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Structure of the Ebola virus polymerase complex

Author

Listed:
  • Bin Yuan

    (CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Qi Peng

    (CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences)

  • Jinlong Cheng

    (CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences)

  • Min Wang

    (CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences)

  • Jin Zhong

    (University of Chinese Academy of Sciences
    CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences)

  • Jianxun Qi

    (CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences)

  • George F. Gao

    (CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Center for Influenza Research and Early-Warning (CASCIRE), CAS–TWAS Center of Excellence for Emerging Infectious Disease (CEEID), Chinese Academy of Sciences
    Chinese Academy of Medical Sciences)

  • Yi Shi

    (CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Center for Influenza Research and Early-Warning (CASCIRE), CAS–TWAS Center of Excellence for Emerging Infectious Disease (CEEID), Chinese Academy of Sciences
    Chinese Academy of Medical Sciences)

Abstract

Filoviruses, including Ebola virus, pose an increasing threat to the public health. Although two therapeutic monoclonal antibodies have been approved to treat the Ebola virus disease1,2, there are no approved broadly reactive drugs to control diverse filovirus infection. Filovirus has a large polymerase (L) protein and the cofactor viral protein 35 (VP35), which constitute the basic functional unit responsible for virus genome RNA synthesis3. Owing to its conservation, the L–VP35 polymerase complex is a promising target for broadly reactive antiviral drugs. Here we determined the structure of Ebola virus L protein in complex with tetrameric VP35 using cryo-electron microscopy (state 1). Structural analysis revealed that Ebola virus L possesses a filovirus-specific insertion element that is essential for RNA synthesis, and that VP35 interacts extensively with the N-terminal region of L by three protomers of the VP35 tetramer. Notably, we captured the complex structure in a second conformation with the unambiguous priming loop and supporting helix away from polymerase active site (state 2). Moreover, we demonstrated that the century-old drug suramin could inhibit the activity of the Ebola virus polymerase in an enzymatic assay. The structure of the L–VP35–suramin complex reveals that suramin can bind at the highly conserved NTP entry channel to prevent substrates from entering the active site. These findings reveal the mechanism of Ebola virus replication and may guide the development of more powerful anti-filovirus drugs.

Suggested Citation

  • Bin Yuan & Qi Peng & Jinlong Cheng & Min Wang & Jin Zhong & Jianxun Qi & George F. Gao & Yi Shi, 2022. "Structure of the Ebola virus polymerase complex," Nature, Nature, vol. 610(7931), pages 394-401, October.
  • Handle: RePEc:nat:nature:v:610:y:2022:i:7931:d:10.1038_s41586-022-05271-2
    DOI: 10.1038/s41586-022-05271-2
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    Cited by:

    1. Tianhao Li & Mingdong Liu & Zhanxi Gu & Xin Su & Yunhui Liu & Jinzhong Lin & Yu Zhang & Qing-Tao Shen, 2024. "Structures of the mumps virus polymerase complex via cryo-electron microscopy," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Jin Xie & Mohamed Ouizougun-Oubari & Li Wang & Guanglei Zhai & Daitze Wu & Zhaohu Lin & Manfu Wang & Barbara Ludeke & Xiaodong Yan & Tobias Nilsson & Lu Gao & Xinyi Huang & Rachel Fearns & Shuai Chen, 2024. "Structural basis for dimerization of a paramyxovirus polymerase complex," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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