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

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, Jiamu Du, Filip Petegem () and Zhiguang Yuchi ()
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Lianyun Lin: Tianjin University
Changshi Wang: Southern University of Science and Technology
Wenlan Wang: Tianjin University
Heng Jiang: Tianjin University
Takashi Murayama: Juntendo University Graduate School of Medicine
Takuya Kobayashi: Juntendo University Graduate School of Medicine
Hadiatullah Hadiatullah: Tianjin University
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
Jiamu Du: Southern University of Science and Technology
Filip Petegem: Juntendo University Graduate School of Medicine
Zhiguang Yuchi: Tianjin University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53490-0

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