Structural adaptability in the ligand-binding pocket of the ecdysone hormone receptor

Isabelle M. L. Billas, Thomas Iwema, Jean-Marie Garnier, André Mitschler, Natacha Rochel and Dino Moras ()
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Isabelle M. L. Billas: CNRS/INSERM/Université Louis Pasteur
Thomas Iwema: CNRS/INSERM/Université Louis Pasteur
Jean-Marie Garnier: CNRS/INSERM/Université Louis Pasteur
André Mitschler: CNRS/INSERM/Université Louis Pasteur
Natacha Rochel: CNRS/INSERM/Université Louis Pasteur
Dino Moras: CNRS/INSERM/Université Louis Pasteur

Nature, 2003, vol. 426, issue 6962, 91-96

Abstract: Abstract 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 factor1,2. To bind either ligand or DNA, EcR must form a heterodimer with ultraspiracle (USP), the homologue of retinoid-X receptor3,4,5. 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 studies6,7. 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.

Date: 2003
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DOI: 10.1038/nature02112

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