Cryo-EM structures of ryanodine receptors and diamide insecticides reveal the mechanisms of selectivity and resistance
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.
Authors
- Changshi Wang (ORCID: https://orcid.org/0000-0001-5206-9737)
- Yu‐Cheng Gu (ORCID: https://orcid.org/0000-0002-6400-6167)
- Jiamu Du (ORCID: https://orcid.org/0000-0002-1337-0786)
- Hadiatullah Hadiatullah (ORCID: https://orcid.org/0000-0002-1025-195X)
- Shun‐Fan Wu (ORCID: https://orcid.org/0000-0003-0096-147X)
- Takashi Murayama (ORCID: https://orcid.org/0000-0002-3845-2980)
- Wenlan Wang (ORCID: https://orcid.org/0000-0002-3324-4517)
- Henryk Korza
- Zhiguang Yuchi (ORCID: https://orcid.org/0000-0003-2595-9106)
- Filip Van Petegem (ORCID: https://orcid.org/0000-0003-2728-8537)
- Yu Seby Chen (ORCID: https://orcid.org/0000-0002-0793-2391)
- Yiwen Wang (ORCID: https://orcid.org/0000-0003-2069-6685)
- Yan Zhang (ORCID: https://orcid.org/0000-0003-2031-0631)
- Takuya Kobayashi (ORCID: https://orcid.org/0000-0003-3992-1889)
- Lianyun Lin
- Heng Jiang (ORCID: https://orcid.org/0000-0003-4806-4516)
Institutions
- Nanjing Agricultural University (CN)
- University of British Columbia (CA)
- Tianjin University (CN)
- Southern University of Science and Technology (CN)
- Juntendo University (JP)
- Syngenta (United Kingdom) (GB)
- Agricultural Genomics Institute at Shenzhen (CN)
- Tianjin Institute of Pharmaceutical Research (China) (CN)
- Tianjin haihe hospital (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-20
- DOI
- https://doi.org/10.1038/s41467-024-53490-0
- Citations
- 20
- Primary Topic
- Insect Resistance and Genetics
- Type
- article
- Field-Weighted Citation Impact
- 4.68
Funders
- Naito Foundation
- National Natural Science Foundation of China
- Ministry of Science and Technology of the People's Republic of China
- Japan Society for the Promotion of Science
- National Key Research and Development Program of China