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Proc Natl Acad Sci U S A. 2017 Oct 17;114(42):11157-11162. doi: 10.1073/pnas.1708727114. Epub 2017 Oct 3.

Tectonic conformational changes of a coronavirus spike glycoprotein promote membrane fusion.

Author information

1
Department of Biochemistry, University of Washington, Seattle, WA 98195.
2
Département de Virologie, Unité de Virologie Structurale, Institut Pasteur, Paris, France.
3
CNRS UMR 3569 Virologie, 75015 Paris, France.
4
Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands.
5
Department of Biochemistry, University of Washington, Seattle, WA 98195; dveesler@uw.edu.

Abstract

The tremendous pandemic potential of coronaviruses was demonstrated twice in the past few decades by two global outbreaks of deadly pneumonia. The coronavirus spike (S) glycoprotein initiates infection by promoting fusion of the viral and cellular membranes through conformational changes that remain largely uncharacterized. Here we report the cryoEM structure of a coronavirus S glycoprotein in the postfusion state, showing large-scale secondary, tertiary, and quaternary rearrangements compared with the prefusion trimer and rationalizing the free-energy landscape of this conformational machine. We also biochemically characterized the molecular events associated with refolding of the metastable prefusion S glycoprotein to the postfusion conformation using limited proteolysis, mass spectrometry, and single-particle EM. The observed similarity between postfusion coronavirus S and paramyxovirus F structures demonstrates that a conserved refolding trajectory mediates entry of these viruses and supports the evolutionary relatedness of their fusion subunits. Finally, our data provide a structural framework for understanding the mode of neutralization of antibodies targeting the fusion machinery and for engineering next-generation subunit vaccines or inhibitors against this medically important virus family.

KEYWORDS:

coronavirus; cryoEM; fusion proteins; membrane fusion; proteolytic activation

PMID:
29073020
PMCID:
PMC5651768
DOI:
10.1073/pnas.1708727114
[Indexed for MEDLINE]
Free PMC Article

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