Structural and functional similarity of amphibian constitutive androstane receptor with mammalian pregnane X receptor

• Published in: PloS one Vol. 9; no. 5; p. e96263
• Main Authors: Mathäs, Marianne, Nusshag, Christian, Nuβhag, Christian, Burk, Oliver, Gödtel-Armbrust, Ute, Herlyn, Holger, Wojnowski, Leszek, Windshügel, Björn
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 05.05.2014; Public Library of Science (PLoS)
• Subjects: Acids; Amino acid composition; Amino acids; Amphibian Proteins - chemistry; Amphibian Proteins - physiology; Animals; Binding; Binding Sites; Biology and Life Sciences; Cell Line; Cercopithecus aethiops; Computer applications; COS Cells; Crystal structure; Crystallography, X-Ray; Enzymes; Evolution (Biology); Humans; Identification; Ligands; Liver; Mammals; Medicine and Health Sciences; Models, Molecular; Molecular Dynamics Simulation; Mutants; Mutation; Nuclear receptors; Pharmacology; Physical Sciences; Physiology; Pregnancy; Receptors; Receptors, Cytoplasmic and Nuclear - chemistry; Receptors, Cytoplasmic and Nuclear - physiology; Receptors, Steroid - chemistry; Receptors, Steroid - physiology; Recruitment; Reptiles & amphibians; Research and Analysis Methods; Structure-function relationships; Studies; Three dimensional models; Xenopus laevis; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0096263

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.