1N46

CRYSTAL STRUCTURE OF HUMAN TR BETA LIGAND-BINDING DOMAIN COMPLEXED WITH A POTENT SUBTYPE-SELECTIVE THYROMIMETIC


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.195 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Discovery of a Novel Series of 6-Azauracil-Based Thyroid Hormone Receptor Ligands: Potent, TRbeta Subtype-Selective Thyromimetics

Dow, R.L.Schneider, S.R.Paight, E.S.Hank, R.F.Chiang, P.Cornelius, P.Lee, E.Newsome, W.P.Swick, A.G.Spitzer, J.Hargrove, D.M.Patterson, T.A.Pandit, J.Chrunyk, B.A.LeMotte, P.K.Danley, D.E.Rosner, M.H.Ammirati, M.J.Simons, S.P.Schulte, G.K.Tate, B.F.DaSilva-Jardine, P.

(2003) Bioorg Med Chem Lett 13: 379-382

  • DOI: https://doi.org/10.1016/s0960-894x(02)00947-2
  • Primary Citation of Related Structures:  
    1N46

  • PubMed Abstract: 

    In this communication, we wish to describe the discovery of a novel series of 6-azauracil-based thyromimetics that possess up to 100-fold selectivities for binding and functional activation of the beta(1)-isoform of the thyroid receptor family. Structure-activity relationship studies on the 3,5- and 3'-positions provided compounds with enhanced TR beta affinity and selectivity. Key binding interactions between the 6-azauracil moiety and the receptor have been determined through of X-ray crystallographic analysis.


  • Organizational Affiliation

    Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, CT 06340, USA. robert_l_dow@groton.pfizer.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Thyroid hormone receptor Beta-1
A, B
258Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P10828 (Homo sapiens)
Explore P10828 
Go to UniProtKB:  P10828
PHAROS:  P10828
GTEx:  ENSG00000151090 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP10828
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
PFA
Query on PFA

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
[4-(4-HYDROXY-3-ISOPROPYL-PHENOXY)-3,5-DIMETHYL-PHENYL]-6-AZAURACIL
C20 H21 N3 O4
RXQAVKWRCZYGMV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
PFA Binding MOAD:  1N46 Ki: 0.03 (nM) from 1 assay(s)
PDBBind:  1N46 Ki: 0.03 (nM) from 1 assay(s)
BindingDB:  1N46 Ki: 0.03 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.195 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.918α = 90
b = 105.315β = 98.19
c = 55.988γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
REFMACrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2003-04-22
    Type: Initial release
  • Version 1.1: 2008-04-28
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2018-01-31
    Changes: Experimental preparation
  • Version 1.4: 2018-04-04
    Changes: Data collection
  • Version 1.5: 2024-02-14
    Changes: Data collection, Database references, Derived calculations, Refinement description