1ZEO

Crystal Structure of Human PPAR-gamma Ligand Binding Domain Complexed with an Alpha-Aryloxyphenylacetic Acid Agonist


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.280 
  • R-Value Work: 0.219 
  • R-Value Observed: 0.222 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Design and Synthesis of alpha-Aryloxyphenylacetic Acid Derivatives: A Novel Class of PPAR alpha/gamma Dual Agonists with Potent Antihyperglycemic and Lipid Modulating Activity

Shi, G.Q.Dropinski, J.F.McKeever, B.M.Xu, S.Becker, J.W.Berger, J.P.MacNaul, K.L.Elbrecht, A.Zhou, G.Doebber, T.W.Wang, P.Chao, Y.-S.Forrest, M.Heck, J.V.Moller, D.E.Jones, B.A.

(2005) J Med Chem 48: 4457-4468

  • DOI: https://doi.org/10.1021/jm0502135
  • Primary Citation of Related Structures:  
    1ZEO

  • PubMed Abstract: 

    The synthesis and structure-activity relationships of novel series of alpha-aryloxyphenylacetic acids as PPARalpha/gamma dual agonists are reported. The initial search for surrogates of the ester group in the screen lead led first to the optimization of a subseries with a ketone moiety. Further efforts to modify the ketone subseries led to the design and synthesis of two new subseries containing fused heterocyclic ring systems. All these analogues were characterized by their "super" PPARalpha agonist activity and weak or partial agonist activity on PPARgamma in PPAR-GAL4 transactivation assays despite their similar binding affinities for both receptors. The cocrystal structures of compounds 7 and rosiglitazone with PPARgamma-LBD were compared, and significant differences were found in their interactions with the receptor. Select analogues in each subseries were further evaluated for in vivo efficacy. They all showed excellent anti-hyperglycemic efficacy in a db/db mouse model and hypolipidemic activity in hamster and dog models without provoking the typical PPARgamma-associated side effects in the rat tolerability assay.


  • Organizational Affiliation

    Departments of Medicinal Chemistry, Merck Research Laboratories, P.O Box 2000, Rahway, New Jersey 07065-0900, USA. guoqiang_shi@merck.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Peroxisome proliferator activated receptor gamma
A, B
277Homo 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
C01
Query on C01

Download Ideal Coordinates CCD File 
C [auth A](2S)-(4-ISOPROPYLPHENYL)[(2-METHYL-3-OXO-5,7-DIPROPYL-2,3-DIHYDRO-1,2-BENZISOXAZOL-6-YL)OXY]ACETATE
C25 H30 N O5
RYNHNIDEKCRWHJ-QFIPXVFZSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
C01 Binding MOAD:  1ZEO IC50: 210 (nM) from 1 assay(s)
PDBBind:  1ZEO IC50: 210 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.280 
  • R-Value Work: 0.219 
  • R-Value Observed: 0.222 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 92.573α = 90
b = 61.442β = 101.72
c = 118.051γ = 90
Software Package:
Software NamePurpose
CNXrefinement
HKL-2000data reduction
SCALEPACKdata scaling
CNXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-04-25
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2018-01-24
    Changes: Database references
  • Version 1.4: 2024-02-14
    Changes: Data collection, Database references, Derived calculations