title: Structure-function analysis of vitamin D and VDR model.
abstract: 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.
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo, 101-0062, Japan. yamada@i-mde.tmd.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Yamada
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: H
authors.initials: H
authors.lastname: Masuno
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D018167:Receptors, Calcitriol / Q000737:chemistry* / Q000502:physiology; D013329:Structure-Activity Relationship; D014807:Vitamin D / Q000737:chemistry* / Q000502:physiology
chemical_list: D018167:Receptors, Calcitriol; D014807:Vitamin D; D002118:Calcium