3VTD

Crystal structure of rat vitamin D receptor bound to a partial agonist 26-adamantyl-23-yne-19-norvitammin D ADTK4


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.278 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.213 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Combination of Triple Bond and Adamantane Ring on the Vitamin D Side Chain Produced Partial Agonists for Vitamin D Receptor.

Kudo, T.Ishizawa, M.Maekawa, K.Nakabayashi, M.Watarai, Y.Uchida, H.Tokiwa, H.Ikura, T.Ito, N.Makishima, M.Yamada, S.

(2014) J Med Chem 

  • DOI: https://doi.org/10.1021/jm401989c
  • Primary Citation of Related Structures:  
    3VTB, 3VTC, 3VTD

  • PubMed Abstract: 

    Vitamin D receptor (VDR) ligands are therapeutic agents that are used for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism and have immense potential as therapeutic agents for autoimmune diseases, cancers, and cardiovascular diseases. However, the major side effect of VDR ligands, the development of hypercalcemia, limits their expanded use. To develop tissue-selective VDR modulators, we have designed vitamin D analogues with an adamantane ring at the side chain terminal, which would interfere with helix 12, the activation function 2, and modulate the VDR potency. Here we report 25- or 26-adamantyl-23,23,24,24-tetradehydro-19-norvitamin D derivatives (ADTK1-4, 4b,a and 5a,b). These compounds showed high VDR affinities (90% at maximum), partial agonistic activities (EC50 10(-9)-10(-8) M with 40-80% efficacy) in transactivation, and tissue-selective activity in target gene expressions. We investigate the structure-activity relationships of these compounds on the basis of their X-ray crystal structures.


  • Organizational Affiliation

    Department of Chemistry, ‡Research Center for Smart Molecules, Faculty of Science, Rikkyo University , Toshima-ku, Tokyo 171-8501, 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: Nr1i1Vdr
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
COACTIVATOR PEPTIDE DRIP13N/AMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
TKD
Query on TKD

Download Ideal Coordinates CCD File 
C [auth A](1R,3R,7E,17beta)-17-{(2R,6S)-6-hydroxy-7-[(3S,5S,7S)-tricyclo[3.3.1.1~3,7~]dec-1-yl]hept-4-yn-2-yl}-2-methylidene-9,10-secoestra-5,7-diene-1,3-diol
C36 H52 O3
UFJLHOSCLNTAFF-OLECLGHFSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.278 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.213 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 153.178α = 90
b = 43.897β = 95.73
c = 42.526γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
CNSrefinement
HKL-2000data reduction
HKL-2000data 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: 2013-06-12
    Type: Initial release
  • Version 1.1: 2014-05-14
    Changes: Database references
  • Version 1.2: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description