Recently, a research team led by Professor Yuchi Zhiguang from Tianjin University, along with collaborators, published a study in Nature Communications titled "Cryo-EM Structures of Ryanodine Receptors and Diamide Insecticides Reveal the Mechanisms of Selectivity and Resistance" (https://doi.org/10.1038/s41467-024-53490-0).
Insects demonstrate extraordinary adaptability in dynamic ecosystems, thanks to their advanced body structures, flexible movement, high reproductive rates, and short life cycles. This adaptability not only allows them to thrive but also enables them to quickly develop resistance to pesticides, posing a severe threat to global food security. Consequently, understanding the mechanisms of insect pesticide resistance has become a crucial issue in agricultural protection.
Using cryo-electron microscopy, the researchers analyzed the complex structures of diamide insecticides from two different families and their target receptors, revealing the molecular mechanisms by which these compounds selectively activate insect receptors. They also investigated receptor structures with common resistance mutations, uncovering how these mutations reduce insecticide efficacy through a dual mechanism, ultimately leading to resistance.
The ryanodine receptor (RyR) is a calcium ion channel located on the endoplasmic reticulum membrane, playing a crucial role in muscle excitation-contraction coupling. Diamide insecticides, which rank among the best-selling insecticides worldwide, specifically activate insect RyR, causing excessive calcium release that results in muscle paralysis and death. In earlier research published in Nature Chemical Biology (2020), Professor Yuchi’s team identified the binding site of chlorantraniliprole—a major diamide insecticide—on rabbit RyR. Building on this foundation, the current study employed an insect-derived chimeric RyR to explore the binding modes of two diamide insecticides: tetraniliprole from the anthranilic diamide class and flubendiamide from the phthalic diamide class. The study demonstrated that both insecticides target the same site but bind in distinct ways, resolving a long-standing debate over their mechanisms. The team also identified key amino acid residues and pharmacophore groups crucial for species selectivity, further enhancing our understanding of the structure-activity relationships of diamide derivatives.
Resistance to RyR-targeting insecticides has emerged in several major agricultural pest populations due to RyR gene mutations, diminishing insecticide efficacy and causing significant crop losses. The research team analyzed cryo-EM structures of RyR with two common resistance mutations, I4790M and G4946E, both alone and in complex with chlorantraniliprole. They discovered that these mutations decrease the channel's opening efficiency, stabilizing it in a closed state, and also alter the structure of the ligand-binding site, which reduces the insecticide binding affinity, resulting in a dual resistance effect.
Overall, the study not only elucidates the mechanisms underlying diamide insecticide action but also provides a detailed understanding of resistance mutations at the molecular level. These insights are invaluable for developing innovative, eco-friendly insecticides to manage resistant pest populations effectively.
By School of Pharmaceutical Science and Technology
Editor: Sun Xiaofang
