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Structure-function analysis of enterovirus protease 2A in complex with its essential host factor SETD3

Author

Listed:
  • Christine E. Peters

    (Stanford University School of Medicine)

  • Ursula Schulze-Gahmen

    (The J. David Gladstone Institutes
    QBI Coronavirus Research Group (QCRG)
    University of California San Francisco)

  • Manon Eckhardt

    (QBI Coronavirus Research Group (QCRG)
    University of California San Francisco
    The J. David Gladstone Institutes
    University of California, San Francisco)

  • Gwendolyn M. Jang

    (QBI Coronavirus Research Group (QCRG)
    University of California San Francisco
    The J. David Gladstone Institutes
    University of California, San Francisco)

  • Jiewei Xu

    (QBI Coronavirus Research Group (QCRG)
    University of California San Francisco
    The J. David Gladstone Institutes
    University of California, San Francisco)

  • Ernst H. Pulido

    (QBI Coronavirus Research Group (QCRG)
    University of California San Francisco
    The J. David Gladstone Institutes
    University of California, San Francisco)

  • Conner Bardine

    (QBI Coronavirus Research Group (QCRG)
    University of California San Francisco
    University of California, San Francisco)

  • Charles S. Craik

    (QBI Coronavirus Research Group (QCRG)
    University of California San Francisco
    University of California, San Francisco)

  • Melanie Ott

    (The J. David Gladstone Institutes
    QBI Coronavirus Research Group (QCRG)
    University of California San Francisco
    University of California, San Francisco)

  • Or Gozani

    (Stanford University)

  • Kliment A. Verba

    (QBI Coronavirus Research Group (QCRG)
    University of California San Francisco
    University of California, San Francisco)

  • Ruth Hüttenhain

    (QBI Coronavirus Research Group (QCRG)
    University of California San Francisco
    The J. David Gladstone Institutes
    University of California, San Francisco)

  • Jan E. Carette

    (Stanford University School of Medicine)

  • Nevan J. Krogan

    (QBI Coronavirus Research Group (QCRG)
    University of California San Francisco
    The J. David Gladstone Institutes
    University of California, San Francisco)

Abstract

Enteroviruses cause a number of medically relevant and widespread human diseases with no approved antiviral therapies currently available. Host-directed therapies present an enticing option for this diverse genus of viruses. We have previously identified the actin histidine methyltransferase SETD3 as a critical host factor physically interacting with the viral protease 2A. Here, we report the 3.5 Å cryo-EM structure of SETD3 interacting with coxsackievirus B3 2A at two distinct interfaces, including the substrate-binding surface within the SET domain. Structure-function analysis revealed that mutations of key residues in the SET domain resulted in severely reduced binding to 2A and complete protection from enteroviral infection. Our findings provide insight into the molecular basis of the SETD3-2A interaction and a framework for the rational design of host-directed therapeutics against enteroviruses.

Suggested Citation

  • Christine E. Peters & Ursula Schulze-Gahmen & Manon Eckhardt & Gwendolyn M. Jang & Jiewei Xu & Ernst H. Pulido & Conner Bardine & Charles S. Craik & Melanie Ott & Or Gozani & Kliment A. Verba & Ruth H, 2022. "Structure-function analysis of enterovirus protease 2A in complex with its essential host factor SETD3," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32758-3
    DOI: 10.1038/s41467-022-32758-3
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    References listed on IDEAS

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    1. Alex W. Wilkinson & Jonathan Diep & Shaobo Dai & Shuo Liu & Yaw Shin Ooi & Dan Song & Tie-Mei Li & John R. Horton & Xing Zhang & Chao Liu & Darshan V. Trivedi & Katherine M. Ruppel & José G. Vilches-M, 2019. "SETD3 is an actin histidine methyltransferase that prevents primary dystocia," Nature, Nature, vol. 565(7739), pages 372-376, January.
    2. David E. Gordon & Gwendolyn M. Jang & Mehdi Bouhaddou & Jiewei Xu & Kirsten Obernier & Kris M. White & Matthew J. O’Meara & Veronica V. Rezelj & Jeffrey Z. Guo & Danielle L. Swaney & Tia A. Tummino & , 2020. "A SARS-CoV-2 protein interaction map reveals targets for drug repurposing," Nature, Nature, vol. 583(7816), pages 459-468, July.
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    Cited by:

    1. Xiaopan Gao & Bei Wang & Kaixiang Zhu & Linyue Wang & Bo Qin & Kun Shang & Wei Ding & Jianwei Wang & Sheng Cui, 2024. "The EV71 2A protease occupies the central cleft of SETD3 and disrupts SETD3-actin interaction," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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