4O8F

Crystal Structure of the complex between PPARgamma mutant R357A and rosiglitazone


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.297 
  • R-Value Work: 0.234 
  • R-Value Observed: 0.240 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural basis of the transactivation deficiency of the human PPAR gamma F360L mutant associated with familial partial lipodystrophy.

Lori, C.Pasquo, A.Montanari, R.Capelli, D.Consalvi, V.Chiaraluce, R.Cervoni, L.Loiodice, F.Laghezza, A.Aschi, M.Giorgi, A.Pochetti, G.

(2014) Acta Crystallogr D Biol Crystallogr 70: 1965-1976

  • DOI: https://doi.org/10.1107/S1399004714009638
  • Primary Citation of Related Structures:  
    4L96, 4L98, 4O8F

  • PubMed Abstract: 

    The peroxisome proliferator-activated receptors (PPARs) are transcription factors that regulate glucose and lipid metabolism. The role of PPARs in several chronic diseases such as type 2 diabetes, obesity and atherosclerosis is well known and, for this reason, they are the targets of antidiabetic and hypolipidaemic drugs. In the last decade, some rare mutations in human PPARγ that might be associated with partial lipodystrophy, dyslipidaemia, insulin resistance and colon cancer have emerged. In particular, the F360L mutant of PPARγ (PPARγ2 residue 388), which is associated with familial partial lipodystrophy, significantly decreases basal transcriptional activity and impairs stimulation by synthetic ligands. To date, the structural reason for this defective behaviour is unclear. Therefore, the crystal structure of PPARγ F360L together with the partial agonist LT175 has been solved and the mutant has been characterized by circular-dichroism spectroscopy (CD) in order to compare its thermal stability with that of the wild-type receptor. The X-ray analysis showed that the mutation induces dramatic conformational changes in the C-terminal part of the receptor ligand-binding domain (LBD) owing to the loss of van der Waals interactions made by the Phe360 residue in the wild type and an important salt bridge made by Arg357, with consequent rearrangement of loop 11/12 and the activation function helix 12 (H12). The increased mobility of H12 makes the binding of co-activators in the hydrophobic cleft less efficient, thereby markedly lowering the transactivation activity. The spectroscopic analysis in solution and molecular-dynamics (MD) simulations provided results which were in agreement and consistent with the mutant conformational changes observed by X-ray analysis. Moreover, to evaluate the importance of the salt bridge made by Arg357, the crystal structure of the PPARγ R357A mutant in complex with the agonist rosiglitazone has been solved.


  • Organizational Affiliation

    Istituto di Cristallografia, CNR, Via Salaria, Km 29,300, Monterotondo Stazione, 00015 Roma, Italy.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Peroxisome proliferator-activated receptor gamma
A, B
287Homo sapiensMutation(s): 1 
Gene Names: NR1C3PPARG
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
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
BRL
Query on BRL

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
2,4-THIAZOLIDIINEDIONE, 5-[[4-[2-(METHYL-2-PYRIDINYLAMINO)ETHOXY]PHENYL]METHYL]-(9CL)
C18 H19 N3 O3 S
YASAKCUCGLMORW-HNNXBMFYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
BRL BindingDB:  4O8F Ki: min: 8, max: 59 (nM) from 5 assay(s)
Kd: min: 0.14, max: 48 (nM) from 3 assay(s)
IC50: min: 1, max: 298 (nM) from 10 assay(s)
EC50: min: 1, max: 1600 (nM) from 35 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.297 
  • R-Value Work: 0.234 
  • R-Value Observed: 0.240 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 85.7α = 90
b = 87.1β = 90
c = 163.8γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
AMoREphasing
CNSrefinement
MOSFLMdata reduction
SCALAdata scaling
HKL-2000data collection

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-07-23
    Type: Initial release
  • Version 1.1: 2019-07-17
    Changes: Data collection, Refinement description
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description