Structure-Function Analysis of Vitamin D and VDR Model

S.      Yamada; K.      Yamamoto; H.      Masuno

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 struc-ture, 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), Affinity for vitamin D binding protein (DBP), Target gene transactivation, Cell differentiation, Bone calcium mobilization, Intestinal calcium absorption, In the third section, homology modeling of VDR-LBD and docking of the natural ligand, 1,25-(OH)2 D 3 , 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)2 D 3 docking model was firmly substantiated by mutation analysis. Using this VDR model, the structure-function relationship of highly potent vitamin D analogs was discussed.

Keywords: ligand binding domain LBD, nuclear receptors NR, NR LBD, DNA binding domain DBD, Transcriptional Activity, Ligand Docking, Mutational Analysis, Peroxisome proliferator activated receptor, Ligand binding pocket, Transactivation function 2, 4 Hydroxytamoxifen, Genistein, Wild type, Retinoid X receptor, Retinoic acid receptor, Thyroid hormone receptor, Estrogen receptors A and B, Progesterone receptor