6O68

Crystal Structure of Human PPARgamma Ligand Binding Domain in Complex with Ciglitazone


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.78 Å
  • R-Value Free: 0.298 
  • R-Value Work: 0.233 

wwPDB Validation 3D Report Full Report


This is version 1.0 of the entry. See complete history

Literature

Quantitative structural assessment of graded receptor agonism.

Shang, J.Brust, R.Griffin, P.R.Kamenecka, T.M.Kojetin, D.J.

(2019) Proc.Natl.Acad.Sci.USA 116: 22179-22188

  • DOI: 10.1073/pnas.1909016116
  • Primary Citation of Related Structures:  

  • PubMed Abstract: 
  • Ligand-receptor interactions, which are ubiquitous in physiology, are described by theoretical models of receptor pharmacology. Structural evidence for graded efficacy receptor conformations predicted by receptor theory has been limited but is critic ...

    Ligand-receptor interactions, which are ubiquitous in physiology, are described by theoretical models of receptor pharmacology. Structural evidence for graded efficacy receptor conformations predicted by receptor theory has been limited but is critical to fully validate theoretical models. We applied quantitative structure-function approaches to characterize the effects of structurally similar and structurally diverse agonists on the conformational ensemble of nuclear receptor peroxisome proliferator-activated receptor ╬│ (PPAR╬│). For all ligands, agonist functional efficacy is correlated to a shift in the conformational ensemble equilibrium from a ground state toward an active state, which is detected by NMR spectroscopy but not observed in crystal structures. For the structurally similar ligands, ligand potency and affinity are also correlated to efficacy and conformation, indicating ligand residence times among related analogs may influence receptor conformation and function. Our results derived from quantitative graded activity-conformation correlations provide experimental evidence and a platform with which to extend and test theoretical models of receptor pharmacology to more accurately describe and predict ligand-dependent receptor activity.


    Organizational Affiliation

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, FL 33458.,Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458.,Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, FL 33458; dkojetin@scripps.edu.




Macromolecules

Find similar proteins by: Sequence  |  Structure

Entity ID: 1
MoleculeChainsSequence LengthOrganismDetails
Peroxisome proliferator-activated receptor gamma
A, B
275Homo sapiensMutation(s): 0 
Gene Names: PPARG (NR1C3)
Find proteins for P37231 (Homo sapiens)
Go to Gene View: PPARG
Go to UniProtKB:  P37231
Small Molecules
Ligands 1 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
LO4
Query on LO4

Download SDF File 
Download CCD File 
A
Ciglitazone
5-({4-[(1-methylcyclohexyl)methoxy]phenyl}methyl)-2H-1lambda~4~,3-thiazole-2,4(3H)-dione
C18 H23 N O3 S
VYHNBSGGAFFFLO-UHFFFAOYSA-N
 Ligand Interaction
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.78 Å
  • R-Value Free: 0.298 
  • R-Value Work: 0.233 
  • Space Group: C 1 2 1
Unit Cell:
Length (Å)Angle (°)
a = 92.390α = 90.00
b = 59.960β = 103.02
c = 117.610γ = 90.00
Software Package:
Software NamePurpose
PHENIXrefinement
PDB_EXTRACTdata extraction
SCALAdata scaling
PHASERphasing

Structure Validation

View Full Validation Report or Ramachandran Plots



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney DiseaseUnited StatesR01DK101871

Revision History 

  • Version 1.0: 2019-11-06
    Type: Initial release