Cryo-EM structures of ryanodine receptors and diamide insecticides reveal the mechanisms of selectivity and resistance
文献类型： 外文期刊
作者： Lin, Lianyun 1 ; Wang, Changshi 3 ; Wang, Wenlan 1 ; Jiang, Heng 1 ; Murayama, Takashi 4 ; Kobayashi, Takuya 4 ; Hadiatullah, Hadiatullah 1 ; Chen, Yu Seby 3 ; Wu, Shunfan 5 ; Wang, Yiwen 1 ; Korza, Henryk 6 ; Gu, Yucheng 6 ; Zhang, Yan 1 ; Du, Jiamu 7 ; Van Petegem, Filip 3 ; Yuchi, Zhiguang 1 ;
作者机构： 1.Tianjin Univ, Tianjin Key Lab Modern Drug Delivery & High Effici, Frontiers Sci Ctr Synthet Biol, Sch Pharmaceut Sci & Technol,Fac Med, Tianjin, Peoples R China
2.Haihe Lab Sustainable Chem Transformat, Tianjin, Peoples R China
3.Univ British Columbia, Life Sci Inst, Dept Biochem & Mol Biol, Vancouver, BC, Canada
4.Juntendo Univ, Grad Sch Med, Dept Cellular & Mol Pharmacol, Tokyo, Japan
5.Nanjing Agr Univ, Coll Plant Protect, State & Local Joint Engn Res Ctr Green Pesticide I, Nanjing, Jiangsu, Peoples R China
6.Syngenta Jealotts Hill Int Res Ctr, Bracknell, Berks, England
7.Southern Univ Sci & Technol, Inst Plant & Food Sci, Dept Biol, Shenzhen, Guangdong, Peoples R China
8.Chinese Acad Agr Sci, Agr Genom Inst Shenzhen, Shenzhen Branch, Guangdong Lab Lingnan Modern Agr, Shenzhen, Guangdong, Peoples R China
期刊名称：NATURE COMMUNICATIONS （ 影响因子：15.7； 五年影响因子：17.2 ）
ISSN：
年卷期： 2024 年 15 卷 1 期
页码：
收录情况： SCI
摘要： 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. Pesticide resistance poses a serious threat to global food security. In this study, the authors show the mode of action of various diamide insecticides and elucidate the molecular mechanisms underlying resistance mutations.
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