3AFR

Crystal Structure of VDR-LBD/22S-Butyl-1a,24R-dihydroxyvitamin D3 complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.216 

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This is version 1.3 of the entry. See complete history


Literature

22S-Butyl-1alpha,24R-dihydroxyvitamin D(3): Recovery of vitamin D receptor agonistic activity

Inaba, Y.Nakabayashi, M.Itoh, T.Yoshimoto, N.Ikura, T.Ito, N.Shimizu, M.Yamamoto, K.

(2010) J Steroid Biochem Mol Biol 121: 146-150

  • DOI: https://doi.org/10.1016/j.jsbmb.2010.02.033
  • Primary Citation of Related Structures:  
    3AFR

  • PubMed Abstract: 

    We recently reported that 22S-butyl-1alpha,24R-dihydroxyvitamin D(3)3 recovers the agonistic activity for vitamin D receptor (VDR), although its 25,26,27-trinor analog 2 is a potent VDR antagonist. To investigate the structural features involved in the recovery of agonism, we crystallized the ternary complex of VDR-ligand-binding domain, ligand 3 and coactivator peptide, and conducted X-ray crystallographic analysis of the complex. Compared with the complex with 2, the complex with 3 recovered the following structural features: a pincer-type hydrogen bond between the 24-hydroxyl group and VDR, the conformation of Leu305, the positioning of His301 and His393, the stability of the complex, and intimate hydrophobic interactions between the ligand and helix 12. In addition, we evaluated the potency of both compounds for recruiting RXR and coactivator. The results indicate that the complex with 3 generates a suitable surface for coactivator recruitment. These studies suggest that the action of 2 as an antagonist is caused by the generation of a surface not suitable for coactivator recruitment due to the lack of hydrophobic interactions with helix 12 as well as insufficient hydrogen bond formation between the 24-hydroxyl group and VDR. We concluded that the action of 3 as an agonist is based on the elimination of these structural defects in the complex with 2.


  • 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 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
13-meric peptide from Mediator of RNA polymerase II transcription subunit 1B [auth C]13Xenopus tropicalisMutation(s): 0 
UniProt
Find proteins for A1L0Z0 (Xenopus tropicalis)
Explore A1L0Z0 
Go to UniProtKB:  A1L0Z0
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA1L0Z0
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ICJ
Query on ICJ

Download Ideal Coordinates CCD File 
C [auth A](1R,3S,5Z)-5-[(2E)-2-{(1R,3aS,7aR)-1-[(1R,2S,4R)-2-butyl-4-hydroxy-1,5-dimethylhexyl]-7a-methyloctahydro-4H-inden-4-yli dene}ethylidene]-4-methylidenecyclohexane-1,3-diol
C31 H52 O3
CJFXAKUNOBKWSJ-ZUNQKOJFSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.216 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 153.448α = 90
b = 43.394β = 95.341
c = 41.992γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
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: 2010-03-31
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-10-11
    Changes: Refinement description
  • Version 1.3: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary