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Structure of engineered hepatitis C virus E1E2 ectodomain in complex with neutralizing antibodies

Author

Listed:
  • Matthew C. Metcalf

    (University of Maryland
    University of Maryland)

  • Benjamin M. Janus

    (University of Maryland
    University of Maryland)

  • Rui Yin

    (University of Maryland
    University of Maryland)

  • Ruixue Wang

    (University of Maryland)

  • Johnathan D. Guest

    (University of Maryland
    University of Maryland)

  • Edwin Pozharski

    (University of Maryland
    University of Maryland School of Medicine
    University of Maryland School of Medicine)

  • Mansun Law

    (The Scripps Research Institute)

  • Roy A. Mariuzza

    (University of Maryland
    University of Maryland)

  • Eric A. Toth

    (University of Maryland)

  • Brian G. Pierce

    (University of Maryland
    University of Maryland)

  • Thomas R. Fuerst

    (University of Maryland
    University of Maryland)

  • Gilad Ofek

    (University of Maryland
    University of Maryland)

Abstract

Hepatitis C virus (HCV) is a major global health burden as the leading causative agent of chronic liver disease and hepatocellular carcinoma. While the main antigenic target for HCV-neutralizing antibodies is the membrane-associated E1E2 surface glycoprotein, the development of effective vaccines has been hindered by complications in the biochemical preparation of soluble E1E2 ectodomains. Here, we present a cryo-EM structure of an engineered, secreted E1E2 ectodomain of genotype 1b in complex with neutralizing antibodies AR4A, HEPC74, and IGH520. Structural characterization of the E1 subunit and C-terminal regions of E2 reveal an overall architecture of E1E2 that concurs with that observed for non-engineered full-length E1E2. Analysis of the AR4A epitope within a region of E2 that bridges between the E2 core and E1 defines the structural basis for its broad neutralization. Our study presents the structure of an E1E2 complex liberated from membrane via a designed scaffold, one that maintains all essential structural features of native E1E2. The study advances the understanding of the E1E2 heterodimer structure, crucial for the rational design of secreted E1E2 antigens in vaccine development.

Suggested Citation

  • Matthew C. Metcalf & Benjamin M. Janus & Rui Yin & Ruixue Wang & Johnathan D. Guest & Edwin Pozharski & Mansun Law & Roy A. Mariuzza & Eric A. Toth & Brian G. Pierce & Thomas R. Fuerst & Gilad Ofek, 2023. "Structure of engineered hepatitis C virus E1E2 ectodomain in complex with neutralizing antibodies," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39659-z
    DOI: 10.1038/s41467-023-39659-z
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    References listed on IDEAS

    as
    1. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    2. Abdul Ghafoor Khan & Jillian Whidby & Matthew T. Miller & Hannah Scarborough & Alexandra V. Zatorski & Alicja Cygan & Aryn A. Price & Samantha A. Yost & Caitlin D. Bohannon & Joshy Jacob & Arash Grako, 2014. "Structure of the core ectodomain of the hepatitis C virus envelope glycoprotein 2," Nature, Nature, vol. 509(7500), pages 381-384, May.
    3. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    4. Kamel El Omari & Oleg Iourin & Jan Kadlec & Geoff Sutton & Karl Harlos & Jonathan M. Grimes & David I. Stuart, 2014. "Unexpected structure for the N-terminal domain of hepatitis C virus envelope glycoprotein E1," Nature Communications, Nature, vol. 5(1), pages 1-5, December.
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