Crystal Structure of the Ryanodine Receptor SPRY2 Domain from the Diamondback Moth Provides Insights into the Development of Novel Insecticides

Abstract

Diamide insecticides targeting ryanodine receptors (RyRs) are a major class of pesticides used to control a wide range of agricultural pests, but their efficacies have been reduced dramatically by the recent emergence of resistance mutations. There is a pressing need to develop novel insecticides, targeting distinct and novel binding sites within insect RyRs to overcome the resistance crisis; however, the limited structural information on insect RyRs is a major roadblock to our understanding of their molecular mechanisms. Here, we report the crystal structure of the RyR SPRY2 domain from the diamondback moth (DBM), Plutella xylostella, a destructive agricultural pest worldwide that has developed resistance to all classes of insecticide at 2.06 Å resolution. The overall fold of DBM SPRY2 is similar to its mammalian homolog, but it shows distinct conformations in several loops. Docking it into the recently published cryo-electron microscope structure of the full-length RyR reveals that two insect-specific loops interact with the BSol domain from the neighboring subunit. The SPRY2-BSol interface will change the conformation upon channel gating, indicating that it might be a potential targeting site for insect-specific insecticides. Interestingly, several previously identified disease-causing mutations also lie in the same interface, implying that this interface is important for channel gating. Another insect-specific loop located in the SPRY2-SPRY3 interface might indirectly affect another gating interface between SPRY3 and Repeat34.