6ONI

Crystal structure of PPARgamma ligand binding domain in complex with N-CoR peptide and inverse agonist T0070907


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.226 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.209 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

A molecular switch regulating transcriptional repression and activation of PPAR gamma.

Shang, J.Mosure, S.A.Zheng, J.Brust, R.Bass, J.Nichols, A.Solt, L.A.Griffin, P.R.Kojetin, D.J.

(2020) Nat Commun 11: 956-956

  • DOI: https://doi.org/10.1038/s41467-020-14750-x
  • Primary Citation of Related Structures:  
    6ONI, 6ONJ, 6PDZ

  • PubMed Abstract: 

    Nuclear receptor (NR) transcription factors use a conserved activation function-2 (AF-2) helix 12 mechanism for agonist-induced coactivator interaction and NR transcriptional activation. In contrast, ligand-induced corepressor-dependent NR repression appears to occur through structurally diverse mechanisms. We report two crystal structures of peroxisome proliferator-activated receptor gamma (PPARγ) in an inverse agonist/corepressor-bound transcriptionally repressive conformation. Helix 12 is displaced from the solvent-exposed active conformation and occupies the orthosteric ligand-binding pocket enabled by a conformational change that doubles the pocket volume. Paramagnetic relaxation enhancement (PRE) NMR and chemical crosslinking mass spectrometry confirm the repressive helix 12 conformation. PRE NMR also defines the mechanism of action of the corepressor-selective inverse agonist T0070907, and reveals that apo-helix 12 exchanges between transcriptionally active and repressive conformations-supporting a fundamental hypothesis in the NR field that helix 12 exchanges between transcriptionally active and repressive conformations.


  • Organizational Affiliation

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, FL, 33458, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Peroxisome proliferator-activated receptor gammaA [auth B]275Homo sapiensMutation(s): 0 
Gene Names: PPARGNR1C3
UniProt & NIH Common Fund Data Resources
Find proteins for P37231 (Homo sapiens)
Explore P37231 
Go to UniProtKB:  P37231
PHAROS:  P37231
GTEx:  ENSG00000132170 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP37231
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
NCOR isoform cB [auth D]23Homo sapiensMutation(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
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
EEY (Subject of Investigation/LOI)
Query on EEY

Download Ideal Coordinates CCD File 
C [auth B]2-chloro-5-nitro-N-(pyridin-4-yl)benzamide
C12 H8 Cl N3 O3
FRPJSHKMZHWJBE-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.226 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.209 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 61.876α = 90
b = 61.876β = 90
c = 164.379γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
SCALAdata scaling
PHASERphasing
PDB_EXTRACTdata extraction
DIALSdata reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)United StatesR01DK101871

Revision History  (Full details and data files)

  • Version 1.0: 2020-03-04
    Type: Initial release
  • Version 1.1: 2023-10-11
    Changes: Data collection, Database references, Refinement description
  • Version 1.2: 2024-10-23
    Changes: Structure summary