Lianyun Lin1, Zhiyuan Hao1, Peng Cao2, Zhiguang Yuchi1. 1. Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China. 2. Key Laboratory of Drug Targets and Drug Leads for Degenerative Diseases, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
Abstract
BACKGROUND: Diamide insecticides, including phthalic and anthranilic diamides, target insect ryanodine receptors (RyRs) and cause misregulation of calcium signaling in insect muscles and neurons. Several resistance mutations have been reported to reduce the efficacy of the diamides, but the exact binding sites and mechanism of resistance mutations are not clear. RESULTS: The recent breakthrough in structural studies of mammalian RyRs has deepened our understanding of these giant calcium-release channels, but structural information about insect RyRs is still scarce. The only reported high-resolution structure is from the N-terminal domain of diamondback moth (DBM) RyR determined by our group. Here, we generate several homology models of full-length DBM RyR representing different functional states and dock the diamide insecticides into the structural models using Schrodinger software. These models reveal the specific structural features, activation mechanism, structural difference between functional states, ligand-binding sites and insecticide-binding sites of DBM RyR. By comparing the structures of wild-type and insecticide-resistant mutants, we propose a model depicting how the mutations affect the insecticide binding. We also identify the key difference between mammalian and insect RyRs that may explain the species-specific binding properties of diamides. CONCLUSION: The binding sites for three activators Ca2+ , ATP and caffeine, and regulator ryanodine are conserved in insect and mammalian RyRs, but the binding site for diamide insecticides is species-specific. The phthalic and anthranilic diamides have distinct binding properties in DBM, which can be interfered by resistance mutations located in the transmembrane region.
BACKGROUND:Diamide insecticides, including phthalic and anthranilic diamides, target insect ryanodine receptors (RyRs) and cause misregulation of calcium signaling in insect muscles and neurons. Several resistance mutations have been reported to reduce the efficacy of the diamides, but the exact binding sites and mechanism of resistance mutations are not clear. RESULTS: The recent breakthrough in structural studies of mammalianRyRs has deepened our understanding of these giant calcium-release channels, but structural information about insect RyRs is still scarce. The only reported high-resolution structure is from the N-terminal domain of diamondback moth (DBM) RyR determined by our group. Here, we generate several homology models of full-length DBMRyR representing different functional states and dock the diamide insecticides into the structural models using Schrodinger software. These models reveal the specific structural features, activation mechanism, structural difference between functional states, ligand-binding sites and insecticide-binding sites of DBMRyR. By comparing the structures of wild-type and insecticide-resistant mutants, we propose a model depicting how the mutations affect the insecticide binding. We also identify the key difference between mammalian and insect RyRs that may explain the species-specific binding properties of diamides. CONCLUSION: The binding sites for three activators Ca2+ , ATP and caffeine, and regulator ryanodine are conserved in insect and mammalianRyRs, but the binding site for diamide insecticides is species-specific. The phthalic and anthranilic diamides have distinct binding properties in DBM, which can be interfered by resistance mutations located in the transmembrane region.
Authors: Sudeeptha Yainna; Nicolas Nègre; Pierre J Silvie; Thierry Brévault; Wee Tek Tay; Karl Gordon; Emmanuelle dAlençon; Thomas Walsh; Kiwoong Nam Journal: Insects Date: 2021-05-18 Impact factor: 2.769