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PDBsum entry 2ath

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protein ligands Protein-protein interface(s) links
Transcription PDB id
2ath
Jmol
Contents
Protein chain
271 a.a. *
Ligands
3EA ×2
Waters ×123
* Residue conservation analysis
PDB id:
2ath
Name: Transcription
Title: Crystal structure of the ligand binding domain of human ppar-gamma im complex with an agonist
Structure: Peroxisome proliferator activated receptor gamma. Chain: a, b. Fragment: ligand binding domain. Synonym: ppar-gamma. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.28Å     R-factor:   0.216     R-free:   0.288
Authors: N.Mahindroo,C.-F.Huang,S.-Y.Wu,H.-P.Hsieh
Key ref: N.Mahindroo et al. (2005). Novel indole-based peroxisome proliferator-activated receptor agonists: design, SAR, structural biology, and biological activities. J Med Chem, 48, 8194-8208. PubMed id: 16366601 DOI: 10.1021/jm0506930
Date:
25-Aug-05     Release date:   25-Aug-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P37231  (PPARG_HUMAN) -  Peroxisome proliferator-activated receptor gamma
Seq:
Struc:
505 a.a.
271 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: 10.1021/jm0506930 J Med Chem 48:8194-8208 (2005)
PubMed id: 16366601  
 
 
Novel indole-based peroxisome proliferator-activated receptor agonists: design, SAR, structural biology, and biological activities.
N.Mahindroo, C.F.Huang, Y.H.Peng, C.C.Wang, C.C.Liao, T.W.Lien, S.K.Chittimalla, W.J.Huang, C.H.Chai, E.Prakash, C.P.Chen, T.A.Hsu, C.H.Peng, I.L.Lu, L.H.Lee, Y.W.Chang, W.C.Chen, Y.C.Chou, C.T.Chen, C.M.Goparaju, Y.S.Chen, S.J.Lan, M.C.Yu, X.Chen, Y.S.Chao, S.Y.Wu, H.P.Hsieh.
 
  ABSTRACT  
 
The synthesis and structure-activity relationship studies of novel indole derivatives as peroxisome proliferator-activated receptor (PPAR) agonists are reported. Indole, a drug-like scaffold, was studied as a core skeleton for the acidic head part of PPAR agonists. The structural features (acidic head, substitution on indole, and linker) were optimized first, by keeping benzisoxazole as the tail part, based on binding and functional activity at PPARgamma protein. The variations in the tail part, by introducing various heteroaromatic ring systems, were then studied. In vitro evaluation led to identification of a novel series of indole compounds with a benzisoxazole tail as potent PPAR agonists with the lead compound 14 (BPR1H036) displaying an excellent pharmacokinetic profile in BALB/c mice and an efficacious glucose lowering activity in KKA(y) mice. Structural biology studies of 14 showed that the indole ring contributes strong hydrophobic interactions with PPARgamma and could be an important moiety for the binding to the protein.
 

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.  
20717101 T.Waku, T.Shiraki, T.Oyama, K.Maebara, R.Nakamori, and K.Morikawa (2010).
The nuclear receptor PPARγ individually responds to serotonin- and fatty acid-metabolites.
  EMBO J, 29, 3395-3407.
PDB codes: 2zk6 3ads 3adt 3adu 3adv 3adw 3adx
20734309 Y.H.Peng, M.S.Coumar, J.S.Leou, J.S.Wu, H.Y.Shiao, C.H.Lin, W.H.Lin, T.W.Lien, X.Chen, J.T.Hsu, Y.S.Chao, C.F.Huang, P.C.Lyu, H.P.Hsieh, and S.Y.Wu (2010).
Structural basis for the improved potency of peroxisome proliferator-activated receptor (PPAR) agonists.
  ChemMedChem, 5, 1707-1716.  
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.  
18083521 D.Chaturvedi, S.Ray, A.K.Srivastava, and R.Chander (2008).
Omega-(2-Naphthyloxy) amino alkanes as a novel class of anti-hyperglycemic and lipid lowering agents.
  Bioorg Med Chem, 16, 2489-2498.  
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.  
18566690 H.Miyachi, and Y.Hashimoto (2008).
Structural Development Studies of Subtype-Selective Ligands for Peroxisome Proliferator-Activated Receptors (PPARs) Based on the 3,4-Disubstituted Phenylpropanoic Acid Scaffold as a Versatile Template.
  PPAR Res, 2008, 689859.  
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.  
18176111 Y.H.Kao, H.P.Hsieh, S.K.Chitlimalla, W.Y.Pan, C.C.Kuo, Y.C.Tsai, W.H.Lin, S.E.Chuang, and J.Y.Chang (2008).
A novel peroxisome proliferator-activated receptor alpha/gamma agonist, BPR1H0101, inhibits topoisomerase II catalytic activity in human cancer cells.
  Anticancer Drugs, 19, 151-158.  
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
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.