PDBsum entry 2fvj

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Signaling protein PDB id
Protein chain
258 a.a. *
Waters ×253
* Residue conservation analysis
PDB id:
Name: Signaling protein
Title: A novel anti-adipogenic partial agonist of peroxisome prolif activated receptor-gamma (pparg) recruits pparg-coactivator (pgc1a) but potentiates insulin signaling in vitro
Structure: Peroxisome proliferator-activated receptor gamma. Chain: a. Fragment: ligand binding domain, residues 207-477. Synonym: ppar-gamma. Engineered: yes. Nuclear receptor coactivator 1. Chain: b. Fragment: coactivator fragment src-1, 13-mer peptide from n receptor coactivator 1.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562
Biol. unit: Dimer (from PQS)
1.99Å     R-factor:   0.192     R-free:   0.246
Authors: J.Benz,E.Burgermeister,A.Flament,A.Schnoebelen,M.Stihle,B.Gs A.Rufer,A.Ruf,B.Kuhn,H.P.Maerki,J.Mizrahi,E.Sebokova,E.Nies M.Meyer
Key ref: E.Burgermeister et al. (2006). A novel partial agonist of peroxisome proliferator-activated receptor-gamma (PPARgamma) recruits PPARgamma-coactivator-1alpha, prevents triglyceride accumulation, and potentiates insulin signaling in vitro. Mol Endocrinol, 20, 809-830. PubMed id: 16373399 DOI: 10.1210/me.2005-0171
31-Jan-06     Release date:   16-May-06    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P37231  (PPARG_HUMAN) -  Peroxisome proliferator-activated receptor gamma
505 a.a.
258 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: 10.1210/me.2005-0171 Mol Endocrinol 20:809-830 (2006)
PubMed id: 16373399  
A novel partial agonist of peroxisome proliferator-activated receptor-gamma (PPARgamma) recruits PPARgamma-coactivator-1alpha, prevents triglyceride accumulation, and potentiates insulin signaling in vitro.
E.Burgermeister, A.Schnoebelen, A.Flament, J.Benz, M.Stihle, B.Gsell, A.Rufer, A.Ruf, B.Kuhn, H.P.Märki, J.Mizrahi, E.Sebokova, E.Niesor, M.Meyer.
Partial agonists of peroxisome proliferator-activated receptor-gamma (PPARgamma), also termed selective PPARgamma modulators, are expected to uncouple insulin sensitization from triglyceride (TG) storage in patients with type 2 diabetes mellitus. These agents shall thus avoid adverse effects, such as body weight gain, exerted by full agonists such as thiazolidinediones. In this context, we describe the identification and characterization of the isoquinoline derivative PA-082, a prototype of a novel class of non-thiazolidinedione partial PPARgamma ligands. In a cocrystal with PPARgamma it was bound within the ligand-binding pocket without direct contact to helix 12. The compound displayed partial agonism in biochemical and cell-based transactivation assays and caused preferential recruitment of PPARgamma-coactivator-1alpha (PGC1alpha) to the receptor, a feature shared with other selective PPARgamma modulators. It antagonized rosiglitazone-driven transactivation and TG accumulation during de novo adipogenic differentiation of murine C3H10T1/2 mesenchymal stem cells. The latter effect was mimicked by overexpression of wild-type PGC1alpha but not its LXXLL-deficient mutant. Despite failing to promote TG loading, PA-082 induced mRNAs of genes encoding components of insulin signaling and adipogenic differentiation pathways. It potentiated glucose uptake and inhibited the negative cross-talk of TNFalpha on protein kinase B (AKT) phosphorylation in mature adipocytes and HepG2 human hepatoma cells. PGC1alpha is a key regulator of energy expenditure and down-regulated in diabetics. We thus propose that selective recruitment of PGC1alpha to favorable PPARgamma-target genes provides a possible molecular mechanism whereby partial PPARgamma agonists dissociate TG accumulation from insulin signaling.

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.  
21069556 R.K.Petersen, K.B.Christensen, A.N.Assimopoulou, X.Fretté, V.P.Papageorgiou, K.Kristiansen, and I.Kouskoumvekaki (2011).
Pharmacophore-driven identification of PPARγ agonists from natural sources.
  J Comput Aided Mol Des, 25, 107-116.  
20419060 A.Majdalawieh, and H.S.Ro (2010).
PPARgamma1 and LXRalpha face a new regulator of macrophage cholesterol homeostasis and inflammatory responsiveness, AEBP1.
  Nucl Recept Signal, 8, e004.  
20364085 B.Lefebvre, Y.Benomar, A.Guédin, A.Langlois, N.Hennuyer, J.Dumont, E.Bouchaert, C.Dacquet, L.Pénicaud, L.Casteilla, F.Pattou, A.Ktorza, B.Staels, and P.Lefebvre (2010).
Proteasomal degradation of retinoid X receptor alpha reprograms transcriptional activity of PPARgamma in obese mice and humans.
  J Clin Invest, 120, 1454-1468.  
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.  
20208423 M.K.Moon, M.Kim, S.S.Chung, H.J.Lee, S.H.Koh, P.Svovoda, M.H.Jung, Y.M.Cho, Y.J.Park, S.H.Choi, H.C.Jang, K.S.Park, and H.K.Lee (2010).
S-Adenosyl-L-methionine ameliorates TNFalpha-induced insulin resistance in 3T3-L1 adipocytes.
  Exp Mol Med, 42, 345-352.  
20628212 M.Yamada, N.Niki, and C.Hamada (2010).
[Evaluation of a partial agonist by a logistic model with relative efficacy.].
  Nippon Yakurigaku Zasshi, 136, 36-41.  
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.  
19172665 K.B.Christensen, A.Minet, H.Svenstrup, K.Grevsen, H.Zhang, E.Schrader, G.Rimbach, S.Wein, S.Wolffram, K.Kristiansen, and L.P.Christensen (2009).
Identification of plant extracts with potential antidiabetic properties: effect on human peroxisome proliferator-activated receptor (PPAR), adipocyte differentiation and insulin-stimulated glucose uptake.
  Phytother Res, 23, 1316-1325.  
19118492 L.Villacorta, F.J.Schopfer, J.Zhang, B.A.Freeman, and Y.E.Chen (2009).
PPARgamma and its ligands: therapeutic implications in cardiovascular disease.
  Clin Sci (Lond), 116, 205-218.  
18815886 R.Ziv, Y.Steinhardt, G.Pelled, D.Gazit, and B.Rubinsky (2009).
Micro-electroporation of mesenchymal stem cells with alternating electrical current pulses.
  Biomed Microdevices, 11, 95.  
19326383 U.Grether, A.Bénardeau, J.Benz, A.Binggeli, D.Blum, H.Hilpert, B.Kuhn, H.P.Märki, M.Meyer, P.Mohr, K.Püntener, S.Raab, A.Ruf, and D.Schlatter (2009).
Design and biological evaluation of novel, balanced dual PPARalpha/gamma agonists.
  ChemMedChem, 4, 951-956.
PDB codes: 3fei 3fej
19072826 X.Xing, E.Burgermeister, F.Geisler, H.Einwächter, L.Fan, M.Hiber, S.Rauser, A.Walch, C.Röcken, M.Ebeling, M.B.Wright, R.M.Schmid, and M.P.Ebert (2009).
Hematopoietically expressed homeobox is a target gene of farnesoid X receptor in chenodeoxycholic acid-induced liver hypertrophy.
  Hepatology, 49, 979-988.  
18596912 E.Burgermeister, and R.Seger (2008).
PPARgamma and MEK Interactions in Cancer.
  PPAR Res, 2008, 309469.  
18354731 G.M.Lehmann, T.M.Garcia-Bates, T.J.Smith, S.E.Feldon, and R.P.Phipps (2008).
Regulation of Lymphocyte Function by PPARgamma: Relevance to Thyroid Eye Disease-Related Inflammation.
  PPAR Res, 2008, 895901.  
18566691 M.C.Cho, K.Lee, S.G.Paik, and D.Y.Yoon (2008).
Peroxisome Proliferators-Activated Receptor (PPAR) Modulators and Metabolic Disorders.
  PPAR Res, 2008, 679137.  
18528521 M.J.Campbell, C.Carlberg, and H.P.Koeffler (2008).
A Role for the PPARgamma in Cancer Therapy.
  PPAR Res, 2008, 314974.  
18554251 O.A.Gani, and I.Sylte (2008).
Ligand-induced stabilization and activation of peroxisome proliferator-activated receptor gamma.
  Chem Biol Drug Des, 72, 50-57.  
18528522 T.M.Garcia-Bates, G.M.Lehmann, P.J.Simpson-Haidaris, S.H.Bernstein, P.J.Sime, and R.P.Phipps (2008).
Role of peroxisome proliferator-activated receptor gamma and its ligands in the treatment of hematological malignancies.
  PPAR Res, 2008, 834612.  
17933688 C.Kremoser, M.Albers, T.P.Burris, U.Deuschle, and M.Koegl (2007).
Panning for SNuRMs: using cofactor profiling for the rational discovery of selective nuclear receptor modulators.
  Drug Discov Today, 12, 860-869.  
17389769 F.Zhang, B.E.Lavan, and F.M.Gregoire (2007).
Selective Modulators of PPAR-gamma Activity: Molecular Aspects Related to Obesity and Side-Effects.
  PPAR Res, 2007, 32696.  
17937915 J.B.Bruning, M.J.Chalmers, S.Prasad, S.A.Busby, T.M.Kamenecka, Y.He, K.W.Nettles, and P.R.Griffin (2007).
Partial agonists activate PPARgamma using a helix 12 independent mechanism.
  Structure, 15, 1258-1271.
PDB codes: 2q59 2q5p 2q5s 2q61 2q6r 2q6s
17960326 P.Markt, D.Schuster, J.Kirchmair, C.Laggner, and T.Langer (2007).
Pharmacophore modeling and parallel screening for PPAR ligands.
  J Comput Aided Mol Des, 21, 575-590.  
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 codes are shown on the right.