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TitleStructural basis for diamide modulation of ryanodine receptor.
Journal, issue, pagesNat Chem Biol, Vol. 16, Issue 11, Page 1246-1254, Year 2020
Publish dateAug 17, 2020
AuthorsRuifang 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 /
PubMed AbstractThe 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 ...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.
External linksNat Chem Biol / PubMed:32807966
MethodsEM (single particle)
Resolution3.8 - 4.7 Å
Structure data

30067

6m2w

EMDB-30067, PDB-6m2w:
Structure of RyR1 (Ca2+/Caffeine/ATP/CaM1234/CHL)
Method: EM (single particle) / Resolution: 3.8 Å

30343

7cf9

EMDB-30343, PDB-7cf9:
Structure of RyR1 (Ca2+/CHL)
Method: EM (single particle) / Resolution: 4.7 Å

Chemicals

ChemComp-CFF:
CAFFEINE / medication*YM

ChemComp-CA:
Unknown entry

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-ZN:
Unknown entry

ChemComp-F0U:
5-bromanyl-N-[4-chloranyl-2-methyl-6-(methylcarbamoyl)phenyl]-2-(3-chloranylpyridin-2-yl)pyrazole-3-carboxamide

Source
  • oryctolagus cuniculus (rabbit)
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Rabbit / Ryanodine receptor1 / CHL.

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