ⁷ ]School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, China.

Author notes

[†]

These authors contributed equally to this work.

[* ]Corresponding author. Email: wcyin@ 123456simm.ac.cn (W.Y.); dengsujun@ 123456jemincare.com (S.-J.D.); eric.xu@ 123456simm.ac.cn (H.E.X.)

Author information

Wanchao Yin https://orcid.org/0000-0002-6889-4907

Youwei Xu https://orcid.org/0000-0001-8069-7511

Peiyu Xu https://orcid.org/0000-0003-3590-4037

Xiaodan Cao https://orcid.org/0000-0002-6458-4805

Canrong Wu https://orcid.org/0000-0002-2272-3838

Chunyin Gu https://orcid.org/0000-0001-8571-7411

Xinheng He https://orcid.org/0000-0001-7813-5480

Xiaoxi Wang https://orcid.org/0000-0002-4274-5698

Sijie Huang https://orcid.org/0000-0001-5653-0260

Zifu Huang https://orcid.org/0000-0001-9436-4590

Zongda Wang https://orcid.org/0000-0002-1662-2934

Kaiwen Xia https://orcid.org/0000-0002-1336-8790

Xueping Wang https://orcid.org/0000-0002-2564-8714

Bin Song https://orcid.org/0000-0002-5327-5839

Jie Zheng https://orcid.org/0000-0001-7932-5753

Hualiang Jiang https://orcid.org/0000-0003-0656-6315

Xi Cheng https://orcid.org/0000-0003-3081-3750

Yi Jiang https://orcid.org/0000-0002-0723-1413

Su-Jun Deng https://orcid.org/0000-0001-9266-0644

H. Eric Xu https://orcid.org/0000-0002-6829-8144

Article

Publisher ID: abn8863

DOI: 10.1126/science.abn8863

PMC ID: 8939775

PubMed ID: 35133176

SO-VID: 5fbafcdc-c112-4ad1-9390-590ab469f9a3

Copyright © Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 27 December 2021

Date accepted : 02 February 2022

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Structures of the Omicron Spike trimer with ACE2 and an anti-Omicron antibody

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Novel Coronavirus Disease COVID-19

Most cited references 35

UCSF Chimera--a visualization system for exploratory research and analysis.

Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

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Cited by 105

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