Authors: Yamada, S.; Yamamoto, K.; Masuno, H.

Source: Current Pharmaceutical Design, Volume 6, Number 7, May 2000 , pp. 733-748(16)

Publisher: Bentham Science Publishers

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

Document Type: Research article

Affiliations: 1: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku Tokyo 101-0062, Japan

Publication date: 2000-05-01

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  Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.

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