Dataset Information


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.


PROVIDER: S-EPMC4010427 | BioStudies | 2014-01-01

REPOSITORIES: biostudies

Similar Datasets

2018-01-01 | S-EPMC5960625 | BioStudies
2018-01-01 | S-EPMC6002932 | BioStudies
2016-01-01 | S-EPMC4975625 | BioStudies
2004-01-01 | S-EPMC524364 | BioStudies
2009-01-01 | S-EPMC2730391 | BioStudies
2018-01-01 | S-EPMC6193428 | BioStudies
2005-01-01 | S-EPMC1952403 | BioStudies
2005-01-01 | S-EPMC1262763 | BioStudies
2011-01-01 | S-EPMC3107492 | BioStudies
2019-01-01 | S-EPMC6701513 | BioStudies