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Structural and functional impact by SARS-CoV-2 Omicron spike mutations

View ORCID ProfileJun Zhang, View ORCID ProfileYongfei Cai, View ORCID ProfileChristy L. Lavine, View ORCID ProfileHanqin Peng, View ORCID ProfileHaisun Zhu, Krishna Anand, View ORCID ProfilePei Tong, View ORCID ProfileAvneesh Gautam, View ORCID ProfileMegan L. Mayer, Sophia Rits-Volloch, Shaowei Wang, View ORCID ProfilePiotr Sliz, View ORCID ProfileDuane R. Wesemann, View ORCID ProfileWei Yang, View ORCID ProfileMichael S. Seaman, Jianming Lu, View ORCID ProfileTianshu Xiao, View ORCID ProfileBing Chen
doi: https://doi.org/10.1101/2022.01.11.475922
Jun Zhang
1Division of Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, 3 Blackfan Street, Boston, MA 02115, USA
2Department of Pediatrics, Harvard Medical School, 3 Blackfan Street, Boston, MA 02115, USA
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Yongfei Cai
1Division of Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, 3 Blackfan Street, Boston, MA 02115, USA
2Department of Pediatrics, Harvard Medical School, 3 Blackfan Street, Boston, MA 02115, USA
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Christy L. Lavine
3Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02215, USA
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Hanqin Peng
1Division of Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, 3 Blackfan Street, Boston, MA 02115, USA
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Haisun Zhu
4Institute for Protein Innovation, Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA 02115, USA
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Krishna Anand
4Institute for Protein Innovation, Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA 02115, USA
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Pei Tong
5Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women’s Hospital, and Ragon Institute of MGH, MIT and Harvard, Boston, MA 02115, USA
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Avneesh Gautam
5Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women’s Hospital, and Ragon Institute of MGH, MIT and Harvard, Boston, MA 02115, USA
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Megan L. Mayer
6The Harvard Cryo-EM Center for Structural Biology, 250 Longwood Avenue, Boston, MA 02115, USA, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA
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Sophia Rits-Volloch
1Division of Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, 3 Blackfan Street, Boston, MA 02115, USA
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Shaowei Wang
7Codex BioSolutions, Inc., 12358 Parklawn Drive, Rockville, MD 20852, USA
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Piotr Sliz
1Division of Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, 3 Blackfan Street, Boston, MA 02115, USA
2Department of Pediatrics, Harvard Medical School, 3 Blackfan Street, Boston, MA 02115, USA
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Duane R. Wesemann
5Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women’s Hospital, and Ragon Institute of MGH, MIT and Harvard, Boston, MA 02115, USA
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Wei Yang
4Institute for Protein Innovation, Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA 02115, USA
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  • ORCID record for Wei Yang
Michael S. Seaman
3Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02215, USA
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Jianming Lu
7Codex BioSolutions, Inc., 12358 Parklawn Drive, Rockville, MD 20852, USA
8Department of Biochemistry and Molecular and Cellular Biology, Georgetown University School of Medicine, 3900 Reservoir Road, N.W., Washington, D.C. 20057, USA
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Tianshu Xiao
1Division of Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, 3 Blackfan Street, Boston, MA 02115, USA
2Department of Pediatrics, Harvard Medical School, 3 Blackfan Street, Boston, MA 02115, USA
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  • For correspondence: bchen@crystal.harvard.edu xiao@crystal.harvard.edu
Bing Chen
1Division of Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, 3 Blackfan Street, Boston, MA 02115, USA
2Department of Pediatrics, Harvard Medical School, 3 Blackfan Street, Boston, MA 02115, USA
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  • For correspondence: bchen@crystal.harvard.edu xiao@crystal.harvard.edu
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Abstract

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), bearing an unusually high number of mutations, has become a dominant strain in many countries within several weeks. We report here structural, functional and antigenic properties of its full-length spike (S) protein with a native sequence in comparison with those of previously prevalent variants. Omicron S requires a substantially higher level of host receptor ACE2 for efficient membrane fusion than other variants, possibly explaining its unexpected cellular tropism. Mutations not only remodel the antigenic structure of the N-terminal domain of the S protein, but also alter the surface of the receptor-binding domain in a way not seen in other variants, consistent with its remarkable resistance to neutralizing antibodies. These results suggest that Omicron S has acquired an extraordinary ability to evade host immunity by excessive mutations, which also compromise its fusogenic capability.

Competing Interest Statement

Competing Interests: W.Y. serves on the scientific advisory boards of Hummingbird Bioscience and GO Therapeutics and is currently an employee of GV20 Therapeutics LLC. All other authors declare no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 12, 2022.
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Structural and functional impact by SARS-CoV-2 Omicron spike mutations
Jun Zhang, Yongfei Cai, Christy L. Lavine, Hanqin Peng, Haisun Zhu, Krishna Anand, Pei Tong, Avneesh Gautam, Megan L. Mayer, Sophia Rits-Volloch, Shaowei Wang, Piotr Sliz, Duane R. Wesemann, Wei Yang, Michael S. Seaman, Jianming Lu, Tianshu Xiao, Bing Chen
bioRxiv 2022.01.11.475922; doi: https://doi.org/10.1101/2022.01.11.475922
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Structural and functional impact by SARS-CoV-2 Omicron spike mutations
Jun Zhang, Yongfei Cai, Christy L. Lavine, Hanqin Peng, Haisun Zhu, Krishna Anand, Pei Tong, Avneesh Gautam, Megan L. Mayer, Sophia Rits-Volloch, Shaowei Wang, Piotr Sliz, Duane R. Wesemann, Wei Yang, Michael S. Seaman, Jianming Lu, Tianshu Xiao, Bing Chen
bioRxiv 2022.01.11.475922; doi: https://doi.org/10.1101/2022.01.11.475922

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