3ET2: Structure Of Ppardelta With 3-[5-methoxy-1-(4-methoxy- Benzenesulfonyl)-1h-indol-3-yl]-propionic Acid

Citation:
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).
PDB ID: 3ET2Download
MMDB ID: 69712
PDB Deposition Date: 2008/10/6
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.24  Å
Source Organism:
Similar Structures:
Biological Unit for 3ET2: monomeric; determined by author and by software (PISA)
Molecular Components in 3ET2
Label Count Molecule
Protein (1 molecule)
1
Peroxisome Proliferator-activated Receptor Delta(Gene symbol: PPARD)
Molecule annotation
Chemicals (4 molecules)
1
1
2
3
* Click molecule labels to explore molecular sequence information.

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