2p54
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| , resolution 1.79Å | |||||||
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| Ligands: | |||||||
| Gene: | PPARA, NR1C1, PPAR (Homo sapiens) | ||||||
| Activity: | Histone acetyltransferase, with EC number 2.3.1.48 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
a crystal structure of PPAR alpha bound with SRC1 peptide and GW735
OverviewOverview
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.
About this StructureAbout this Structure
2P54 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Substituted 2-[(4-aminomethyl)phenoxy]-2-methylpropionic acid PPARalpha agonists. 1. Discovery of a novel series of potent HDLc raising agents., Sierra ML, Beneton V, Boullay AB, Boyer T, Brewster AG, Donche F, Forest MC, Fouchet MH, Gellibert FJ, Grillot DA, Lambert MH, Laroze A, Le Grumelec C, Linget JM, Montana VG, Nguyen VL, Nicodeme E, Patel V, Penfornis A, Pineau O, Pohin D, Potvain F, Poulain G, Ruault CB, Saunders M, Toum J, Xu HE, Xu RX, Pianetti PM, J Med Chem. 2007 Feb 22;50(4):685-95. Epub 2007 Jan 23. PMID:17243659
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