title: Molecular switch in the glucocorticoid receptor: active and passive antagonist conformations.
abstract: Mifepristone is known to induce mixed passive antagonist, active antagonist, and agonist effects via the glucocorticoid receptor (GR) pathway. Part of the antagonist effects of mifepristone are due to the repression of gene transcription mediated by the nuclear receptor corepressor (NCoR). Here, we report the crystal structure of a ternary complex of the GR ligand binding domain (GR-LBD) with mifepristone and a receptor-interacting motif of NCoR. The structures of three different conformations of the GR-LBD mifepristone complex show in the oxosteroid hormone receptor family how helix 12 modulates LBD corepressor and coactivator binding. Differences in NCoR binding and in helix 12 conformation reveal how the 11beta substituent in mifepristone triggers the helix 12 molecular switch to reshape the coactivator site into the corepressor site. Two observed conformations exemplify the active antagonist state of GR with NCoR bound. In another conformation, helix 12 completely blocks the coregulator binding site and explains the passive antagonistic effect of mifepristone on GR.
authors.affiliation: F Hoffmann-La Roche Ltd, Pharma Research, Discovery Technologies, Grenzacherstrasse 124, CH-4070 Basel, Switzerland. guillaume.schoch@roche.com
authors.forename: Guillaume A
authors.initials: GA
authors.lastname: Schoch
authors.forename: Brigitte
authors.initials: B
authors.lastname: D'Arcy
authors.forename: Martine
authors.initials: M
authors.lastname: Stihle
authors.forename: Dominique
authors.initials: D
authors.lastname: Burger
authors.forename: Dominik
authors.initials: D
authors.lastname: Bär
authors.forename: Jörg
authors.initials: J
authors.lastname: Benz
authors.forename: Ralf
authors.initials: R
authors.lastname: Thoma
authors.forename: Armin
authors.initials: A
authors.lastname: Ruf
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D056970:Co-Repressor Proteins / Q000737:chemistry / Q000235:genetics; D018360:Crystallography, X-Ray; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D046911:Macromolecular Substances; D015735:Mifepristone / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D056970:Co-Repressor Proteins; D006727:Hormone Antagonists; D008024:Ligands; D046911:Macromolecular Substances; D011965:Receptors, Glucocorticoid; D011994:Recombinant Proteins; D015735:Mifepristone