5TTO

X-ray crystal structure of PPARgamma in complex with SR1643


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.25 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.206 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure-Activity Relationship of 2,4-Dichloro-N-(3,5-dichloro-4-(quinolin-3-yloxy)phenyl)benzenesulfonamide (INT131) Analogs for PPAR gamma-Targeted Antidiabetics.

Frkic, R.L.He, Y.Rodriguez, B.B.Chang, M.R.Kuruvilla, D.Ciesla, A.Abell, A.D.Kamenecka, T.M.Griffin, P.R.Bruning, J.B.

(2017) J Med Chem 60: 4584-4593

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b01727
  • Primary Citation of Related Structures:  
    5TTO

  • PubMed Abstract: 

    Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor central to fatty acid and glucose homeostasis. PPARγ is the molecular target for type 2 diabetes mellitus (T2DM) therapeutics TZDs (thiazolidinediones), full agonists of PPARγ with robust antidiabetic properties, which are confounded with significant side effects. Partial agonists of PPARγ, such as INT131 (1), have displayed similar insulin-sensitizing efficacy as TZDs, but lack many side effects. To probe the structure-activity relationship (SAR) of the scaffold 1, we synthesized 14 analogs of compound 1 which revealed compounds with higher transcriptional potency for PPARγ and identification of moieties of the scaffold 1 key to high transcriptional potency. The sulfonamide linker is critical to activity, substitutions at position 4 of the benzene ring A were associated with higher transcriptional activity, substitutions at position 2 aided in tighter packing and activity, and the ring type and size of ring A affected the degree of activity.


  • Organizational Affiliation

    Department of Molecular Medicine, The Scripps Research Institute, Scripps Florida , Jupiter, Florida 33458, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Peroxisome proliferator-activated receptor gamma
A, B
273Homo 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
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
7KK
Query on 7KK

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
4-bromo-N-{3,5-dichloro-4-[(quinolin-3-yl)oxy]phenyl}-2,5-difluorobenzene-1-sulfonamide
C21 H11 Br Cl2 F2 N2 O3 S
IMNDKCZZKHFDEJ-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.25 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.206 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 93.11α = 90
b = 62.24β = 102.2
c = 118.88γ = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
MOSFLMdata reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-05-24
    Type: Initial release
  • Version 1.1: 2017-06-21
    Changes: Database references
  • Version 1.2: 2023-10-04
    Changes: Data collection, Database references, Refinement description