5E7V

Potent Vitamin D Receptor Agonist

Summary for 5E7V

• Entry DOI: 10.2210/pdb5e7v/pdb
• Descriptor: Vitamin D3 receptor A, Nuclear receptor coactivator 1, 1-ALPHA-HYDROXY-27-NOR-25-O-CARBONYL-VITAMIN D3, ... (4 entities in total)
• Functional Keywords: transcription, vitamin d nuclear receptor, vdr, ligand binding domain
• Biological source: Danio rerio (Zebrafish); More
• Cellular location: Nucleus: Q9PTN2
• Total number of polymer chains: 2
• Total formula weight: 36182.30

Authors

Otero, R.,Seoane, S.,Sigueiro, R.,Belorusova, A.Y.,Maestro, M.A.,Perez-Fernandez, R.,Rochel, N.,Mourino, A. (deposition date: 2015-10-13, release date: 2015-11-25, Last modification date: 2024-01-10)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.4 Å)