4PRG

0072 PARTIAL AGONIST PPAR GAMMA COCRYSTAL

Summary for 4PRG

• Entry DOI: 10.2210/pdb4prg/pdb
• Descriptor: PROTEIN (PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA), (+/-)(2S,5S)-3-(4-(4-CARBOXYPHENYL)BUTYL)-2-HEPTYL-4-OXO-5-THIAZOLIDINE (2 entities in total)
• Functional Keywords: thiazolidinone, ligand-binding domain, nuclear receptor, orphan receptor, receptor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 125794.75

Authors

Milburn, M.V. (deposition date: 1999-05-07, release date: 1999-05-27, Last modification date: 2023-12-27)

Primary citation

Oberfield, J.L.,Collins, J.L.,Holmes, C.P.,Goreham, D.M.,Cooper, J.P.,Cobb, J.E.,Lenhard, J.M.,Hull-Ryde, E.A.,Mohr, C.P.,Blanchard, S.G.,Parks, D.J.,Moore, L.B.,Lehmann, J.M.,Plunket, K.,Miller, A.B.,Milburn, M.V.,Kliewer, S.A.,Willson, T.M.
A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation.
Proc.Natl.Acad.Sci.USA, 96:6102-6106, 1999

PubMed 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.

PubMed: 10339548
DOI: 10.1073/pnas.96.11.6102

Experimental method

X-RAY DIFFRACTION (2.9 Å)