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Letters to Nature

Nature 426, 91-96 (6 November 2003) | doi:10.1038/nature02112; Received 24 July 2003; Accepted 14 October 2003; Published online 2 November 2003

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

Isabelle M. L. Billas1, Thomas Iwema1, Jean-Marie Garnier1, André Mitschler1, Natacha Rochel1 & Dino Moras1

  1. Département de Biologie et de Génomique Structurales, IGBMC, CNRS/INSERM/Université Louis Pasteur, Parc d'Innovation BP10142, 67404 Illkirch cedex, France

Correspondence to: Dino Moras1 Email: moras@igbmc.u-strasbg.fr
Atomic coordinates have been deposited in the Protein Data Bank under accession codes 1R1K and 1R20.

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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.