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PDBsum entry 2g0h
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Transcription activator PDB id
2g0h

 

 

 

 

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Contents
Protein chain
271 a.a. *
Ligands
SP3 ×2
Waters ×87
* Residue conservation analysis
PDB id:
2g0h
Name: Transcription activator
Title: Structure-based drug design of a novel family of ppar partial agonists: virtual screening, x-ray crystallography and in vitro/in vivo biological activities
Structure: Peroxisome proliferator-activated receptor gamma. Chain: a, b. Fragment: ligand binding domain(residues 207-477). 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.
Resolution:
2.30Å     R-factor:   0.238     R-free:   0.293
Authors: I.L.Lu,Y.H.Peng,C.F.Huang,Y.T.Lin,J.T.A.Hsu,S.Y.Wu
Key ref: I.L.Lu et al. (2006). Structure-based drug design of a novel family of PPARgamma partial agonists: virtual screening, X-ray crystallography, and in vitro/in vivo biological activities. J Med Chem, 49, 2703-2712. PubMed id: 16640330 DOI: 10.1021/jm051129s
Date:
13-Feb-06     Release date:   16-May-06    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
P37231  (PPARG_HUMAN) -  Peroxisome proliferator-activated receptor gamma from Homo sapiens
Seq:
Struc: 		505 a.a.
271 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 

 
DOI no: 10.1021/jm051129s J Med Chem 49:2703-2712 (2006)
PubMed id: 16640330  
 
 
Structure-based drug design of a novel family of PPARgamma partial agonists: virtual screening, X-ray crystallography, and in vitro/in vivo biological activities.
I.L.Lu, C.F.Huang, Y.H.Peng, Y.T.Lin, H.P.Hsieh, C.T.Chen, T.W.Lien, H.J.Lee, N.Mahindroo, E.Prakash, A.Yueh, H.Y.Chen, C.M.Goparaju, X.Chen, C.C.Liao, Y.S.Chao, J.T.Hsu, S.Y.Wu.
 
  ABSTRACT  
 
Peroxisome proliferator-activated receptor gamma (PPARgamma) is well-known as the receptor of thiazolidinedione antidiabetic drugs. In this paper, we present a successful example of employing structure-based virtual screening, a method that combines shape-based database search with a docking study and analogue search, to discover a novel family of PPARgamma agonists based upon pyrazol-5-ylbenzenesulfonamide. Two analogues in the family show high affinity for, and specificity to, PPARgamma and act as partial agonists. They also demonstrate glucose-lowering efficacy in vivo. A structural biology study reveals that they both adopt a distinct binding mode and have no H-bonding interactions with PPARgamma. The absence of H-bonding interaction with the protein provides an explanation why both function as partial agonists since most full agonists form conserved H-bonds with the activation function helix (AF-2 helix) which, in turn, enhances the recruitment of coactivators. Moreover, the structural biology and computer docking studies reveal the specificity of the compounds for PPARgamma could be due to the restricted access to the binding pocket of other PPAR subtypes, i.e., PPARalpha and PPARdelta, and steric hindrance upon the ligand binding.
 

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.  
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.  
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.  
20182551 A.Leonardini, L.Laviola, S.Perrini, A.Natalicchio, and F.Giorgino (2009).
Cross-Talk between PPARgamma and Insulin Signaling and Modulation of Insulin Sensitivity.
  PPAR Res, 2009, 818945.  
19429508 N.Ai, M.D.Krasowski, W.J.Welsh, and S.Ekins (2009).
Understanding nuclear receptors using computational methods.
  Drug Discov Today, 14, 486-494.  
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.  
17229415 I.M.Kapetanovic (2008).
Computer-aided drug discovery and development (CADDD): in silico-chemico-biological approach.
  Chem Biol Interact, 171, 165-176.  
18338225 J.H.Hsieh, X.S.Wang, D.Teotico, A.Golbraikh, and A.Tropsha (2008).
Differentiation of AmpC beta-lactamase binders vs. decoys using classification kNN QSAR modeling and application of the QSAR classifier to virtual screening.
  J Comput Aided Mol Des, 22, 593-609.  
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.  
18398904 Y.C.Chou, E.Prakash, C.F.Huang, T.W.Lien, X.Chen, I.J.Su, Y.S.Chao, H.P.Hsieh, and J.T.Hsu (2008).
Bioassay-guided purification and identification of PPARalpha/gamma agonists from Chlorella sorokiniana.
  Phytother Res, 22, 605-613.  
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
17403688 G.Pochetti, C.Godio, N.Mitro, D.Caruso, A.Galmozzi, S.Scurati, F.Loiodice, G.Fracchiolla, P.Tortorella, A.Laghezza, A.Lavecchia, E.Novellino, F.Mazza, and M.Crestani (2007).
Insights into the mechanism of partial agonism: crystal structures of the peroxisome proliferator-activated receptor gamma ligand-binding domain in the complex with two enantiomeric ligands.
  J Biol Chem, 282, 17314-17324.
PDB codes: 2i4j 2i4p 2i4z
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.  
17549046 S.Ekins, J.Mestres, and B.Testa (2007).
In silico pharmacology for drug discovery: applications to targets and beyond.
  Br J Pharmacol, 152, 21-37.  
17066499 S.Derksen, O.Rau, P.Schneider, M.Schubert-Zsilavecz, and G.Schneider (2006).
Virtual screening for PPAR modulators using a probabilistic neural network.
  ChemMedChem, 1, 1346-1350.  
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.

 

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