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May 24, 2023

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Nature (2023)Cite this

Nature (2023)Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells depends on refolding of the virus-encoded spike protein from a prefusion conformation, metastable after cleavage, to a lower energy, stable postfusion conformation1,2. This transition overcomes kinetic barriers for fusion of viral and target cell membranes3,4. We report here a cryo-EM structure of the intact postfusion spike in a lipid bilayer that represents single-membrane product of the fusion reaction. The structure provides structural definition of the functionally critical membrane-interacting segments, including the fusion peptide and transmembrane anchor. The internal fusion peptide forms a hairpin-like wedge that spans almost the entire lipid bilayer and the transmembrane segment wraps around the fusion peptide at the last stage of membrane fusion. These results advance our understanding of the spike protein in a membrane environment and may guide development of intervention strategies.

Yongfei Cai

Present address: CSL Seqirus, 225 Wyman Street, Waltham, MA, USA

These authors contributed equally: Wei Shi, Jun Zhang

Division of Molecular Medicine, Boston Children's Hospital, Boston, MA, USA

Wei Shi, Yongfei Cai, Hanqin Peng, Jewel Voyer, Sophia Rits-Volloch, Jun Zhang & Bing Chen

Department of Pediatrics, Harvard Medical School, 3 Blackfan Street, Boston, MA, USA

Wei Shi, Yongfei Cai, Jun Zhang & Bing Chen

Institute for Protein Innovation, Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA, USA

Haisun Zhu

Codex BioSolutions, Inc., 12358 Parklawn Drive, Rockville, MD, USA

Hong Cao & Jianming Lu

The Harvard Cryo-EM Center for Structural Biology, 250 Longwood Avenue, Boston, MA, USA

Megan L. Mayer

Department of Biochemistry & Molecular Biotechnology, and CryoEM Core Facility, University of Massachusetts Chan Medical School, 55 Lake Avenue, Worcester, MA, USA

Kangkang Song & Chen Xu

Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, 3900 Reservoir Road, N.W., Washington, DC, USA

Jianming Lu

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Correspondence to Jun Zhang or Bing Chen.

This file contains Supplementary Figs. 1–3. Supplementary Fig. 1 contains the uncropped blots, Supplementary Fig. 2 shows the sequence alignment of the S2 proteins from various coronaviruses, and Supplementary Fig. 3 contains the gating graphs for the flow cytometry experiments.

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Shi, W., Cai, Y., Zhu, H. et al. Cryo-EM structure of SARS-CoV-2 postfusion spike in membrane. Nature (2023). https://doi.org/10.1038/s41586-023-06273-4

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Received: 03 December 2022

Accepted: 31 May 2023

Published: 07 June 2023

DOI: https://doi.org/10.1038/s41586-023-06273-4

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