3VRT

VDR ligand binding domain in complex with 2-Mehylidene-19,25,26,27-tetranor-1alpha,24-dihydroxyvitaminD3


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.273 
  • R-Value Work: 0.225 
  • R-Value Observed: 0.227 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Butyl pocket formation in the vitamin d receptor strongly affects the agonistic or antagonistic behavior of ligands

Yoshimoto, N.Sakamaki, Y.Haeta, M.Kato, A.Inaba, Y.Itoh, T.Nakabayashi, M.Ito, N.Yamamoto, K.

(2012) J Med Chem 55: 4373-4381

  • DOI: https://doi.org/10.1021/jm300230a
  • Primary Citation of Related Structures:  
    3VRT, 3VRU, 3VRV, 3VRW

  • PubMed Abstract: 

    Previously, we reported that 22S-butyl-25,26,27-trinor-1α,24-dihydroxyvitamin D(3)2 represents a new class of antagonist for the vitamin D receptor (VDR). The crystal structure of the ligand-binding domain (LBD) of VDR complexed with 2 showed the formation of a butyl pocket to accommodate the 22-butyl group and insufficient interactions between ligand 2 and the C-terminus of VDR. Here, we designed and synthesized new analogues 5a-c and evaluated their biological activities to probe whether agonistic activity is recovered when the analogue restores interactions with the C-terminus of VDR. Analogues 5a-c exhibited full agonistic activity in transactivation. Interestingly, 5c, which bears a 24-diethyl group, completely recovered agonistic activity, although 3c and 4c act as an antagonist and a weak agonist, respectively. The crystal structures of VDR-LBD complexed with 3a, 4a, 5a, and 5c were solved, and the results confirmed that butyl pocket formation in VDR strongly affects the agonistic or antagonistic behaviors 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 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
13-meric peptide from 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
YS2
Query on YS2

Download Ideal Coordinates CCD File 
C [auth A](1R,3R,7E,17beta)-17-[(2R)-5-hydroxypentan-2-yl]-2-methylidene-9,10-secoestra-5,7-diene-1,3-diol
C24 H38 O3
JPGZPBYJMAWTHF-HCMYXCKPSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
YS2 Binding MOAD:  3VRT IC50: 2.7 (nM) from 1 assay(s)
PDBBind:  3VRT IC50: 2.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.273 
  • R-Value Work: 0.225 
  • R-Value Observed: 0.227 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 152.988α = 90
b = 43.867β = 95.94
c = 42.428γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
CNSrefinement
REFMACrefinement
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: 2012-05-23
    Type: Initial release
  • Version 1.1: 2024-03-20
    Changes: Data collection, Database references, Derived calculations