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PDBsum entry 3et3
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protein ligands Protein-protein interface(s) links
Transcription PDB id
3et3

 

 

 

 

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Contents
Protein chains
260 a.a. *
16 a.a. *
Ligands
ET1
Waters ×217
* Residue conservation analysis
PDB id:
3et3
Name: Transcription
Title: Structure of ppargamma with 3-[5-methoxy-1-(4-methoxy- benzenesulfonyl)-1h-indol-3-yl]-propionic acid
Structure: Peroxisome proliferator-activated receptor gamma. Chain: a. Fragment: ligand binding domain. Synonym: ppar-gamma, nuclear receptor subfamily 1 group c member 3. Engineered: yes. Steroid receptor coactivator 1. Chain: p. Fragment: residues 681-696. Synonym: ncoa-1, nuclear receptor coactivator 1, src-1, rip160,
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pparg, nr1c3. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: ncoa1, src1.
Resolution:
1.95Å     R-factor:   0.182     R-free:   0.236
Authors: K.Y.J.Zhang,W.Wang
Key ref:
D.R.Artis et al. (2009). Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent. Proc Natl Acad Sci U S A, 106, 262-267. PubMed id: 19116277 DOI: 10.1073/pnas.0811325106
Date:
06-Oct-08     Release date:   17-Feb-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P37231  (PPARG_HUMAN) -  Peroxisome proliferator-activated receptor gamma from Homo sapiens
Seq:
Struc: 		505 a.a.
260 a.a.*
Protein chain
Pfam   ArchSchema ?
Q15788  (NCOA1_HUMAN) -  Nuclear receptor coactivator 1 from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1441 a.a.
16 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chain P: E.C.2.3.1.48  - histone acetyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: L-lysyl-[protein] + acetyl-CoA = N6-acetyl-L-lysyl-[protein] + CoA + H+
L-lysyl-[protein]
 + acetyl-CoA
 = N(6)-acetyl-L-lysyl-[protein]
 + CoA
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    Added reference    
 
 
DOI no: 10.1073/pnas.0811325106 Proc Natl Acad Sci U S A 106:262-267 (2009)
PubMed id: 19116277  
 
 
Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent.
D.R.Artis, J.J.Lin, C.Zhang, W.Wang, U.Mehra, M.Perreault, D.Erbe, H.I.Krupka, B.P.England, J.Arnold, A.N.Plotnikov, A.Marimuthu, H.Nguyen, S.Will, M.Signaevsky, J.Kral, J.Cantwell, C.Settachatgull, D.S.Yan, D.Fong, A.Oh, S.Shi, P.Womack, B.Powell, G.Habets, B.L.West, K.Y.Zhang, M.V.Milburn, G.P.Vlasuk, K.P.Hirth, K.Nolop, G.Bollag, P.N.Ibrahim, J.F.Tobin.
 
  ABSTRACT  
 
In a search for more effective anti-diabetic treatment, we used a process coupling low-affinity biochemical screening with high-throughput co-crystallography in the design of a series of compounds that selectively modulate the activities of all three peroxisome proliferator-activated receptors (PPARs), PPARalpha, PPARgamma, and PPARdelta. Transcriptional transactivation assays were used to select compounds from this chemical series with a bias toward partial agonism toward PPARgamma, to circumvent the clinically observed side effects of full PPARgamma agonists. Co-crystallographic characterization of the lead molecule, indeglitazar, in complex with each of the 3 PPARs revealed the structural basis for its PPAR pan-activity and its partial agonistic response toward PPARgamma. Compared with full PPARgamma-agonists, indeglitazar is less potent in promoting adipocyte differentiation and only partially effective in stimulating adiponectin gene expression. Evaluation of the compound in vivo confirmed the reduced adiponectin response in animal models of obesity and diabetes while revealing strong beneficial effects on glucose, triglycerides, cholesterol, body weight, and other metabolic parameters. Indeglitazar has now progressed to Phase II clinical evaluations for Type 2 diabetes mellitus (T2DM).
 
  Selected figure(s)  
 
Figure 1.
Discovery and structural characterization of indeglitazar. (A) Crystal structure of scaffold 1 with PPARγ. The blue mesh encompassing 1 delineates the productive hydrophobic interaction space common to PPARα, PPARγ, and PPARδ (see SI Experimental Procedures). The 4 residues shown in sticks comprise the core signaling linkage to the ligand acidic moiety. (B) Overlap of indeglitazar in complex with PPARα (red), PPARγ (green), and PPARδ (blue). (C–E) Close-up of the individual structures in the region highlighted from B. Note the water-mediated interactions in D and E. The chemical structures of the compounds 1, 2, and 3 (indeglitazar) are shown. 		Figure 2.
Cellular activity of indeglitazar and its effect on the expression of adiponectin and in vivo adiponectin response. (A–C) Transactivation assay activity of indeglitazar (filled circles) and reference compound (open circles) in PPARα, PPARγ, and PPARδ, respectively. Note the partial response of indeglitazar toward PPARγ. (D) Preadipocyte differentiation stimulated by rosiglitazone (open circles) and indeglitazar (filled circles). (E) Taqman analysis of the expression of adiponectin by mature adipocytes treated by indeglitazar and rosiglitazone. (F) Effect of indeglitazar and pioglitazone on adiponectin levels in the ob/ob mice after 14 days of treatment.
 
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23060265 G.Bollag, J.Tsai, J.Zhang, C.Zhang, P.Ibrahim, K.Nolop, and P.Hirth (2012).
Vemurafenib: the first drug approved for BRAF-mutant cancer.
  Nat Rev Drug Discov, 11, 873-886.  
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.  
21521130 L.M.Younk, L.Uhl, and S.N.Davis (2011).
Pharmacokinetics, efficacy and safety of aleglitazar for the treatment of type 2 diabetes with high cardiovascular risk.
  Expert Opin Drug Metab Toxicol, 7, 753-763.  
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.  
20471246 C.W.Murray, and T.L.Blundell (2010).
Structural biology in fragment-based drug design.
  Curr Opin Struct Biol, 20, 497-507.  
20723571 L.Jin, and Y.Li (2010).
Structural and functional insights into nuclear receptor signaling.
  Adv Drug Deliv Rev, 62, 1218-1226.  
20367191 L.S.Doshi, M.K.Brahma, U.A.Bahirat, A.V.Dixit, and K.V.Nemmani (2010).
Discovery and development of selective PPAR gamma modulators as safe and effective antidiabetic agents.
  Expert Opin Investig Drugs, 19, 489-512.  
20152000 M.Perreault, S.Will, D.Panza, T.Gareski, K.Harding, D.Kubasiak, M.Jalenak, K.Gartrell, S.Wang, G.Bollag, D.R.Artis, P.N.Ibrahim, P.Womack, J.J.Lin, E.Saiah, T.S.Mansour, G.P.Vlasuk, D.V.Erbe, and J.F.Tobin (2010).
Modulation of nutrient sensing nuclear hormone receptors promotes weight loss through appetite suppression in mice.
  Diabetes Obes Metab, 12, 234-245.  
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
19427404 G.Chessari, and A.J.Woodhead (2009).
From fragment to clinical candidate--a historical perspective.
  Drug Discov Today, 14, 668-675.  
19622862 T.Oyama, K.Toyota, T.Waku, Y.Hirakawa, N.Nagasawa, J.I.Kasuga, Y.Hashimoto, H.Miyachi, and K.Morikawa (2009).
Adaptability and selectivity of human peroxisome proliferator-activated receptor (PPAR) pan agonists revealed from crystal structures.
  Acta Crystallogr D Biol Crystallogr, 65, 786-795.
PDB codes: 2znn 2zno 2znp 2znq
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.

 

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