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Cryo-EM structures of ryanodine receptors and diamide insecticides reveal the mechanisms of selectivity and resistance

Author

Listed:
  • Lianyun Lin

    (Tianjin University
    Haihe Laboratory of Sustainable Chemical Transformations)

  • Changshi Wang

    (Southern University of Science and Technology)

  • Wenlan Wang

    (Tianjin University
    Haihe Laboratory of Sustainable Chemical Transformations)

  • Heng Jiang

    (Tianjin University
    Haihe Laboratory of Sustainable Chemical Transformations)

  • Takashi Murayama

    (Juntendo University Graduate School of Medicine)

  • Takuya Kobayashi

    (Juntendo University Graduate School of Medicine)

  • Hadiatullah Hadiatullah

    (Tianjin University
    Haihe Laboratory of Sustainable Chemical Transformations)

  • Yu Seby Chen

    (University of British Columbia)

  • Shunfan Wu

    (Nanjing Agricultural University)

  • Yiwen Wang

    (Tianjin University)

  • Henryk Korza

    (Syngenta Jealott’s Hill International Research Centre)

  • Yucheng Gu

    (Syngenta Jealott’s Hill International Research Centre)

  • Yan Zhang

    (Tianjin University
    Haihe Laboratory of Sustainable Chemical Transformations)

  • Jiamu Du

    (Southern University of Science and Technology)

  • Filip Petegem

    (Juntendo University Graduate School of Medicine)

  • Zhiguang Yuchi

    (Tianjin University
    Haihe Laboratory of Sustainable Chemical Transformations
    Chinese Academy of Agricultural Sciences)

Abstract

The resistance of pests to common insecticides is a global issue that threatens food production worldwide. Diamide insecticides target insect ryanodine receptors (RyRs), causing uncontrolled calcium release from the sarcoplasmic and endoplasmic reticulum. Despite their high potency and species selectivity, several resistance mutations have emerged. Using a chimeric RyR (chiRyR) approach and cryo-electron microscopy (cryo-EM), we investigate how insect RyRs engage two different diamide insecticides from separate families: flubendiamide, a phthalic acid derivative, and tetraniliprole, an anthranilic compound. Both compounds target the same site in the transmembrane region of the RyR, albeit with different poses, and promote channel opening through coupling with the pore-forming domain. To explore the resistance mechanisms, we also solve two cryo-EM structures of chiRyR carrying the two most common resistance mutations, I4790M and G4946E, both alone and in complex with the diamide insecticide chlorantraniliprole. The resistance mutations perturb the local structure, directly reducing the binding affinity and altering the binding pose. Our findings elucidate the mode of action of different diamide insecticides, reveal the molecular mechanism of resistance mutations, and provide important clues for the development of novel pesticides that can bypass the resistance mutations.

Suggested Citation

  • Lianyun Lin & Changshi Wang & Wenlan Wang & Heng Jiang & Takashi Murayama & Takuya Kobayashi & Hadiatullah Hadiatullah & Yu Seby Chen & Shunfan Wu & Yiwen Wang & Henryk Korza & Yucheng Gu & Yan Zhang , 2024. "Cryo-EM structures of ryanodine receptors and diamide insecticides reveal the mechanisms of selectivity and resistance," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53490-0
    DOI: 10.1038/s41467-024-53490-0
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    References listed on IDEAS

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    1. Junji Suzuki & Kazunori Kanemaru & Kuniaki Ishii & Masamichi Ohkura & Yohei Okubo & Masamitsu Iino, 2014. "Imaging intraorganellar Ca2+ at subcellular resolution using CEPIA," Nature Communications, Nature, vol. 5(1), pages 1-13, September.
    2. Deshun Gong & Ximin Chi & Jinhong Wei & Gewei Zhou & Gaoxingyu Huang & Lin Zhang & Ruiwu Wang & Jianlin Lei & S. R. Wayne Chen & Nieng Yan, 2019. "Modulation of cardiac ryanodine receptor 2 by calmodulin," Nature, Nature, vol. 572(7769), pages 347-351, August.
    3. Takuya Kobayashi & Akihisa Tsutsumi & Nagomi Kurebayashi & Kei Saito & Masami Kodama & Takashi Sakurai & Masahide Kikkawa & Takashi Murayama & Haruo Ogawa, 2022. "Molecular basis for gating of cardiac ryanodine receptor explains the mechanisms for gain- and loss-of function mutations," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
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