Journal
NATURE CHEMICAL BIOLOGY
Volume 16, Issue 11, Pages 1246-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41589-020-0627-5
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Funding
- Canadian Foundation of Innovation
- BC Knowledge Development Fund
- UBC
- Westgrid Cedar cluster
- Compute Canada
- National Key Research and Development Program of China [2017YFD0201400, 2017YFD0201403]
- National Natural Science Foundation of China [31972287]
- CIHR [PJT-159601]
- Japan Agency for Medical Research and Development [JP20am0101080j0004]
- Japan Society for the Promotion of Science [19H03404]
- CIHR
- Michael Smith Foundation for Health Research
- Grants-in-Aid for Scientific Research [19H03404] Funding Source: KAKEN
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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-angstrom 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.
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