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Structure of the hepatitis C virus E1E2 glycoprotein complex

View ORCID ProfileAlba Torrents de la Peña, View ORCID ProfileKwinten Sliepen, View ORCID ProfileLisa Eshun-Wilson, View ORCID ProfileMaddy Newby, View ORCID ProfileJoel D. Allen, Sylvie Koekkoek, Ian Zon, View ORCID ProfileAna Chumbe, View ORCID ProfileMax Crispin, View ORCID ProfileJanke Schinkel, View ORCID ProfileGabriel C. Lander, View ORCID ProfileRogier W. Sanders, View ORCID ProfileAndrew B. Ward
doi: https://doi.org/10.1101/2021.12.16.472992
Alba Torrents de la Peña
1Department of Structural Biology and Computational Biology, The Scripps Research Institute, La Jolla, California, USA
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  • ORCID record for Alba Torrents de la Peña
Kwinten Sliepen
2Department of Medical Microbiology, Amsterdam Institute for Infection and Immunity, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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  • For correspondence: andrew@scripps.edu
Lisa Eshun-Wilson
1Department of Structural Biology and Computational Biology, The Scripps Research Institute, La Jolla, California, USA
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Maddy Newby
3School of Biological Sciences, University of Southampton, Southampton, UK
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Joel D. Allen
3School of Biological Sciences, University of Southampton, Southampton, UK
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Sylvie Koekkoek
2Department of Medical Microbiology, Amsterdam Institute for Infection and Immunity, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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Ian Zon
2Department of Medical Microbiology, Amsterdam Institute for Infection and Immunity, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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Ana Chumbe
2Department of Medical Microbiology, Amsterdam Institute for Infection and Immunity, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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Max Crispin
3School of Biological Sciences, University of Southampton, Southampton, UK
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Janke Schinkel
2Department of Medical Microbiology, Amsterdam Institute for Infection and Immunity, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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Gabriel C. Lander
1Department of Structural Biology and Computational Biology, The Scripps Research Institute, La Jolla, California, USA
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  • For correspondence: andrew@scripps.edu
Rogier W. Sanders
2Department of Medical Microbiology, Amsterdam Institute for Infection and Immunity, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
4Weill Medical College of Cornell University, New York, New York, USA
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Andrew B. Ward
1Department of Structural Biology and Computational Biology, The Scripps Research Institute, La Jolla, California, USA
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  • For correspondence: andrew@scripps.edu
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Abstract

Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma in humans, and afflicts more than 58 million people worldwide. The HCV envelope E1 and E2 glycoproteins are essential for viral entry and infection, and comprise the primary antigenic target for neutralizing antibody responses. The molecular mechanisms of E1E2 assembly, as well as how the E1E2 heterodimer binds broadly neutralizing antibodies, remains elusive. We present the cryo-electron microscopy (cryoEM) structure of the membrane-extracted full-length E1E2 heterodimer in complex with broadly neutralizing antibodies (bNAbs) AR4A, AT12009 and IGH505 at ∼3.5 Å resolution. We resolve the long sought-after interface between the E1 and E2 ectodomains and reveal how it is stabilized by hydrophobic interactions and glycans. This structure deepens our understanding of the HCV fusion glycoprotein and delivers a blueprint for the rational design of novel vaccine immunogens and anti-viral drugs.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted December 16, 2021.
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Structure of the hepatitis C virus E1E2 glycoprotein complex
Alba Torrents de la Peña, Kwinten Sliepen, Lisa Eshun-Wilson, Maddy Newby, Joel D. Allen, Sylvie Koekkoek, Ian Zon, Ana Chumbe, Max Crispin, Janke Schinkel, Gabriel C. Lander, Rogier W. Sanders, Andrew B. Ward
bioRxiv 2021.12.16.472992; doi: https://doi.org/10.1101/2021.12.16.472992
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Structure of the hepatitis C virus E1E2 glycoprotein complex
Alba Torrents de la Peña, Kwinten Sliepen, Lisa Eshun-Wilson, Maddy Newby, Joel D. Allen, Sylvie Koekkoek, Ian Zon, Ana Chumbe, Max Crispin, Janke Schinkel, Gabriel C. Lander, Rogier W. Sanders, Andrew B. Ward
bioRxiv 2021.12.16.472992; doi: https://doi.org/10.1101/2021.12.16.472992

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