5E7V

Potent Vitamin D Receptor Agonist


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.187 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Carborane-based design of a potent vitamin D receptor agonist.

Otero, R.Seoane, S.Sigueiro, R.Belorusova, A.Y.Maestro, M.A.Perez-Fernandez, R.Rochel, N.Mourino, A.

(2016) Chem Sci 7: 1033-1037

  • DOI: https://doi.org/10.1039/c5sc03084f
  • Primary Citation of Related Structures:  
    5E7V

  • 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 3 (1,25D) and an o -carborane (dicarba- o-closo -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.


  • Organizational Affiliation

    Departamento de Química Orgánica , Laboratorio de Investigación Ignacio Ribas , Universidad de Santiago de Compostela , Avda. Ciencias s/n , 15782 Santiago de Compostela , Spain . Email: antonio.mourino@usc.es.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Vitamin D3 receptor A300Danio rerioMutation(s): 0 
Gene Names: vdranr1i1avdr
UniProt
Find proteins for Q9PTN2 (Danio rerio)
Explore Q9PTN2 
Go to UniProtKB:  Q9PTN2
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9PTN2
Sequence Annotations
Expand
  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor coactivator 115Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q15788 (Homo sapiens)
Explore Q15788 
Go to UniProtKB:  Q15788
PHAROS:  Q15788
GTEx:  ENSG00000084676 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ15788
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
M7E
Query on M7E

Download Ideal Coordinates CCD File 
C [auth A]1-ALPHA-HYDROXY-27-NOR-25-O-CARBONYL-VITAMIN D3
C26 H37 B10 O2
AHSCVXNUZMYYOY-UUSULHAXSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
M7E Binding MOAD:  5E7V IC50: 2.9 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.187 
  • Space Group: P 65 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 66.49α = 90
b = 66.49β = 90
c = 263.34γ = 120
Software Package:
Software NamePurpose
BUSTERrefinement
HKL-2000data reduction
HKL-2000data scaling
BUSTERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
French National Research AgencyFranceANR-13-BSV8-0024-01

Revision History  (Full details and data files)

  • Version 1.0: 2015-11-25
    Type: Initial release
  • Version 1.1: 2017-08-30
    Changes: Database references
  • Version 1.2: 2017-09-06
    Changes: Author supporting evidence
  • Version 1.3: 2021-02-24
    Changes: Derived calculations
  • Version 1.4: 2024-01-10
    Changes: Data collection, Database references, Refinement description