Structural adaptability in the ligand-binding pocket of the ecdysone hormone receptor.
The ecdysteroid hormones coordinate the major stages of insect development, notably moulting and metamorphosis, by binding to the ecdysone receptor (EcR); a ligand-inducible nuclear transcription factor. To bind either ligand or DNA, EcR must form a heterodimer with ultraspiracle (USP), the homologue of retinoid-X receptor. Here we report the crystal structures of the ligand-binding domains of the moth Heliothis virescens EcR-USP heterodimer in complex with the ecdysteroid ponasterone A and with a non-steroidal, lepidopteran-specific agonist BYI06830 used in agrochemical pest control. The two structures of EcR-USP emphasize the universality of heterodimerization as a general mechanism common to both vertebrates and invertebrates. Comparison of the EcR structures in complex with steroidal and non-steroidal ligands reveals radically different and only partially overlapping ligand-binding pockets that could not be predicted by molecular modelling and docking studies. These findings offer new perspectives for the design of insect-specific, environmentally safe insecticides. The concept of a ligand-dependent binding pocket in EcR provides an insight into the moulding of nuclear receptors to their ligand, and has potential applications for human nuclear receptors.
Billas
Isabelle M L
IM
Département de Biologie et de Génomique Structurales, IGBMC, CNRS/INSERM/Université Louis Pasteur, Parc d'Innovation BP10142, 67404 Illkirch cedex, France.
Iwema
Thomas
T
Garnier
Jean-Marie
JM
Mitschler
André
A
Rochel
Natacha
N
Moras
Dino
D
D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D004146:Dioxanes / Q000737:chemistry / Q000378:metabolism*; D004441:Ecdysterone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D009036:Moths / Q000737:chemistry*; D011487:Protein Conformation; D011987:Receptors, Steroid / Q000737:chemistry* / Q000378:metabolism*
C479521:BYI 06830; D004146:Dioxanes; D006834:Hydrazines; D008024:Ligands; D011987:Receptors, Steroid; C055469:ecdysone receptor; D004441:Ecdysterone; C008999:ponasterone A