title: The X-ray structure of a hemipteran ecdysone receptor ligand-binding domain: comparison with a lepidopteran ecdysone receptor ligand-binding domain and implications for insecticide design.
abstract: The ecdysone receptor is a hormone-dependent transcription factor that plays a central role in regulating the expression of vast networks of genes during development and reproduction in the phylum Arthropoda. The functional receptor is a heterodimer of the two nuclear receptor proteins ecdysone receptor (EcR) and ultraspiracle protein. The receptor is the target of the environmentally friendly bisacylhydrazine insecticides, which are effective against Lepidoptera but not against Hemiptera or several other insect orders. Here we present evidence indicating that much of the selectivity of the bisacylhydrazine insecticides can be studied at the level of their binding to purified ecdysone receptor ligand-binding domain (LBD) heterodimers. We report the crystal structure of the ecdysone receptor LBD heterodimer of the hemipteran Bemisia tabaci (Bt, sweet potato whitefly) in complex with the ecdysone analogue ponasterone A. Although comparison with the corresponding known LBD structure from the lepidopteran Heliothis virescens (Hv) ecdysone receptor revealed the overall mode of ponasterone A binding to be very similar in the two cases, we observed that the BtEcR ecdysteroid-binding pocket is structured differently to that of HvEcR in those parts that are not in contact with ponasterone A. We suggest that these differences in the ligand-binding pocket may provide a molecular basis for the taxonomic order selectivity of bisacylhydrazine insecticides.
authors.affiliation: CSIRO Health Sciences and Nutrition, 343 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Carmichael
authors.forename: Michael C
authors.initials: MC
authors.lastname: Lawrence
authors.forename: Lloyd D
authors.initials: LD
authors.lastname: Graham
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Pilling
authors.forename: V Chandana
authors.initials: VC
authors.lastname: Epa
authors.forename: Leonie
authors.initials: L
authors.lastname: Noyce
authors.forename: George
authors.initials: G
authors.lastname: Lovrecz
authors.forename: David A
authors.initials: DA
authors.lastname: Winkler
authors.forename: Anna
authors.initials: A
authors.lastname: Pawlak-Skrzecz
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Eaton
authors.forename: Garry N
authors.initials: GN
authors.lastname: Hannan
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Hill
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D018507:Gene Expression Regulation, Developmental; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology*; D007313:Insecta; D007306:Insecticides / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011987:Receptors, Steroid / Q000737:chemistry* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D006834:Hydrazines; D007306:Insecticides; D008024:Ligands; D011987:Receptors, Steroid; C055469:ecdysone receptor