Mathäs Marianne, Nusshag Christian, Burk Oliver, Gödtel-Armbrust Ute, Herlyn Holger, Wojnowski Leszek, Windshügel Björn
Department of Pharmacology, University Medical Center, Mainz, Germany.
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
PLoS One. 2014 May 5;9(5):e96263. doi: 10.1371/journal.pone.0096263. eCollection 2014.
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.
核受体及外源性物质感受器组成型雄甾烷受体（CAR，NR1I3）和孕烷X受体（PXR，NR1I2）可诱导外源性物质代谢酶和转运蛋白的表达，这也会影响各种内源性物质。虽然人类和小鼠的CAR具有较高的基础活性，且在配体暴露时诱导作用较低，但我们最近在非洲爪蟾中鉴定出两种组成型雄甾烷受体（爪蟾CARα和β），它们具有类似PXR的特征，如基础活性较低，并能对结构多样的化合物产生激活反应。我们使用了一系列互补的计算和生化方法，证明爪蟾CARα是哺乳动物PXR的结构和功能对应物。爪蟾CARα配体结合域（LBD）的三维模型显示出一个类似人类PXR的L形配体结合口袋，其体积比人类和小鼠CAR中的结合口袋更大。爪蟾CAR配体结合口袋的形状和氨基酸组成表明其对化学性质多样的配体具有类似PXR的结合能力，这一点已通过生化方法得到证实。与PXR类似，爪蟾CARα也具有灵活的螺旋11'。共激活因子PGC-1α募集的适度增加可能有助于三种功能获得性爪蟾CARα突变体（其关键LBD氨基酸残基已人源化）基础活性的增强。爪蟾CARα和PXR似乎构成了趋同进化的一个例子。
