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PDBsum entry 2gtk

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Transcription regulator PDB id
2gtk
Jmol
Contents
Protein chain
258 a.a. *
Ligands
HIS-LYS-LEU-VAL-
GLN-LEU-LEU-THR-
THR-THR
208
Waters ×254
* Residue conservation analysis
PDB id:
2gtk
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, 2.3.1.48
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)
Resolution:
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
Date:
28-Apr-06     Release date:   26-Sep-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P37231  (PPARG_HUMAN) -  Peroxisome proliferator-activated receptor gamma
Seq:
Struc:
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.
 
  ABSTRACT  
 
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.  
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.