1NQ1

TR Receptor Mutations Conferring Hormone Resistance and Reduced Corepressor Release Exhibit Decreased Stability in the Nterminal LBD


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.287 
  • R-Value Work: 0.239 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Thyroid hormone receptor-beta mutations conferring hormone resistance and reduced corepressor release exhibit decreased stability in the N-terminal ligand-binding domain

Huber, B.R.Desclozeaux, M.West, B.L.Cunha-Lima, S.T.Nguyen, H.T.Baxter, J.D.Ingraham, H.A.Fletterick, R.J.

(2003) Mol Endocrinol 17: 107-116

  • DOI: https://doi.org/10.1210/me.2002-0097
  • Primary Citation of Related Structures:  
    1NQ0, 1NQ1

  • PubMed Abstract: 

    Resistance to thyroid hormone (RTH) syndrome is associated with mutations in the human thyroid hormone receptor-beta (hTRbeta), many of which show marked reduction in hormone binding. Here, we investigated the structural consequences of two RTH mutants (A234T and R243Q), residing in the flexible N-terminal portion of the ligand binding domain (LBD), which exhibit modestly reduced hormone binding with impaired release of corepressor. X-ray crystallography analyses revealed that these two RTH mutants modulate the position of this flexible region by either altering the movement of helix 1 (A234T) or disrupting a salt bridge (R243Q). The subsequent increased flexibility and mobility in regions after the two sites of mutation coincided with a disorganized LBD. Consistent with this finding, the ability of these mutant N-terminal regions (234-260) to recruit the remaining LBD was decreased in a ligand-dependent helix assembly assay. Collectively, these data suggest that structural information imparted by the flexible segment in the N-terminal LBD is critical for overall stability of the LBD. Thus, these structural analyses provide mechanistic insight into the etiology of RTH disease in human TRbeta mutants that exhibit hormone binding with decreased ligand-dependent corepressor release.


  • Organizational Affiliation

    Graduate Group in Biophysics, University of California, San Francisco, California 94143-0448, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Thyroid hormone receptor beta-1263Homo sapiensMutation(s): 1 
Gene Names: THRB OR NR1A2 OR ERBA2 OR THR1
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 2 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
ARS
Query on ARS

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
ARSENIC
As
RBFQJDQYXXHULB-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
4HY BindingDB:  1NQ1 IC50: min: 0.04, max: 0.15 (nM) from 4 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.287 
  • R-Value Work: 0.239 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.839α = 90
b = 68.839β = 90
c = 130.53γ = 120
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
CNSphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2003-04-15
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Derived calculations, Version format compliance
  • Version 1.3: 2021-10-27
    Changes: Database references, Derived calculations
  • Version 1.4: 2024-02-14
    Changes: Data collection