Structure-function analysis of vitamin D and VDR model.
Structure-function analysis of vitamin D and VDR model.
复制标题
维生素D和VDR模型的结构功能分析。
DOI：
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发表时间：
2000
影响因子：
3.1
通讯作者：
H. Masuno
中科院分区：
文献类型：
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作者：
S. Yamada;K. Yamamoto;H. Masuno
在第一部分中，根据核受体的X射线晶体结构，简要描述了核受体配体结合域的一般三维结构。重点介绍了NR-LBD的三种主要构象及其在反式激活功能中的作用。第二部分以配体结构为基础，以系统构象分析为工具，对维生素D的构效关系进行了分析。在对维生素D侧链的构象分析和构象限制性合成维生素D类似物研究的基础上，我们提出了维生素D活性空间区的概念：将维生素D侧链区域分为五个区域(A、G、EA、EG和F)。就空间区而言，这些研究发现的活性顺序如下：与维生素D受体(VDR)的亲和力，EA>；A>；F>；G>；EG；与维生素D结合蛋白(DBP)的亲和力，A>；G，EA，EG；靶基因反式激活，EA>；F>；EG G；细胞分化，EA>；F>；A>；EG G；骨钙动员，EA>；G A>；F EG；肠道钙吸收，EA=G>；>；EG。在第三部分中，描述了VDR-LBD的同源建模和天然配体1，25-(OH)2D3在模型的配体结合腔中的对接。鉴定了与生物上重要的1α和25-羟基形成氢键的氨基酸残基：1α-OH与R274和S237形成钳形氢键，25-OH与H397形成钳形氢键。突变分析证实了VDR-LBD/1，25-(OH)2D3对接模型。利用VDR模型对高效维生素D类似物的结构与功能关系进行了讨论。
In the first section, the general three-dimensional structure of the ligand-binding domain (LBD) of nuclear receptors (NR) was briefly described on the basis of their x-ray crystal structures. Emphasis was placed on the three major conformations of NR-LBD and their role in the transactivation function. In the second part, the structure-function relationship of vitamin D was analyzed based on the ligand structure, in particular by using systematic conformational analysis as a tool. On the basis of the conformational analysis of the vitamin D side chain and studies using conformationally restricted synthetic vitamin D analogs, we suggested the active space region concept of vitamin D: The vitamin D side-chain region was grouped into five regions (A, G, EA, EG and F). Activity orders, in terms of the spatial region, found by these studies are as follows: Affinity for vitamin D receptor (VDR), EA>A>F>G>EG; Affinity for vitamin D binding protein (DBP), A>>G,EA, EG; Target gene transactivation, EA>F>A>EG G; Cell differentiation, EA>F>A>EG G; Bone calcium mobilization, EA>G A>F EG; Intestinal calcium absorption, EA=A G>>EG. In the third section, homology modeling of VDR-LBD and docking of the natural ligand, 1,25-(OH)2D3, into the ligand binding cavity of the model are described. Amino acid residues forming hydrogen bonds with the biologically important 1alpha- and 25-OH groups were identified: 1alpha-OH forms a pincer-type hydrogen bond with R274 and S237 and 25-OH with H397. This VDR-LBD/1,25-(OH)2D3 docking model was firmly substantiated by mutation analysis. Using this VDR model, the structure-function relationship of highly potent vitamin D analogs was discussed.