Ligand recognition by the vitamin D receptor
Ligand recognition by the vitamin D receptor
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DOI：
10.1016/s0968-0896(01)00060-8
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发表时间：
2001-07-01
影响因子：
3.5
通讯作者：
Yamada, S
中科院分区：
文献类型：
--
作者：
Choi, MW;Yamamoto, K;Yamada, S
维生素D受体（VDR）与天然配体1 α，25-二羟基维生素D-3 [1，25-（OH）（2）D-3]对接的配体结合结构域（LBD）的三维结构主要通过缺失突变体（VDR-LBD Delta 165-215）的X射线晶体学分析来解决。从现在开始，重要的焦点是VDR如何识别并与有效的合成配体相互作用。我们现在报告VDR与三种功能和结构上有趣的配体22-oxa-1.25-（OH）（2）D-3（OCT）、20-epi-1，25-（OH）（2）D-3和20-epi-22-oxa-24，26，27-trihomo-1.25-（OH）（2）D-3的对接模型。在计算对接研究的同时，我们制备了12个排列在VDR配体结合口袋的氨基酸残基的一点突变体，并检查了它们由1125-（OH）（2）D-3和这些合成配体诱导的反式激活效力。结果表明，L233、R274、W286、H397和Y 401对所有配体的稳定性都是必需的，S278和Q400对所有配体的稳定性都不重要，而S237、V234、S275、C288和H305的稳定性随配体侧链结构的不同而不同。基于这些研究，我们提出了关键的结构因素，赋予OCT的选择性作用和增强活性的20-epi-ligands。此外，对接模型符合我们提出的维生素D的活性空间区域理论的基础上的配体的构象分析。(C)2001爱思唯尔科技有限公司版权所有。
Three-dimensional structure of the ligand binding domain (LBD) of the vitamin D receptor (VDR) docked with the natural ligand 1 alpha ,25-dihydroxyvitamin D-3 [1,25-(OH)(2)D-3] has been mostly solved by the X-ray crystallographic analysis of the deletion mutant (VDR-LBD Delta 165-215). The important focus, from now on. is how the VDR recognizes and interacts with potent synthetic ligands. We now report the docking models of the VDR with three functionally and structurally interesting ligands, 22-oxa-1.25-(OH)(2)D-3 (OCT), 20-epi-1,25-(OH)(2)D-3 and 20-epi-22-oxa-24,26,27-trihomo-1.25-(OH)(2)D-3. In parallel with the computational docking studies, we prepared twelve one-point mutants of amino acid residues lining the ligand binding pocket of the VDR and examined their transactivation potency induced by 1125-(OH)(2)D-3 and these synthetic ligands. The results indicate that L233, R274, W286, H397 and Y401 are essential for holding the all ligands tested, S278 and Q400 are not important at all, and the importance of S237, V234, S275, C288 and H305 is variable depending on the side-chain structure of the ligands. Based on these studies, we suggested key structural factors to bestow the selective action on OCT and the augmented activities on 20-epi-ligands. Furthermore, the docking models coincided well with our proposed active space-region theory of vitamin D based on the conformational analyses of ligands. (C) 2001 Elsevier Science Ltd. All rights reserved.