5E7V

Potent Vitamin D Receptor Agonist

5E7V の概要

• エントリーDOI: 10.2210/pdb5e7v/pdb
• 分子名称: Vitamin D3 receptor A, Nuclear receptor coactivator 1, 1-ALPHA-HYDROXY-27-NOR-25-O-CARBONYL-VITAMIN D3, ... (4 entities in total)
• 機能のキーワード: transcription, vitamin d nuclear receptor, vdr, ligand binding domain
• 由来する生物種: Danio rerio (Zebrafish); 詳細
• 細胞内の位置: Nucleus: Q9PTN2
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 36182.30

構造登録者

Otero, R.,Seoane, S.,Sigueiro, R.,Belorusova, A.Y.,Maestro, M.A.,Perez-Fernandez, R.,Rochel, N.,Mourino, A. (登録日: 2015-10-13, 公開日: 2015-11-25, 最終更新日: 2024-01-10)

主引用文献

Otero, R.,Seoane, S.,Sigueiro, R.,Belorusova, A.Y.,Maestro, M.A.,Perez-Fernandez, R.,Rochel, N.,Mourino, A.
Carborane-based design of a potent vitamin D receptor agonist.
Chem Sci, 7:1033-1037, 2016

PubMed Abstract: The vitamin D nuclear receptor (VDR) is a potential target for cancer therapy. It is expressed in many tumors and its ligand shows anticancer actions. To combine these properties with the application of boron neutron capture therapy (BNCT), we design and synthesize a potent VDR agonist based on the skeleton of the hormone 1α,25-dihydroxyvitamin D (1,25D) and an -carborane (dicarba--1,2-dodecaborane) at the end of its side chain. The present ligand is the first secosteroidal analog with the carborane unit that efficiently binds to VDR and functions as an agonist with 1,25D-like potency in transcriptional assay on vitamin D target genes. Moreover it exhibits similar antiproliferative and pro-differentiating activities but is significantly less hypercalcemic than 1,25D. The crystal structure of its complex with VDR ligand binding domain reveals its binding mechanism involving boron-mediated dihydrogen bonds that mimic vitamin D hydroxyl interactions. In addition to the therapeutic interest, this study establishes the basis for the design of new unconventional vitamin D analogs containing carborane moieties for specific molecular recognition, and drug research and development.

PubMed: 28808527
DOI: 10.1039/c5sc03084f

実験手法

X-RAY DIFFRACTION (2.4 Å)