Evolution of pharmacologic specificity in the pregnane X receptor.
Evolution of pharmacologic specificity in the pregnane X receptor.
复制标题
孕烷 X 受体药理学特异性的演变。
DOI：
10.1186/1471-2148-8-103
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发表时间：
2008-04-02
影响因子：
3.4
通讯作者：
Krasowski, Matthew D.
中科院分区：
文献类型：
--
作者：
Ekins, Sean;Reschly, Erica J.;Hagey, Lee R.;Krasowski, Matthew D.
在脊椎动物核激素受体中，妊娠X受体（PXR）具有最高的跨物种序列多样性。在这项研究中，我们使用一组共同的16个配体，确定了激活人、小鼠、大鼠、兔、鸡和斑马鱼PXRs的药效团。此外，我们还详细比较了人类和斑马鱼的PXRs对甾体化合物和外源药物的选择性。研究了热带爪蛙（Xenopus tropicalis） PXR和本研究从无脊椎脊索动物海鞘（Ciona ninteinalis）中克隆的推定维生素D受体(VDR)/PXR的配体激活特性。使用一组共同的配体，人类、小鼠和大鼠的PXRs具有结构相似的药效团，包括疏水性特征和宽间隔的排除体积，表明大的结合袋。斑马鱼PXR具有最受空间约束的药效团，表明其配体结合口袋比其他PXR更小。鸡PXR具有对称的药效团，具有四个疏水基团，一个氢键受体，以及排除体积。人类和斑马鱼PXR的比较表明，斑马鱼的PXR可以被人类PXR激动剂的一个子集激活。Ciona VDR/PXR在配体结合区域与脊椎动物VDR和PXR的序列同源性较低，并优先被6-甲酰基林多罗-[3,2-b]咔唑等平面外源药物激活。最后，热带爪蛙（Xenopus tropicalis） PXR对维生素和甾体化合物不敏感，仅被苯甲酸盐激活。与其他核激素受体相比，PXRs在物种间的配体特异性有显著差异。通过药效团分析，某些PXRs具有类似的特征，如人类，小鼠和大鼠的PXRs，这表明功能重叠，可能是共同的进化力量。西方爪蛙的PXR，就像描述非洲爪蛙的PXR一样，在配体选择性上与鱼类、鸟类和哺乳动物的PXR有很大的不同。
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.
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DOI：
10.1073/pnas.95.21.12208
发表时间：
1998-10-13
影响因子：
11.1
作者：
Bertilsson, G;Heidrich, J;Berkenstam, A
通讯作者：
Berkenstam, A
影响因子：
9.3
作者：
Bachmann, K;Patel, H;Sambucetti, L
通讯作者：
Sambucetti, L
影响因子：
3.6
作者：
Ekins, Sean;Chang, Cheng;Bachmann, Kenneth
通讯作者：
Bachmann, Kenneth
影响因子：
64.8
作者：
Delsuc, F;Brinkmann, H;Philippe, H
通讯作者：
Philippe, H
影响因子：
10.7
作者：
Goldstone, Jared V.;Goldstone, Heather M. H.;Stegeman, John J.
通讯作者：
Stegeman, John J.