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Structure of the hepatitis C virus E1E2 glycoprotein complex

Structure of the hepatitis C virus E1E2 glycoprotein complex
Structure of the hepatitis C virus E1E2 glycoprotein complex

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 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, remain elusive. Here, we present the cryo-electron microscopy structure of the membrane-extracted full-length E1E2 heterodimer in complex with three broadly neutralizing antibodies-AR4A, AT1209, and IGH505-at ~3.5-angstrom resolution. We resolve the interface between the E1 and E2 ectodomains and deliver a blueprint for the rational design of vaccine immunogens and antiviral drugs.

Antibodies, Neutralizing, Antiviral Agents/pharmacology, Broadly Neutralizing Antibodies, Cryoelectron Microscopy, Hepacivirus, Hepatitis C, Humans, Liver Neoplasms, Vaccines, Viral Envelope Proteins
0036-8075
263-269
Torrents de la Peña, Alba
5aa8f573-c651-4d0d-b816-93544ea46457
Sliepen, Kwinten
d2551fe9-7d04-459e-85b5-29fc4b35317a
Eshun-Wilson, Lisa
3b594663-842f-448a-b907-769daaf1fb70
Newby, Maddy L.
417cba47-6a6f-42b9-8b9c-640f0518c621
Allen, Joel D.
c89d5569-7659-4835-b535-c9586e956b3a
Zon, Ian
3fc54942-3866-4a46-a033-6c4b5e9a06b6
Koekkoek, Sylvie
d44a5340-7757-484b-a2c0-4ce7ac7ce398
Chumbe, Ana
83e6bcf9-5c13-4305-bc6f-cf36ebc3295e
Crispin, Max
cd980957-0943-4b89-b2b2-710f01f33bc9
Schinkel, Janke
3ed6b416-30dd-4492-89ba-bca83fa9b5ab
Lander, Gabriel C.
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Sanders, Rogier W.
d3b67c2c-c725-42e7-b972-50b30be67c74
Ward, Andrew B.
7b743524-72d4-448d-b645-11c55782b656
Torrents de la Peña, Alba
5aa8f573-c651-4d0d-b816-93544ea46457
Sliepen, Kwinten
d2551fe9-7d04-459e-85b5-29fc4b35317a
Eshun-Wilson, Lisa
3b594663-842f-448a-b907-769daaf1fb70
Newby, Maddy L.
417cba47-6a6f-42b9-8b9c-640f0518c621
Allen, Joel D.
c89d5569-7659-4835-b535-c9586e956b3a
Zon, Ian
3fc54942-3866-4a46-a033-6c4b5e9a06b6
Koekkoek, Sylvie
d44a5340-7757-484b-a2c0-4ce7ac7ce398
Chumbe, Ana
83e6bcf9-5c13-4305-bc6f-cf36ebc3295e
Crispin, Max
cd980957-0943-4b89-b2b2-710f01f33bc9
Schinkel, Janke
3ed6b416-30dd-4492-89ba-bca83fa9b5ab
Lander, Gabriel C.
2f9853e4-1ea0-4ddd-9402-15e1de51808d
Sanders, Rogier W.
d3b67c2c-c725-42e7-b972-50b30be67c74
Ward, Andrew B.
7b743524-72d4-448d-b645-11c55782b656

Torrents de la Peña, Alba, Sliepen, Kwinten, Eshun-Wilson, Lisa, Newby, Maddy L., Allen, Joel D., Zon, Ian, Koekkoek, Sylvie, Chumbe, Ana, Crispin, Max, Schinkel, Janke, Lander, Gabriel C., Sanders, Rogier W. and Ward, Andrew B. (2022) Structure of the hepatitis C virus E1E2 glycoprotein complex. Science (New York, N.Y.), 378 (6617), 263-269. (doi:10.1101/2021.12.16.472992).

Record type: Article

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 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, remain elusive. Here, we present the cryo-electron microscopy structure of the membrane-extracted full-length E1E2 heterodimer in complex with three broadly neutralizing antibodies-AR4A, AT1209, and IGH505-at ~3.5-angstrom resolution. We resolve the interface between the E1 and E2 ectodomains and deliver a blueprint for the rational design of vaccine immunogens and antiviral drugs.

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Accepted/In Press date: 27 September 2022
Published date: 21 October 2022
Keywords: Antibodies, Neutralizing, Antiviral Agents/pharmacology, Broadly Neutralizing Antibodies, Cryoelectron Microscopy, Hepacivirus, Hepatitis C, Humans, Liver Neoplasms, Vaccines, Viral Envelope Proteins

Identifiers

Local EPrints ID: 474549
URI: http://eprints.soton.ac.uk/id/eprint/474549
ISSN: 0036-8075
PURE UUID: 9557ed02-5601-4bbe-b2ba-fe5ac561f181
ORCID for Joel D. Allen: ORCID iD orcid.org/0000-0003-2547-968X
ORCID for Max Crispin: ORCID iD orcid.org/0000-0002-1072-2694

Catalogue record

Date deposited: 24 Feb 2023 17:37
Last modified: 02 May 2024 02:00

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Contributors

Author: Alba Torrents de la Peña
Author: Kwinten Sliepen
Author: Lisa Eshun-Wilson
Author: Maddy L. Newby
Author: Joel D. Allen ORCID iD
Author: Ian Zon
Author: Sylvie Koekkoek
Author: Ana Chumbe
Author: Max Crispin ORCID iD
Author: Janke Schinkel
Author: Gabriel C. Lander
Author: Rogier W. Sanders
Author: Andrew B. Ward

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