title: Structural and functional similarity of amphibian constitutive androstane receptor with mammalian pregnane X receptor.
abstract: The nuclear receptors and xenosensors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) induce the expression of xenobiotic metabolizing enzymes and transporters, which also affects various endobiotics. While human and mouse CAR feature a high basal activity and low induction upon ligand exposure, we recently identified two constitutive androstane receptors in Xenopus laevis (xlCARá and â) that possess PXR-like characteristics such as low basal activity and activation in response to structurally diverse compounds. Using a set of complementary computational and biochemical approaches we provide evidence for xlCARá being the structural and functional counterpart of mammalian PXR. A three-dimensional model of the xlCARá ligand-binding domain (LBD) reveals a human PXR-like L-shaped ligand binding pocket with a larger volume than the binding pockets in human and murine CAR. The shape and amino acid composition of the ligand-binding pocket of xlCAR suggests PXR-like binding of chemically diverse ligands which was confirmed by biochemical methods. Similarly to PXR, xlCARá possesses a flexible helix 11'. Modest increase in the recruitment of coactivator PGC-1á may contribute to the enhanced basal activity of three gain-of-function xlCARá mutants humanizing key LBD amino acid residues. xlCARá and PXR appear to constitute an example of convergent evolution.
authors.affiliation: Department of Pharmacology, University Medical Center, Mainz, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Mathäs
authors.forename: Christian
authors.initials: C
authors.lastname: Nusshag
authors.affiliation: Department of Pharmacology, University Medical Center, Mainz, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Nuβhag
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Burk
authors.affiliation: Department of Pharmacology, University Medical Center, Mainz, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Gödtel-Armbrust
authors.affiliation: Institute of Anthropology, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Herlyn
authors.affiliation: Department of Pharmacology, University Medical Center, Mainz, Germany.
authors.forename: Leszek
authors.initials: L
authors.lastname: Wojnowski
authors.affiliation: Centre for Bioinformatics, University of Hamburg, Hamburg, Germany; European ScreeningPort GmbH, Hamburg, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Windshügel
mesh_terms: D029845:Amphibian Proteins / Q000737:chemistry* / Q000502:physiology; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D000090702:Constitutive Androstane Receptor; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000502:physiology; D011987:Receptors, Steroid / Q000737:chemistry* / Q000502:physiology; D014982:Xenopus laevis
chemical_list: D029845:Amphibian Proteins; D000090702:Constitutive Androstane Receptor; C000625852:NR1I2 protein, human; C000716327:NR1I3 protein, human; C000625853:Nr1i2 protein, mouse; C000716328:Nr1i3 protein, mouse; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid