2P54

a crystal structure of PPAR alpha bound with SRC1 peptide and GW735

Summary for 2P54

• Entry DOI: 10.2210/pdb2p54/pdb
• Descriptor: Peroxisome proliferator-activated receptor alpha, Nuclear receptor coactivator 1, 2-METHYL-2-(4-{[({4-METHYL-2-[4-(TRIFLUOROMETHYL)PHENYL]-1,3-THIAZOL-5-YL}CARBONYL)AMINO]METHYL}PHENOXY)PROPANOIC ACID, ... (4 entities in total)
• Functional Keywords: ppar alpha gw735 src1 agonist hdlc, transcription
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: Q07869; Nucleus (By similarity): Q15788
• Total number of polymer chains: 2
• Total formula weight: 32267.71

Authors

Xu, R.X.,Xu, H.E.,Sierra, M.L.,Montana, V.G.,Lambert, M.H.,Pianetti, P.M. (deposition date: 2007-03-14, release date: 2007-04-24, Last modification date: 2024-04-03)

Primary citation

Sierra, M.L.,Beneton, V.,Boullay, A.B.,Boyer, T.,Brewster, A.,Donche, F.,Forest, M.C.,Fouchet, M.H.,Gellibert, F.J.,Grillot, D.A.,Lambert, M.H.,Laroze, A.,Grumelec, C.L.,Linget, J.M.,Montana, V.G.,Nguyen, V.L.,Nicodeme, E.,Patel, V.,Penfornis, A.,Pineau, O.,Pohin, D.,Potvain, F.,Paulain, G.,Ruault, C.B.,Saunders, M.,Toum, J.,Xu, H.E.,Xu, R.X.,Pianetti, P.M.
Substituted 2-[(4-Aminomethyl)phenoxy]-2-methylpropionic Acid PPAR Agonists. 1.Discovery of a Novel Series of Potent HDLc Raising Agents.
J.Med.Chem., 50:685-695, 2007

PubMed Abstract: 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.

PubMed: 17243659
DOI: 10.1021/jm058056x

Experimental method

X-RAY DIFFRACTION (1.79 Å)