A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation.

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.
Mesh Terms:
Adipocytes, Animals, Binding Sites, Cell Differentiation, Cell Line, Cercopithecus aethiops, Crystallography, X-Ray, Humans, Kinetics, Ligands, Mice, Models, Molecular, Molecular Conformation, Molecular Sequence Data, Nuclear Proteins, Protein Structure, Secondary, Receptors, Cytoplasmic and Nuclear, Recombinant Proteins, Thiazoles, Thiazolidinediones, Thiazolidines, Transcription Factors, Transfection
Proc. Natl. Acad. Sci. U.S.A.
Date: May. 25, 1999
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