3H52

Crystal structure of the antagonist form of human glucocorticoid receptor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.283 
  • R-Value Work: 0.226 
  • R-Value Observed: 0.228 

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This is version 1.4 of the entry. See complete history


Literature

Molecular switch in the glucocorticoid receptor: active and passive antagonist conformations

Schoch, G.A.D'Arcy, B.Stihle, M.Burger, D.Bar, D.Benz, J.Thoma, R.Ruf, A.

(2010) J Mol Biol 395: 568-577

  • DOI: https://doi.org/10.1016/j.jmb.2009.11.011
  • Primary Citation of Related Structures:  
    3H52

  • PubMed Abstract: 

    Mifepristone is known to induce mixed passive antagonist, active antagonist, and agonist effects via the glucocorticoid receptor (GR) pathway. Part of the antagonist effects of mifepristone are due to the repression of gene transcription mediated by the nuclear receptor corepressor (NCoR). Here, we report the crystal structure of a ternary complex of the GR ligand binding domain (GR-LBD) with mifepristone and a receptor-interacting motif of NCoR. The structures of three different conformations of the GR-LBD mifepristone complex show in the oxosteroid hormone receptor family how helix 12 modulates LBD corepressor and coactivator binding. Differences in NCoR binding and in helix 12 conformation reveal how the 11beta substituent in mifepristone triggers the helix 12 molecular switch to reshape the coactivator site into the corepressor site. Two observed conformations exemplify the active antagonist state of GR with NCoR bound. In another conformation, helix 12 completely blocks the coregulator binding site and explains the passive antagonistic effect of mifepristone on GR.


  • Organizational Affiliation

    F Hoffmann-La Roche Ltd, Pharma Research, Discovery Technologies, Grenzacherstrasse 124, CH-4070 Basel, Switzerland. guillaume.schoch@roche.com


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glucocorticoid receptor
A, B, C, D
254Homo sapiensMutation(s): 5 
UniProt & NIH Common Fund Data Resources
Find proteins for P04150 (Homo sapiens)
Explore P04150 
Go to UniProtKB:  P04150
PHAROS:  P04150
GTEx:  ENSG00000113580 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04150
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor corepressor 1E [auth N],
F [auth M]
19N/AMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for O75376 (Homo sapiens)
Explore O75376 
Go to UniProtKB:  O75376
PHAROS:  O75376
GTEx:  ENSG00000141027 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO75376
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
486 BindingDB:  3H52 Ki: min: 0.09, max: 169 (nM) from 18 assay(s)
Kd: 15 (nM) from 1 assay(s)
IC50: min: 8.00e-3, max: 33 (nM) from 31 assay(s)
EC50: min: 0.6, max: 2500 (nM) from 6 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.283 
  • R-Value Work: 0.226 
  • R-Value Observed: 0.228 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 99.53α = 90
b = 99.53β = 90
c = 252.43γ = 120
Software Package:
Software NamePurpose
PHASERphasing
REFMACrefinement
XDSdata reduction
XSCALEdata 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: 2009-12-01
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.2: 2014-02-05
    Changes: Database references, Refinement description
  • Version 1.3: 2021-11-10
    Changes: Database references, Derived calculations, Structure summary
  • Version 1.4: 2023-11-01
    Changes: Data collection, Refinement description