PDBsum entry 2gtk

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Transcription regulator PDB id
Protein chain
258 a.a. *
Waters ×254
* Residue conservation analysis
PDB id:
Name: Transcription regulator
Title: Structure-based design of indole propionic acids as novel pparag co-agonists
Structure: Peroxisome proliferator-activated receptor gamma. Chain: a. Synonym: pparg-lbd. Ppar-gamma. Engineered: yes. Decamer from nuclear receptor coactivator 1. Chain: b. Fragment: residues 631-640. Engineered: yes. Other_details: full protein is transferase,
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pparg, nr1c3. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: this sequence occurs naturally in homo sapiens
Biol. unit: Dimer (from PQS)
2.10Å     R-factor:   0.198     R-free:   0.261
Authors: B.Kuhn,H.Hilpert,J.Benz,A.Binggeli,U.Grether,R.Humm,H.- P.Maerki,M.Meyer,P.Mohr
Key ref: B.Kuhn et al. (2006). Structure-based design of indole propionic acids as novel PPARalpha/gamma co-agonists. Bioorg Med Chem Lett, 16, 4016-4020. PubMed id: 16737814 DOI: 10.1016/j.bmcl.2006.05.007
28-Apr-06     Release date:   26-Sep-06    
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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: 10.1016/j.bmcl.2006.05.007 Bioorg Med Chem Lett 16:4016-4020 (2006)
PubMed id: 16737814  
Structure-based design of indole propionic acids as novel PPARalpha/gamma co-agonists.
B.Kuhn, H.Hilpert, J.Benz, A.Binggeli, U.Grether, R.Humm, H.P.Märki, M.Meyer, P.Mohr.
In the quest for novel PPARalpha/gamma co-agonists as putative drugs for the treatment of type 2 diabetes and dyslipidemia, we have used a structure-based design approach to identify propionic acids with a 1,5-disubstituted indole scaffold as potent PPARalpha/gamma activators. Compounds 13, 24, and 28 are examples of submicromolar dual agonists with different alpha/gamma EC50 ratios that are selective against the delta-isoform. Analysis of the X-ray complex structure of PPARgamma with the indole propionic acid 13 provides a rationalization for some of the observed SAR.

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.  
21157612 Y.Bhurruth-Alcor, T.Røst, M.R.Jorgensen, C.Kontogiorgis, J.Skorve, R.G.Cooper, J.M.Sheridan, W.D.Hamilton, J.R.Heal, R.K.Berge, and A.D.Miller (2011).
Synthesis of novel PPARα/γ dual agonists as potential drugs for the treatment of the metabolic syndrome and diabetes type II designed using a new de novo design program protobuild.
  Org Biomol Chem, 9, 1169-1188.  
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.  
19058280 E.Proschak, K.Sander, H.Zettl, Y.Tanrikulu, O.Rau, P.Schneider, M.Schubert-Zsilavecz, H.Stark, and G.Schneider (2009).
From molecular shape to potent bioactive agents II: fragment-based de novo design.
  ChemMedChem, 4, 45-48.  
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
18665581 A.S.Felts, B.S.Siegel, S.M.Young, C.W.Moth, T.P.Lybrand, A.J.Dannenberg, L.J.Marnett, and K.Subbaramaiah (2008).
Sulindac derivatives that activate the peroxisome proliferator-activated receptor gamma but lack cyclooxygenase inhibition.
  J Med Chem, 51, 4911-4919.  
18793305 C.Giaginis, S.Theocharis, and A.Tsantili-Kakoulidou (2008).
Quantitative structure-activity relationships for PPAR-gamma binding and gene transactivation of tyrosine-based agonists using multivariate statistics.
  Chem Biol Drug Des, 72, 257-264.  
17929009 D.Genest, N.Garnier, A.Arrault, C.Marot, L.Morin-Allory, and M.Genest (2008).
Ligand-escape pathways from the ligand-binding domain of PPARgamma receptor as probed by molecular dynamics simulations.
  Eur Biophys J, 37, 369-379.  
18250627 K.U.Wendt, M.S.Weiss, P.Cramer, and D.W.Heinz (2008).
Structures and diseases.
  Nat Struct Mol Biol, 15, 117-120.  
17200111 L.Michalik, V.Zoete, G.Krey, A.Grosdidier, L.Gelman, P.Chodanowski, J.N.Feige, B.Desvergne, W.Wahli, and O.Michielin (2007).
Combined simulation and mutagenesis analyses reveal the involvement of key residues for peroxisome proliferator-activated receptor alpha helix 12 dynamic behavior.
  J Biol Chem, 282, 9666-9677.  
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