3ET1

Structure of PPARalpha with 3-[5-Methoxy-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid

Summary for 3ET1

• Entry DOI: 10.2210/pdb3et1/pdb
• Related: 3ET0 3ET2 3ET3
• Descriptor: Peroxisome proliferator-activated receptor alpha, Steroid receptor coactivator 1, 3-{5-methoxy-1-[(4-methoxyphenyl)sulfonyl]-1H-indol-3-yl}propanoic acid, ... (4 entities in total)
• Functional Keywords: ppar, ppara, pparalpha, drug discovery, diabetes, adiponectin, metabolic disease, fragment-based drug discovery, scaffold-based drug discovery, activator, dna-binding, metal-binding, nucleus, polymorphism, receptor, transcription, transcription regulation, zinc, zinc-finger, acyltransferase, alternative splicing, chromosomal rearrangement, phosphoprotein, proto-oncogene, transferase, ubl conjugation, transcription-transferase complex, transcription/transferase
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: Q07869; Nucleus (By similarity): Q15788
• Total number of polymer chains: 4
• Total formula weight: 70457.90

Authors

Zhang, K.Y.J.,Wang, W. (deposition date: 2008-10-06, release date: 2009-02-17, Last modification date: 2023-09-06)

Primary citation

Artis, D.R.,Lin, J.J.,Zhang, C.,Wang, W.,Mehra, U.,Perreault, M.,Erbe, D.,Krupka, H.I.,England, B.P.,Arnold, J.,Plotnikov, A.N.,Marimuthu, A.,Nguyen, H.,Will, S.,Signaevsky, M.,Kral, J.,Cantwell, J.,Settachatgull, C.,Yan, D.S.,Fong, D.,Oh, A.,Shi, S.,Womack, P.,Powell, B.,Habets, G.,West, B.L.,Zhang, K.Y.,Milburn, M.V.,Vlasuk, G.P.,Hirth, K.P.,Nolop, K.,Bollag, G.,Ibrahim, P.N.,Tobin, J.F.
Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent
Proc.Natl.Acad.Sci.USA, 106:262-267, 2009

PubMed 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).

PubMed: 19116277
DOI: 10.1073/pnas.0811325106

Experimental method

X-RAY DIFFRACTION (2.5 Å)