{'fraction_non_alphanumeric': 0.020728008088978768, 'fraction_numerical': 0.0005055611729019212, 'mean_word_length': 5.618729096989966, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Homology modeling and docking study of diamondback moth ryanodine receptor reveals the mechanisms for channel activation, insecticide binding and resistance.

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 the structural studies of mammalian RyRs has deepened our understanding of these giant calcium-release channels, but the 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 by 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 the 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, 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 has distinct binding properties in DBM, which can be interfered by resistance mutations located in the transmembrane region. This article is protected by copyright. All rights reserved.