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These receptors serve as primary targets for various insecticides, including noncompetitive antagonists (NCAs) such as cyclodiene organochlorines and phenylpyrazoles, as well as allosteric modulators like meta\u2010diamides and isoxazolines. This study focuses on a newly discovered A2\u2032N mutation within the RDL receptors, identified in fipronil\u2010resistant planthoppers. Despite\n                      <jats:italic>in vitro<\/jats:italic>\n                      electrophysiological studies have proposed its role in conferring target\u2010site resistance,\n                      <jats:italic>in vivo<\/jats:italic>\n                      genetic functional validation of this mutation remains unexplored.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Our research employed toxicity bioassays, assessing various\n                      <jats:italic>Rdl<\/jats:italic>\n                      genotypes against a spectrum of insecticides, including fipronil, \u03b1\u2010endosulfan, broflanilide, and isocycloseram. Results revealed distinct resistance profiles for A2\u2032N and A2\u2032S mutants, indicating different binding interactions of RDL receptors with NCAs. Significantly, the A2\u2032N heterozygote showed substantial resistance to fipronil, despite its homozygous lethality. Molecular modeling and docking simulations further supported these findings, highlighting unique binding poses for fipronil and \u03b1\u2010endosulfan.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>\n                      This study confirmed that A2\u2032N mutation of the RDL GABA receptor confer high resistance to fipronil\n                      <jats:italic>in vivo<\/jats:italic>\n                      . The observed resistance in A2\u2032N mutants is likely attributable to a steric hindrance mechanism, wherein the introduction of larger side chains hampers fipronil binding, even in a heterozygous state. \u00a9 2023 Society of Chemical Industry.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ps.7929","type":"journal-article","created":{"date-parts":[[2023,12,12]],"date-time":"2023-12-12T21:42:17Z","timestamp":1702417337000},"page":"1924-1929","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Functional validation of\n                    <scp>A2<\/scp>\n                    \u2032N mutation of the\n                    <scp>RDL GABA<\/scp>\n                    receptor against fipronil\n                    <i>via<\/i>\n                    molecular modeling and genome engineering in drosophila"],"prefix":"10.1002","volume":"80","author":[{"given":"Xiaomu","family":"Qiao","sequence":"first","affiliation":[{"name":"Xianghu Laboratory  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianhao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Ministry of Agriculture Key Laboratory of Molecular Biology of Crop Pathogens and Insects, Institute of Insect Sciences Zhejiang University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Functional Molecules Shenyang University of Chemical Technology  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Functional Molecules Shenyang University of Chemical Technology  Shenyang 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