A Peroxisome Proliferator-Activated Receptor γ Ligand Inhibits Adipocyte Differentiation
The peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate glucose and lipid homeostasis. The PPARγ subtype plays a central role in the regulation of adipogenesis and is the molecular target for the 2,4-thiazolidinedione class of antidiabetic drugs. Structura...
Saved in:
Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 96; no. 11; pp. 6102 - 6106 |
---|---|
Main Authors | , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences of the United States of America
25.05.1999
National Acad Sciences The National Academy of Sciences |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | The peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate glucose and lipid homeostasis. The PPARγ 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 PPARγ ligand that was a weak partial agonist of PPARγ 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. |
---|---|
Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 To whom reprint requests should be addressed at: Glaxo Wellcome, NTH-M1421, 5 Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709-3398. e-mail: tmw20653@glaxowellcome.com. Communicated by Michael G. Rosenfeld, University of California, San Diego, La Jolla, CA |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.96.11.6102 |