3JZC

Crystal Structure of TR-beta bound to the selective thyromimetic TRIAC


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.200 

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Literature

Gaining ligand selectivity in thyroid hormone receptors via entropy.

Martinez, L.Nascimento, A.S.Nunes, F.M.Phillips, K.Aparicio, R.Dias, S.M.Figueira, A.C.Lin, J.H.Nguyen, P.Apriletti, J.W.Neves, F.A.Baxter, J.D.Webb, P.Skaf, M.S.Polikarpov, I.

(2009) Proc Natl Acad Sci U S A 106: 20717-20722

  • DOI: https://doi.org/10.1073/pnas.0911024106
  • Primary Citation of Related Structures:  
    3JZB, 3JZC

  • PubMed Abstract: 

    Nuclear receptors are important targets for pharmaceuticals, but similarities between family members cause difficulties in obtaining highly selective compounds. Synthetic ligands that are selective for thyroid hormone (TH) receptor beta (TRbeta) vs. TRalpha reduce cholesterol and fat without effects on heart rate; thus, it is important to understand TRbeta-selective binding. Binding of 3 selective ligands (GC-1, KB141, and GC-24) is characterized at the atomic level; preferential binding depends on a nonconserved residue (Asn-331beta) in the TRbeta ligand-binding cavity (LBC), and GC-24 gains extra selectivity from insertion of a bulky side group into an extension of the LBC that only opens up with this ligand. Here we report that the natural TH 3,5,3'-triodothyroacetic acid (Triac) exhibits a previously unrecognized mechanism of TRbeta selectivity. TR x-ray structures reveal better fit of ligand with the TRalpha LBC. The TRbeta LBC, however, expands relative to TRalpha in the presence of Triac (549 A(3) vs. 461 A(3)), and molecular dynamics simulations reveal that water occupies the extra space. Increased solvation compensates for weaker interactions of ligand with TRbeta and permits greater flexibility of the Triac carboxylate group in TRbeta than in TRalpha. We propose that this effect results in lower entropic restraint and decreases free energy of interactions between Triac and TRbeta, explaining subtype-selective binding. Similar effects could potentially be exploited in nuclear receptor drug design.


  • Organizational Affiliation

    Instituto de Química, Universidade Estadual de Campinas, SP 13084-862, Campinas, Brazil.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Thyroid hormone receptor beta263Homo 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
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4HY
Query on 4HY

Download Ideal Coordinates CCD File 
B [auth A][4-(4-HYDROXY-3-IODO-PHENOXY)-3,5-DIIODO-PHENYL]-ACETIC ACID
C14 H9 I3 O4
UOWZUVNAGUAEQC-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CAS
Query on CAS
A
L-PEPTIDE LINKINGC5 H12 As N O2 SCYS
Binding Affinity Annotations 
IDSourceBinding Affinity
4HY BindingDB:  3JZC IC50: min: 0.04, max: 0.15 (nM) from 4 assay(s)
PDBBind:  3JZC IC50: 2.94 (nM) from 1 assay(s)
Binding MOAD:  3JZC IC50: 1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.200 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.781α = 90
b = 68.781β = 90
c = 131.013γ = 120
Software Package:
Software NamePurpose
MAR345dtbdata collection
MOLREPphasing
PHENIXrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-12-08
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description