2P54

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

2P54 の概要

• エントリーDOI: 10.2210/pdb2p54/pdb
• 分子名称: 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)
• 機能のキーワード: ppar alpha gw735 src1 agonist hdlc, transcription
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Nucleus: Q07869; Nucleus (By similarity): Q15788
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 32267.71

構造登録者

Xu, R.X.,Xu, H.E.,Sierra, M.L.,Montana, V.G.,Lambert, M.H.,Pianetti, P.M. (登録日: 2007-03-14, 公開日: 2007-04-24, 最終更新日: 2024-04-03)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.79 Å)