Ryanodine receptors (RyRs) are the molecular target of diamides, a new chemical class of insecticides. Diamide insecticides are used to control lepidopteran pests and were considered relatively safe for mammals and non-targeted beneficial insects, including honey bees. However, recent studies showed that exposure to diamides could cause long-lasting locomotor deficits of bees. Here we report the crystal structure of RyR N-terminal domain A (NTD-A) from the honeybee, Apis mellifera, at 2.5 Å resolution. It shows a similar overall fold as the RyR NTD-A from mammals and the diamondback moth (DBM), Plutella xylostella, and still several loops located at the inter-domain interfaces show insect-specific or bee-specific structural features. A potential insecticide-binding pocket formed by loop9 and loop13 is conserved in lepidopteran but different in both mammals and bees, making it a good candidate targeting site for the development of pest-selective insecticides. Furthermore, a conserved intra-domain disulfide bond was observed in both DBM and bee RyR NTD-A crystal structures, which explains their higher thermal stability compared to mammalian RyR NTD-A. This work provides a basis for the development of novel insecticides with better selectivity between pests and bees by targeting a distinct site on pest RyRs, which would be a promising strategy to overcome the current toxicity problem.
Keywords: Crystal structure; Honeybee; Insecticide; N-terminal domain; Ryanodine receptor.
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