2ZXM

A New Class of Vitamin D Receptor Ligands that Induce Structural Rearrangement of the Ligand-binding Pocket


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.01 Å
  • R-Value Free: 0.295 
  • R-Value Work: 0.226 
  • R-Value Observed: 0.226 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

A New Class of Vitamin D Analogues that Induce Structural Rearrangement of the Ligand-Binding Pocket of the Receptor

Inaba, Y.Yoshimoto, N.Sakamaki, Y.Nakabayashi, M.Ikura, T.Tamamura, H.Ito, N.Shimizu, M.Yamamoto, K.

(2009) J Med Chem 52: 1438-1449

  • DOI: https://doi.org/10.1021/jm8014348
  • Primary Citation of Related Structures:  
    2ZXM, 2ZXN

  • PubMed Abstract: 

    To identify novel vitamin D receptor (VDR) ligands that induce a novel architecture within the ligand-binding pocket (LBP), we have investigated eight 22-butyl-1alpha,24-dihydroxyvitamin D(3) derivatives (3-10), all having a butyl group as the branched alkyl side chain. We found that the 22S-butyl-20-epi-25,26,27-trinorvitamin D derivative 5 was a potent VDR agonist, whereas the corresponding compound 4 with the natural configuration at C(20) was a potent VDR antagonist. Analogues with the full vitamin D(3) side chain were less potent agonist, and whether they were agonists or antagonists depended on the 24-configuration. X-ray crystal structures demonstrated that the VDR-LBD accommodating the potent agonist 5 has an architecture wherein the lower side and the helix 11 side of the LBP is simply expanded relative to the canonical active-VDR situation; in contrast, the potent antagonist 4 induces an extra cavity to accommodate the branched moiety. This is the first report of a VDR antagonist that generates a new cavity to alter the canonical pocket structure of the ligand occupied VDR.


  • Organizational Affiliation

    Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, Tokyo, 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
Mediator of RNA polymerase II transcription subunit 1B [auth C]13N/AMutation(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
JB1
Query on JB1

Download Ideal Coordinates CCD File 
C [auth A](1R,3S,5Z)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(2R,3S)-3-(2-hydroxyethyl)heptan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-4-methylidene-cyclohexane-1,3-diol
C28 H46 O3
MBUIFNPNESWHQQ-LGKYDQOKSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.01 Å
  • R-Value Free: 0.295 
  • R-Value Work: 0.226 
  • R-Value Observed: 0.226 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 153.252α = 90
b = 43.424β = 95.97
c = 42.369γ = 90
Software Package:
Software NamePurpose
CNSrefinement
HKL-2000data collection
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: 2009-02-17
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description