5AWJ

Crystal structure of VDR-LBD/partial agonist complex: 22S-hexyl analogue


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.260 
  • R-Value Work: 0.214 
  • R-Value Observed: 0.216 

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This is version 1.2 of the entry. See complete history


Literature

Fine tuning of agonistic/antagonistic activity for vitamin D receptor by 22-alkyl chain length of ligands: 22S-Hexyl compound unexpectedly restored agonistic activity.

Anami, Y.Sakamaki, Y.Itoh, T.Inaba, Y.Nakabayashi, M.Ikura, T.Ito, N.Yamamoto, K.

(2015) Bioorg Med Chem 23: 7274-7281

  • DOI: https://doi.org/10.1016/j.bmc.2015.10.026
  • Primary Citation of Related Structures:  
    5AWJ, 5AWK

  • PubMed Abstract: 

    1α,25-Dihydroxyvitamin D3 exerts its actions by binding to vitamin D receptor (VDR). We are continuing the study related to the alteration of pocket structure of VDR by 22-alkyl substituent of ligands and the relationships between the alteration and agonistic/antagonistic activity. Previously we reported that compounds 2 (22-H), 3 (22S-Et), and 4 (22S-Bu) are VDR agonist, partial agonist and antagonist, respectively. Here, we describe the synthesis and biological evaluation of 22S-hexyl analog 5 (22S-Hex), which was designed to be a stronger VDR antagonist than 4. Unexpectedly, 5 showed partial agonistic but not antagonistic activity when bound to VDR, indicating that it is not necessarily true that the bulkier the side chain is, the stronger the antagonistic activity will be. X-ray crystallographic analysis of the VDR-ligand-binding domain (VDR-LBD) accommodating compound 5 indicated that the partial agonist activity of 5 is dependent on the mixed population of the agonistic and antagonistic conformations. Binding of compound 5 may not bring the complex into the only antagonistic conformation due to the large conformational change of the VDR-LBD. From this study it was found that fine tuning of agonistic/antagonistic activity for VDR is possible by 22-alkyl chain length of ligands.


  • Organizational Affiliation

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


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Vitamin D3 receptor,Vitamin D3 receptor271Rattus 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]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
YSL
Query on YSL

Download Ideal Coordinates CCD File 
C [auth A](1R,3R)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(2R,3S)-3-(2-hydroxyethyl)nonan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-2-methylidene-cyclohexane-1,3-diol
C30 H50 O3
JUQILRKVRIIJNO-FJOOTJEJSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
YSL Binding MOAD:  5AWJ IC50: 0.21 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.260 
  • R-Value Work: 0.214 
  • R-Value Observed: 0.216 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 153.477α = 90
b = 43.447β = 100.53
c = 42.317γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-11-18
    Type: Initial release
  • Version 1.1: 2020-02-26
    Changes: Data collection, Database references, Derived calculations
  • Version 1.2: 2024-03-20
    Changes: Data collection, Database references