Structural basis for diamide modulation of ryanodine receptor

Ruifang Ma, Omid Haji-Ghassemi, Dan Ma, Heng Jiang, Lianyun Lin, Li Yao, Arthur Samurkas, Yuxin Li, Yiwen Wang, Peng Cao, Shian Wu, Yan Zhang, Takashi Murayama, Bernard Moussian, Filip Van Petegem*, Zhiguang Yuchi*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)

Abstract

The diamide insecticide class is one of the top-selling insecticides globally. They are used to control a wide range of pests by targeting their ryanodine receptors (RyRs). Here, we report the highest-resolution cryo-electron microscopy (cryo-EM) structure of RyR1 in the open state, in complex with the anthranilic diamide chlorantraniliprole (CHL). The 3.2-Å local resolution map facilitates unambiguous assignment of the CHL binding site. The molecule induces a conformational change by affecting the S4–S5 linker, triggering channel opening. The binding site is further corroborated by mutagenesis data, which reveal how diamide insecticides are selective to the Lepidoptera group of insects over honeybee or mammalian RyRs. Our data reveal that several pests have developed resistance via two mechanisms, steric hindrance and loss of contact. Our results provide a foundation for the development of highly selective pesticides aimed at overcoming resistance and therapeutic molecules to treat human myopathies. [Figure not available: see fulltext.].

Original languageEnglish
Pages (from-to)1246-1254
JournalNature Chemical Biology
Volume16
Early online date17 Aug 2020
DOIs
Publication statusPublished - Nov 2020

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