2P54: A Crystal Structure Of Ppar Alpha Bound With Src1 Peptide And Gw735

The peroxisome proliferator activated receptors PPARalpha, PPARgamma, and PPARdelta are ligand-activated transcription factors that play a key role in lipid homeostasis. The fibrates raise circulating levels of high-density lipoprotein cholesterol and lower levels of triglycerides in part through their activity as PPARalpha agonists; however, the low potency and restricted selectivity of the fibrates may limit their efficacy, and it would be desirable to develop more potent and selective PPARalpha agonists. Modification of the selective PPARdelta agonist 1 (GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of the fibrates led to a marked shift in potency and selectivity toward PPARalpha agonism. Optimization of the series gave 25a, which shows EC50 = 4 nM on PPARalpha and at least 500-fold selectivity versus PPARdelta and PPARgamma. Compound 25a (GW590735) has been progressed to clinical trials for the treatment of diseases of lipid imbalance.
PDB ID: 2P54Download
MMDB ID: 45728
PDB Deposition Date: 2007/3/14
Updated in MMDB: 2011/10
Experimental Method:
x-ray diffraction
Resolution: 1.79  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 2P54: dimeric; determined by author
Molecular Components in 2P54
Label Count Molecule
Proteins (2 molecules)
Peroxisome Proliferator-activated Receptor Alpha(Gene symbol: PPARA)
Molecule annotation
Nuclear Receptor Coactivator 1(Gene symbol: NCOA1)
Molecule annotation
Chemical (1 molecule)
* Click molecule labels to explore molecular sequence information.

Citing MMDB