| Literature DB >> 10339548 |
J L Oberfield1, J L Collins, C P Holmes, D M Goreham, J P Cooper, J E Cobb, J M Lenhard, E A Hull-Ryde, C P Mohr, S G Blanchard, D J Parks, L B Moore, J M Lehmann, K Plunket, A B Miller, M V Milburn, S A Kliewer, T M Willson.
Abstract
The peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate glucose and lipid homeostasis. The PPARgamma subtype plays a central role in the regulation of adipogenesis and is the molecular target for the 2, 4-thiazolidinedione class of antidiabetic drugs. Structural studies have revealed that agonist ligands activate the PPARs through direct interactions with the C-terminal region of the ligand-binding domain, which includes the activation function 2 helix. GW0072 was identified as a high-affinity PPARgamma ligand that was a weak partial agonist of PPARgamma transactivation. X-ray crystallography revealed that GW0072 occupied the ligand-binding pocket by using different epitopes than the known PPAR agonists and did not interact with the activation function 2 helix. In cell culture, GW0072 was a potent antagonist of adipocyte differentiation. These results establish an approach to the design of PPAR ligands with modified biological activities.Entities:
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Year: 1999 PMID： 10339548 PMCID： PMC26842 DOI： 10.1073/pnas.96.11.6102
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205