PDBsum entry 2p4y

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protein ligands Protein-protein interface(s) links
Transcription PDB id
Protein chains
244 a.a. *
227 a.a. *
C03 ×2
Waters ×93
* Residue conservation analysis
PDB id:
Name: Transcription
Title: Crystal structure of human ppar-gamma-ligand binding domain complexed with an indole-based modulator
Structure: Peroxisome proliferator-activated receptor gamma. Chain: a, b. Fragment: ligand-binding domain (lbd), residues 231-505. 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.
2.25Å     R-factor:   0.232     R-free:   0.274
Authors: B.M.Mckeever
Key ref: M.Einstein et al. (2008). The differential interactions of peroxisome proliferator-activated receptor gamma ligands with Tyr473 is a physical basis for their unique biological activities. Mol Pharmacol, 73, 62-74. PubMed id: 17940191 DOI: 10.1124/mol.107.041202
13-Mar-07     Release date:   08-Jan-08    
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Protein chain
Pfam   ArchSchema ?
P37231  (PPARG_HUMAN) -  Peroxisome proliferator-activated receptor gamma
505 a.a.
244 a.a.
Protein chain
Pfam   ArchSchema ?
P37231  (PPARG_HUMAN) -  Peroxisome proliferator-activated receptor gamma
505 a.a.
227 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: 10.1124/mol.107.041202 Mol Pharmacol 73:62-74 (2008)
PubMed id: 17940191  
The differential interactions of peroxisome proliferator-activated receptor gamma ligands with Tyr473 is a physical basis for their unique biological activities.
M.Einstein, T.E.Akiyama, G.A.Castriota, C.F.Wang, B.McKeever, R.T.Mosley, J.W.Becker, D.E.Moller, P.T.Meinke, H.B.Wood, J.P.Berger.
Despite their proven antidiabetic efficacy, widespread use of peroxisome proliferator-activated receptor (PPAR)gamma agonists has been limited by adverse cardiovascular effects. To overcome this shortcoming, selective PPARgamma modulators (SPPARgammaMs) have been identified that have antidiabetic efficacy comparable with full agonists with improved tolerability in preclinical species. The results of structural studies support the proposition that SPPARgammaMs interact with PPARgamma differently from full agonists, thereby providing a physical basis for their novel activities. Herein, we describe a novel PPARgamma ligand, SPPARgammaM2. This compound was a partial agonist in a cell-based transcriptional activity assay, with diminished adipogenic activity and an attenuated gene signature in cultured human adipocytes. X-ray cocrystallography studies demonstrated that, unlike rosiglitazone, SPPARgammaM2 did not interact with the Tyr473 residue located within helix 12 of the ligand binding domain (LBD). Instead, SPPARgammaM2 was found to bind to and activate human PPARgamma in which the Tyr473 residue had been mutated to alanine (hPPARgammaY473A), with potencies similar to those observed with the wild-type receptor (hPPARgammaWT). In additional studies, we found that the intrinsic binding and functional potencies of structurally distinct SPPARgammaMs were not diminished by the Y473A mutation, whereas those of various thiazolidinedione (TZD) and non-TZD PPARgamma full agonists were reduced in a correlative manner. These results directly demonstrate the important role of Tyr473 in mediating the interaction of full agonists but not SPPARgammaMs with the PPARgamma LBD, thereby providing a precise molecular determinant for their differing pharmacologies.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21482446 B.O.Al-Najjar, H.A.Wahab, T.S.Tengku Muhammad, A.C.Shu-Chien, N.A.Ahmad Noruddin, and M.O.Taha (2011).
Discovery of new nanomolar peroxisome proliferator-activated receptor γ activators via elaborate ligand-based modeling.
  Eur J Med Chem, 46, 2513-2529.  
20496064 J.Fidelak, S.Ferrer, M.Oberlin, D.Moras, A.Dejaegere, and R.H.Stote (2010).
Dynamic correlation networks in human peroxisome proliferator-activated receptor-γ nuclear receptor protein.
  Eur Biophys J, 39, 1503-1512.  
20367191 L.S.Doshi, M.K.Brahma, U.A.Bahirat, A.V.Dixit, and K.V.Nemmani (2010).
Discovery and development of selective PPAR gamma 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.  
19847917 T.Venäläinen, F.Molnár, C.Oostenbrink, C.Carlberg, and M.Peräkylä (2010).
Molecular mechanism of allosteric communication in the human PPARalpha-RXRalpha heterodimer.
  Proteins, 78, 873-887.  
19404482 A.Chandalia, H.J.Clarke, L.E.Clemens, B.Pandey, V.Vicena, P.Lee, B.E.Lavan, and F.M.Gregoire (2009).
MBX-102/JNJ39659100, a Novel Non-TZD Selective Partial PPAR-gamma Agonist Lowers Triglyceride Independently of PPAR-alpha Activation.
  PPAR Res, 2009, 706852.  
18836710 M.Peräkylä (2009).
Ligand unbinding pathways from the vitamin D receptor studied by molecular dynamics simulations.
  Eur Biophys J, 38, 185-198.  
18528521 M.J.Campbell, C.Carlberg, and H.P.Koeffler (2008).
A Role for the PPARgamma in Cancer Therapy.
  PPAR Res, 2008, 314974.  
18316956 P.R.Devchand (2008).
Glitazones and the cardiovascular system.
  Curr Opin Endocrinol Diabetes Obes, 15, 188-192.  
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