title: Structure of the murine constitutive androstane receptor complexed to androstenol: a molecular basis for inverse agonism.
abstract: The nuclear receptor CAR is a xenobiotic responsive transcription factor that plays a central role in the clearance of drugs and bilirubin while promoting cocaine and acetaminophen toxicity. In addition, CAR has established a "reverse" paradigm of nuclear receptor action where the receptor is active in the absence of ligand and inactive when bound to inverse agonists. We now report the crystal structure of murine CAR bound to the inverse agonist androstenol. Androstenol binds within the ligand binding pocket, but unlike many nuclear receptor ligands, it makes no contacts with helix H12/AF2. The transition from constitutive to basal activity (androstenol bound) appears to be associated with a ligand-induced kink between helices H10 and H11. This disrupts the previously predicted salt bridge that locks H12 in the transcriptionally active conformation. This mechanism of inverse agonism is distinct from traditional nuclear receptor antagonists thereby offering a new approach to receptor modulation.
authors.affiliation: Biochemistry, Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Shan
authors.forename: Jeremy
authors.initials: J
authors.lastname: Vincent
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Brunzelle
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dussault
authors.forename: Min
authors.initials: M
authors.lastname: Lin
authors.forename: Irina
authors.initials: I
authors.lastname: Ianculescu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sherman
authors.forename: Barry M
authors.initials: BM
authors.lastname: Forman
authors.forename: Elias J
authors.initials: EJ
authors.lastname: Fernandez
mesh_terms: D000737:Androstenols / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D000090702:Constitutive Androstane Receptor; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000737:Androstenols; D000090702:Constitutive Androstane Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors