2PIN

Thyroid receptor beta in complex with inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.216 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Structural insight into the mode of action of a direct inhibitor of coregulator binding to the thyroid hormone receptor.

Estebanez-Perpina, E.Arnold, L.A.Jouravel, N.Togashi, M.Blethrow, J.Mar, E.Nguyen, P.Phillips, K.J.Baxter, J.D.Webb, P.Guy, R.K.Fletterick, R.J.

(2007) Mol Endocrinol 21: 2919-2928

  • DOI: https://doi.org/10.1210/me.2007-0174
  • Primary Citation of Related Structures:  
    2PIN

  • PubMed Abstract: 

    The development of nuclear hormone receptor antagonists that directly inhibit the association of the receptor with its essential coactivators would allow useful manipulation of nuclear hormone receptor signaling. We previously identified 3-(dibutylamino)-1-(4-hexylphenyl)-propan-1-one (DHPPA), an aromatic beta-amino ketone that inhibits coactivator recruitment to thyroid hormone receptor beta (TRbeta), in a high-throughput screen. Initial evidence suggested that the aromatic beta-enone 1-(4-hexylphenyl)-prop-2-en-1-one (HPPE), which alkylates a specific cysteine residue on the TRbeta surface, is liberated from DHPPA. Nevertheless, aspects of the mechanism and specificity of action of DHPPA remained unclear. Here, we report an x-ray structure of TRbeta with the inhibitor HPPE at 2.3-A resolution. Unreacted HPPE is located at the interface that normally mediates binding between TRbeta and its coactivator. Several lines of evidence, including experiments with TRbeta mutants and mass spectroscopic analysis, showed that HPPE specifically alkylates cysteine residue 298 of TRbeta, which is located near the activation function-2 pocket. We propose that this covalent adduct formation proceeds through a two-step mechanism: 1) beta-elimination to form HPPE; and 2) a covalent bond slowly forms between HPPE and TRbeta. DHPPA represents a novel class of potent TRbeta antagonist, and its crystal structure suggests new ways to design antagonists that target the assembly of nuclear hormone receptor gene-regulatory complexes and block transcription.


  • Organizational Affiliation

    Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2240, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Thyroid hormone receptor beta-1
A, B
253Homo sapiensMutation(s): 1 
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
4HY BindingDB:  2PIN IC50: min: 0.04, max: 0.15 (nM) from 4 assay(s)
LEG BindingDB:  2PIN IC50: 1500 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.216 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 55.13α = 90
b = 92.87β = 109.65
c = 58.35γ = 90
Software Package:
Software NamePurpose
ELVESrefinement
CNSrefinement
ELVESdata reduction
SCALAdata 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: 2008-02-26
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-10-18
    Changes: Refinement description
  • Version 1.3: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.4: 2024-02-21
    Changes: Data collection