3DR1

Side-chain fluorine atoms of non-steroidal vitamin D3 analogs stabilize helix 12 of vitamin D receptor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.286 
  • R-Value Work: 0.226 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Superagonistic fluorinated vitamin D3 analogs stabilize helix 12 of the vitamin D receptor.

Eelen, G.Valle, N.Sato, Y.Rochel, N.Verlinden, L.De Clercq, P.Moras, D.Bouillon, R.Munoz, A.Verstuyf, A.

(2008) Chem Biol 15: 1029-1034

  • DOI: https://doi.org/10.1016/j.chembiol.2008.08.008
  • Primary Citation of Related Structures:  
    3DR1

  • PubMed Abstract: 

    Side chain fluorination is often used to make analogs of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] resistant to degradation by 24-hydroxylase. The fluorinated nonsteroidal analogs CD578, WU515, and WY1113 have an increased prodifferentiating action on SW480-ADH colon cancer cells, which correlated with stronger induction of vitamin D receptor (VDR)-coactivator interactions and stronger repression of beta-catenin/TCF activity. Cocrystallization of analog CD578 with the zebrafish (z)VDR and an SRC-1 coactivator peptide showed that the fluorine atoms of CD578 make additional contacts with Val444 and Phe448 of activation helix 12 (H12) of the zVDR and with Leu440 of the H11-H12 loop. Consequently, the SRC-1 peptide makes more contacts with the VDR-CD578 complex than with the VDR-1,25(OH)2D3 complex. These data show that fluorination not only affects degradation of an analog but can also have direct effects on H12 stabilization.


  • Organizational Affiliation

    LEGENDO, K.U. Leuven, B-3000 Leuven, Belgium.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Vitamin D3 receptor A302Danio 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
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
SRC-1 (LXXLL motif) from Nuclear receptor coactivator 115Homo sapiensMutation(s): 0 
EC: 2.3.1.48
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
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  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
C5D
Query on C5D

Download Ideal Coordinates CCD File 
D [auth A](1R,3R)-5-[(2E)-3-{(1S,3R)-2,2,3-trimethyl-3-[6,6,6-trifluoro-5-hydroxy-5-(trifluoromethyl)hex-3-yn-1-yl]cyclopentyl}prop-2-en-1-ylidene]cyclohexane-1,3-diol
C24 H32 F6 O3
PCHUQQNKOFNVDU-OSXMSNBXSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
C [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.286 
  • R-Value Work: 0.226 
  • Space Group: P 65 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 66.1α = 90
b = 66.1β = 90
c = 265.6γ = 120
Software Package:
Software NamePurpose
HKL-2000data collection
CNSrefinement
HKL-2000data reduction
SCALAdata scaling
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-06-16
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2021-03-03
    Changes: Database references, Derived calculations, Source and taxonomy
  • Version 1.3: 2023-11-01
    Changes: Data collection, Database references, Refinement description