Review of the Structural and Dynamic Mechanisms of PPARγ Partial Agonism

被引:159
作者
Kroker, Alice J. [1 ]
Bruning, John B. [1 ]
机构
[1] Univ Adelaide, Sch Biol Sci, Adelaide, SA 5005, Australia
关键词
PROLIFERATOR-ACTIVATED-RECEPTOR; LIGAND-BINDING DOMAIN; II TYPE-1 RECEPTOR; NUCLEAR RECEPTORS; CRYSTAL-STRUCTURE; (-)-CERCOSPORAMIDE DERIVATIVES; DISTINCT PROPERTIES; GLYCEMIC CONTROL; ADIPOSE-TISSUE; DUAL ACTIVITY;
D O I
10.1155/2015/816856
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
PPAR gamma (peroxisome proliferator activated receptor gamma) is a ligand activated transcription factor of the nuclear receptor superfamily that controls the expression of a variety of genes involved in fatty acid metabolism, adipogenesis, and insulin sensitivity. While endogenous ligands of PPAR gamma include fatty acids and eicosanoids, synthetic full agonists of the receptor, including members of the thiazolidinedione (TZD) class, have been widely prescribed for the treatment of type II diabetes mellitus (T2DM). Unfortunately, the use of full agonists has been hampered by harsh side effects with some removed from the market in many countries. In contrast, partial agonists of PPAR gamma have been shown to retain favourable insulin sensitizing effects while exhibiting little to no side effects and thus represent a new potential class of therapeutics for the treatment of T2DM. Partial agonists have been found to not only display differences in transcriptional and cellular outcomes, but also act through distinct structural and dynamic mechanisms within the ligand binding cavity compared to full agonists.
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页数:15
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