%0 Journal Article
%T Structural and Functional Similarity of Amphibian Constitutive Androstane Receptor with Mammalian Pregnane X Receptor
%A Marianne Math£¿s
%A Christian Nu¦Âhag
%A Oliver Burk
%A Ute G£¿dtel-Armbrust
%A Holger Herlyn
%A Leszek Wojnowski
%A Bj£¿rn Windsh¨¹gel
%J PLOS ONE
%D 2014
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0096263
%X 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 (xlCAR¨¢ and a) 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 xlCAR¨¢ being the structural and functional counterpart of mammalian PXR. A three-dimensional model of the xlCAR¨¢ 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, xlCAR¨¢ possesses a flexible helix 11¡ä. Modest increase in the recruitment of coactivator PGC-1¨¢ may contribute to the enhanced basal activity of three gain-of-function xlCAR¨¢ mutants humanizing key LBD amino acid residues. xlCAR¨¢ and PXR appear to constitute an example of convergent evolution.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0096263