Ekins Sean, Reschly Erica J, Hagey Lee R, Krasowski Matthew D
Collaborations in Chemistry, Inc., Jenkintown, PA, USA.
BMC Evol Biol. 2008 Apr 2;8:103. doi: 10.1186/1471-2148-8-103.
The pregnane X receptor (PXR) shows the highest degree of cross-species sequence diversity of any of the vertebrate nuclear hormone receptors. In this study, we determined the pharmacophores for activation of human, mouse, rat, rabbit, chicken, and zebrafish PXRs, using a common set of sixteen ligands. In addition, we compared in detail the selectivity of human and zebrafish PXRs for steroidal compounds and xenobiotics. The ligand activation properties of the Western clawed frog (Xenopus tropicalis) PXR and that of a putative vitamin D receptor (VDR)/PXR cloned in this study from the chordate invertebrate sea squirt (Ciona intestinalis) were also investigated.
Using a common set of ligands, human, mouse, and rat PXRs share structurally similar pharmacophores consisting of hydrophobic features and widely spaced excluded volumes indicative of large binding pockets. Zebrafish PXR has the most sterically constrained pharmacophore of the PXRs analyzed, suggesting a smaller ligand-binding pocket than the other PXRs. Chicken PXR possesses a symmetrical pharmacophore with four hydrophobes, a hydrogen bond acceptor, as well as excluded volumes. Comparison of human and zebrafish PXRs for a wide range of possible activators revealed that zebrafish PXR is activated by a subset of human PXR agonists. The Ciona VDR/PXR showed low sequence identity to vertebrate VDRs and PXRs in the ligand-binding domain and was preferentially activated by planar xenobiotics including 6-formylindolo-[3,2-b]carbazole. Lastly, the Western clawed frog (Xenopus tropicalis) PXR was insensitive to vitamins and steroidal compounds and was activated only by benzoates.
In contrast to other nuclear hormone receptors, PXRs show significant differences in ligand specificity across species. By pharmacophore analysis, certain PXRs share similar features such as human, mouse, and rat PXRs, suggesting overlap of function and perhaps common evolutionary forces. The Western clawed frog PXR, like that described for African clawed frog PXRs, has diverged considerably in ligand selectivity from fish, bird, and mammalian PXRs.
孕烷X受体（PXR）在所有脊椎动物核激素受体中表现出最高程度的跨物种序列多样性。在本研究中，我们使用一组共16种配体确定了人、小鼠、大鼠、兔、鸡和斑马鱼PXR激活的药效团。此外，我们详细比较了人和斑马鱼PXR对甾体化合物和外源性物质的选择性。还研究了西方爪蟾（热带爪蟾）PXR以及本研究中从脊索动物无脊椎动物海鞘（肠鳃纲海鞘）克隆的假定维生素D受体（VDR）/PXR的配体激活特性。
使用一组共同的配体，人、小鼠和大鼠PXR具有结构相似的药效团，由疏水特征和表明大结合口袋的广泛间隔的排除体积组成。斑马鱼PXR在所分析的PXR中具有空间限制最大的药效团，表明其配体结合口袋比其他PXR小。鸡PXR具有对称的药效团，有四个疏水基团、一个氢键受体以及排除体积。对人和斑马鱼PXR针对多种可能激活剂的比较表明，斑马鱼PXR被人PXR激动剂的一个子集激活。海鞘VDR/PXR在配体结合域与脊椎动物VDR和PXR的序列同一性较低，并且优先被包括6-甲酰基吲哚并-[3,2-b]咔唑在内的平面外源性物质激活。最后，西方爪蟾（热带爪蟾）PXR对维生素和甾体化合物不敏感，仅被苯甲酸盐激活。
与其他核激素受体不同，PXR在物种间的配体特异性上表现出显著差异。通过药效团分析，某些PXR具有相似特征，如人、小鼠和大鼠PXR，表明功能重叠以及可能存在共同的进化力量。西方爪蟾PXR与非洲爪蟾PXR一样，在配体选择性上与鱼类、鸟类和哺乳动物PXR有很大差异。
