Yamada Sachiko, Shimizu Masato, Yamamoto Keiko
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
Med Res Rev. 2003 Jan;23(1):89-115. doi: 10.1002/med.10023.
First, the general structure and function of nuclear receptors (NRs) are described briefly to help our understanding of the mechanism of action of vitamin D mediated by the vitamin D receptor (VDR), a member of the NRs. Then we discuss the structure-function relationship (SFR) of vitamin D on the basis of ligand structures and the interaction of the ligand with the VDR. The SFR of vitamin D side chain analogs is discussed extensively in terms of our active space group concept, which was derived from conformational analyses of the side chains of vitamin D analogs and from studies with conformationally restricted 22-methyl-1,25-(OH)(2)D(3) isomers. The mobile area of the side chain of vitamin D can be grouped into five regions (E, G, EA, EG, and F), and the SFR has been analyzed in terms of these spatial regions. The SFR of ligand/VDR interaction is discussed on the basis of the crystal structure of VDR-LBD(delta 165-215), docking of various vitamin D ligands into the ligand binding pocket (LBP) of the VDR, and functional analysis of amino acids lining the LBP. Finally, we discuss total SFR, combining the results of the two approaches, and future aspects of structure-based design of vitamin D analogs.
首先，简要描述核受体（NRs）的一般结构和功能，以帮助我们理解由NRs成员维生素D受体（VDR）介导的维生素D的作用机制。然后，我们根据配体结构以及配体与VDR的相互作用来讨论维生素D的结构-功能关系（SFR）。维生素D侧链类似物的SFR根据我们的活性空间组概念进行了广泛讨论，该概念源自维生素D类似物侧链的构象分析以及对构象受限的22-甲基-1,25-（OH）₂D₃异构体的研究。维生素D侧链的可移动区域可分为五个区域（E、G、EA、EG和F），并已根据这些空间区域对SFR进行了分析。基于VDR-LBD（δ165-215）的晶体结构、各种维生素D配体对接至VDR的配体结合口袋（LBP）以及对LBP内衬氨基酸的功能分析，讨论了配体/VDR相互作用的SFR。最后，我们结合两种方法的结果讨论总SFR以及维生素D类似物基于结构设计的未来发展方向。
