1XZX

Thyroxine-Thyroid Hormone Receptor Interactions


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.191 

wwPDB Validation   3D Report Full Report


This is version 2.0 of the entry. See complete history


Literature

Thyroxine-thyroid hormone receptor interactions.

Sandler, B.Webb, P.Apriletti, J.W.Huber, B.R.Togashi, M.Cunha Lima, S.T.Juric, S.Nilsson, S.Wagner, R.Fletterick, R.J.Baxter, J.D.

(2004) J Biol Chem 279: 55801-55808

  • DOI: https://doi.org/10.1074/jbc.M410124200
  • Primary Citation of Related Structures:  
    1XZX, 1Y0X

  • PubMed Abstract: 

    Thyroid hormone (TH) actions are mediated by nuclear receptors (TRs alpha and beta) that bind triiodothyronine (T(3), 3,5,3'-triiodo-l-thyronine) with high affinity, and its precursor thyroxine (T(4), 3,5,3',5'-tetraiodo-l-thyronine) with lower affinity. T(4) contains a bulky 5' iodine group absent from T(3). Because T(3) is buried in the core of the ligand binding domain (LBD), we have predicted that TH analogues with 5' substituents should fit poorly into the ligand binding pocket and perhaps behave as antagonists. We therefore examined how T(4) affects TR activity and conformation. We obtained several lines of evidence (ligand dissociation kinetics, migration on hydrophobic interaction columns, and non-denaturing gels) that TR-T(4) complexes adopt a conformation that differs from TR-T(3) complexes in solution. Nonetheless, T(4) behaves as an agonist in vitro (in effects on coregulator and DNA binding) and in cells, when conversion to T(3) does not contribute to agonist activity. We determined x-ray crystal structures of the TRbeta LBD in complex with T(3) and T(4) at 2.5-A and 3.1-A resolution. Comparison of the structures reveals that TRbeta accommodates T(4) through subtle alterations in the loop connecting helices 11 and 12 and amino acid side chains in the pocket, which, together, enlarge a niche that permits helix 12 to pack over the 5' iodine and complete the coactivator binding surface. While T(3) is the major active TH, our results suggest that T(4) could activate nuclear TRs at appropriate concentrations. The ability of TR to adapt to the 5' extension should be considered in TR ligand design.


  • Organizational Affiliation

    Metabolic Research Unit and Diabetes Center, School of Medicine, University of California-San Francisco, 513 Parnassus Avenue, San Francisco, CA 94122-0540, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Thyroid hormone receptor beta-1A [auth X]281Homo sapiensMutation(s): 0 
Gene Names: THRBERBA2NR1A2THR1
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
Binding Affinity Annotations 
IDSourceBinding Affinity
T3 BindingDB:  1XZX Ki: min: 0.08, max: 2.3 (nM) from 5 assay(s)
Kd: min: 0.08, max: 0.14 (nM) from 4 assay(s)
IC50: min: 0.26, max: 500 (nM) from 5 assay(s)
EC50: min: 1.49, max: 15 (nM) from 5 assay(s)
Binding MOAD:  1XZX Kd: 0.06 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.191 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.764α = 90
b = 68.764β = 90
c = 130.943γ = 120
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
EPMRphasing

Structure Validation

View Full Validation Report



Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2004-12-07
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Derived calculations, Version format compliance
  • Version 1.3: 2017-10-11
    Changes: Refinement description
  • Version 2.0: 2023-11-15
    Changes: Atomic model, Data collection, Database references, Derived calculations