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PDBsum entry 1zeo

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protein ligands Protein-protein interface(s) links
Transcription PDB id
1zeo
Jmol
Contents
Protein chains
263 a.a. *
247 a.a. *
Ligands
C01
Waters ×114
* Residue conservation analysis
PDB id:
1zeo
Name: Transcription
Title: Crystal structure of human ppar-gamma ligand binding domain complexed with an alpha-aryloxyphenylacetic acid agonist
Structure: Peroxisome proliferator activated receptor gamma. Chain: a, b. Fragment: ligand binding domain (lbd), residues 203-477. Synonym: ppar-gamma. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pparg, nr1c3. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Dimer (from PQS)
Resolution:
2.50Å     R-factor:   0.222     R-free:   0.280
Authors: G.Q.Shi,J.F.Dropinski,B.M.Mckeever,A.D.Adams,K.L.Macnaul, A.Elbrecht,J.P.Berger,G.Zhou,T.W.Doebber
Key ref: G.Q.Shi et al. (2005). Design and synthesis of alpha-aryloxyphenylacetic acid derivatives: a novel class of PPARalpha/gamma dual agonists with potent antihyperglycemic and lipid modulating activity. J Med Chem, 48, 4457-4468. PubMed id: 15974597 DOI: 10.1021/jm0502135
Date:
19-Apr-05     Release date:   25-Apr-06    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P37231  (PPARG_HUMAN) -  Peroxisome proliferator-activated receptor gamma
Seq:
Struc:
505 a.a.
263 a.a.
Protein chain
Pfam   ArchSchema ?
P37231  (PPARG_HUMAN) -  Peroxisome proliferator-activated receptor gamma
Seq:
Struc:
505 a.a.
247 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     steroid hormone mediated signaling pathway   2 terms 
  Biochemical function     DNA binding     4 terms  

 

 
DOI no: 10.1021/jm0502135 J Med Chem 48:4457-4468 (2005)
PubMed id: 15974597  
 
 
Design and synthesis of alpha-aryloxyphenylacetic acid derivatives: a novel class of PPARalpha/gamma dual agonists with potent antihyperglycemic and lipid modulating activity.
G.Q.Shi, J.F.Dropinski, B.M.McKeever, S.Xu, J.W.Becker, J.P.Berger, K.L.MacNaul, A.Elbrecht, G.Zhou, T.W.Doebber, P.Wang, Y.S.Chao, M.Forrest, J.V.Heck, D.E.Moller, A.B.Jones.
 
  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.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21162086 D.Vidović, S.A.Busby, P.R.Griffin, and S.C.Schürer (2011).
A combined ligand- and structure-based virtual screening protocol identifies submicromolar PPARγ partial agonists.
  ChemMedChem, 6, 94.  
20367191 L.S.Doshi, M.K.Brahma, U.A.Bahirat, A.V.Dixit, and K.V.Nemmani (2010).
Discovery and development of selective PPARgamma modulators as safe and effective antidiabetic agents.
  Expert Opin Investig Drugs, 19, 489-512.  
19746174 S.N.Lewis, J.Bassaganya-Riera, and D.R.Bevan (2010).
Virtual Screening as a Technique for PPAR Modulator Discovery.
  PPAR Res, 2010, 861238.  
17462987 A.L.Ambrosio, S.M.Dias, I.Polikarpov, R.B.Zurier, S.H.Burstein, and R.C.Garratt (2007).
Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator-activated receptor gamma.
  J Biol Chem, 282, 18625-18633.
PDB code: 2om9
17468099 J.N.Feige, L.Gelman, D.Rossi, V.Zoete, R.Métivier, C.Tudor, S.I.Anghel, A.Grosdidier, C.Lathion, Y.Engelborghs, O.Michielin, W.Wahli, and B.Desvergne (2007).
The endocrine disruptor monoethyl-hexyl-phthalate is a selective peroxisome proliferator-activated receptor gamma modulator that promotes adipogenesis.
  J Biol Chem, 282, 19152-19166.  
16582875 S.M.Grundy (2006).
Drug therapy of the metabolic syndrome: minimizing the emerging crisis in polypharmacy.
  Nat Rev Drug Discov, 5, 295-309.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.