3WT5

A mixed population of antagonist and agonist binding conformers in a single crystal explains partial agonism against vitamin D receptor: Active vitamin D analogues with 22R-alkyl group


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.189 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.164 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

A Mixed Population of Antagonist and Agonist Binding Conformers in a Single Crystal Explains Partial Agonism against Vitamin D Receptor: Active Vitamin D Analogues with 22R-Alkyl Group.

Anami, Y.Itoh, T.Egawa, D.Yoshimoto, N.Yamamoto, K.

(2014) J Med Chem 57: 4351-4367

  • DOI: https://doi.org/10.1021/jm500392t
  • Primary Citation of Related Structures:  
    3WT5, 3WT6, 3WT7

  • PubMed Abstract: 

    We are continuing to study the structural basis of vitamin D receptor (VDR) agonism and antagonism by using 22S-alkyl vitamin D analogues. Here we report the synthesis and biological evaluation of 22R-alkyl analogues and the X-ray crystallographic analysis of vitamin D receptor ligand-binding domain (VDR-LBD) complexed with a 22R-analogue. VDR-LBD complexed with the partial agonist 8a showed that 8a binds to VDR-LBD with two conformations, one of which is the antagonist/VDR-LBD complex structure and the other is the agonist/VDR-LBD complex structure. The results indicate that the partial agonist activity of 8a depends on the sum of antagonistic and agonistic activities caused by the antagonist and agonist binding conformers, respectively. The structural basis observed here must be applicable to the partial agonism of other ligand-dependent nuclear receptors. This is the first report describing the trapping of a conformational subset of the ligand and the nuclear receptor in a single crystal.


  • 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 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

Find similar proteins by:  Sequence   |   3D Structure  

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
YA1
Query on YA1

Download Ideal Coordinates CCD File 
C [auth A](1R,3R,7E,17beta)-17-[(2R,3R)-3-butyl-6-hydroxy-6-methylheptan-2-yl]-2-methylidene-9,10-secoestra-5,7-diene-1,3-diol
C31 H52 O3
RSXHMKSDJHHTDU-PJSVQGINSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
YA1 Binding MOAD:  3WT5 IC50: 0.29 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.189 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.164 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 127.84α = 90
b = 44.81β = 93.57
c = 46.06γ = 90
Software Package:
Software NamePurpose
SERGUIdata collection
REFMACrefinement
MOSFLMdata reduction
SCALAdata 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: 2014-06-11
    Type: Initial release
  • Version 1.1: 2017-11-22
    Changes: Refinement description
  • Version 1.2: 2024-03-20
    Changes: Data collection, Database references, Derived calculations