5B5B

Crystal structure of VDR-LBD complexed with 2-methylidene-26,27-diphenyl-19-nor-1,25-dihydroxyvitamin D3


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.183 

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This is version 1.3 of the entry. See complete history


Literature

Helix12-Stabilization Antagonist of Vitamin D Receptor

Kato, A.Itoh, T.Anami, Y.Egawa, D.Yamamoto, K.

(2016) Bioconjug Chem 27: 1750-1761

  • DOI: https://doi.org/10.1021/acs.bioconjchem.6b00246
  • Primary Citation of Related Structures:  
    5B5B

  • PubMed Abstract: 

    To develop strong vitamin D receptor (VDR) antagonists and reveal their antagonistic mechanism, we designed and synthesized vitamin D analogues with bulky side chains based on the "active antagonist" concept in which antagonist prevents helix 12 (H12) folding. Of the synthesized analogues, compounds 3a and 3b showed strong antagonistic activity. Dynamic hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS) and static X-ray crystal structure analyses indicated that compound 3a stabilizes H11-H12 but displaces H6-H7 so that 3a is a novel rather than "active" or "passive" type of antagonist. We classified 3a as a third type of antagonist and called it "H11-H12 stabilization antagonist". HDX-MS analysis indicated that antagonist 3b is an "active" antagonist. To date there are no reports relating to nuclear receptor antagonist that strongly stabilizes H12. In this study, we found first VDR antagonist that stabilizes H12 and we showed that antagonistic mechanism is diverse depending on each antagonist structure. Additionally, HDX-MS was proven to be very useful for investigations of protein structure alterations resulting from ligand binding.


  • Organizational Affiliation

    Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University , 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Vitamin D3 receptorA,
C [auth D]
271Rattus norvegicusMutation(s): 0 
Gene Names: VdrNr1i1
UniProt
Find proteins for P13053 (Rattus norvegicus)
Explore P13053 
Go to UniProtKB:  P13053
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP13053
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Mediator of RNA polymerase II transcription subunit 1B [auth C],
D [auth F]
13Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q15648 (Homo sapiens)
Explore Q15648 
Go to UniProtKB:  Q15648
PHAROS:  Q15648
GTEx:  ENSG00000125686 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ15648
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
AKX
Query on AKX

Download Ideal Coordinates CCD File 
E [auth A],
F [auth D]
(1R,3R)-5-[(2E)-2-[(1R,3aS,7aR)-7a-methyl-1-[(2R)-6-oxidanyl-7-phenyl-6-(phenylmethyl)heptan-2-yl]-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-2-methylidene-cyclohexane-1,3-diol
C39 H52 O3
RRDOSUMZWOEOPZ-BYWDIONYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
AKX Binding MOAD:  5B5B IC50: 0.43 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.183 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 154.06α = 90
b = 41.49β = 97.44
c = 83.89γ = 90
Software Package:
Software NamePurpose
REFMACrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-06-29
    Type: Initial release
  • Version 1.1: 2016-08-03
    Changes: Database references
  • Version 1.2: 2020-02-26
    Changes: Data collection, Database references, Derived calculations
  • Version 1.3: 2024-03-20
    Changes: Data collection, Database references