Structural basis for the activation of PPARγ by oxidized fatty acids

被引：379

作者：

Itoh, Toshimasa ^{[1
]}

Fairall, Louise ^{[1
]}

Amin, Kush ^{[1
]}

Inaba, Yuka ^{[2
]}

Szanto, Attila ^{[3
]}

Balint, Balint L. ^{[3
]}

Nagy, Laszlo ^{[3
]}

Yamamoto, Keiko ^{[2
]}

Schwabe, John W. R. ^{[1
]}

机构：

[1] Univ Leicester, Dept Biochem, Henry Wellcome Labs Struct Biol, Leicester LE1 9HN, Leics, England

[2] Showa Pharmaceut Univ, Lab Drug Design & Med Chem, Tokyo 1948543, Japan

[3] Univ Debrecen, Med & Hlth Sci Ctr, Dept Biochem & Mol Biol, Hungarian Acad Sci,Apoptosis & Genom Res Grp, H-4032 Debrecen, Hungary

来源：

NATURE STRUCTURAL & MOLECULAR BIOLOGY | 2008年 / 15卷 / 09期

基金：

英国医学研究理事会; 匈牙利科学研究基金会; 英国惠康基金;

关键词：

D O I：

10.1038/nsmb.1474

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR gamma) has important roles in adipogenesis and immune response as well as roles in both lipid and carbohydrate metabolism. Although synthetic agonists for PPAR gamma are widely used as insulin sensitizers, the identity of the natural ligand(s) for PPAR gamma is still not clear. Suggested natural ligands include 15-deoxy-Delta(12,14)-prostaglandin J2 and oxidized fatty acids such as 9-HODE and 13-HODE. Crystal structures of PPAR gamma have revealed the mode of recognition for synthetic compounds. Here we report structures of PPAR gamma bound to oxidized fatty acids that are likely to be natural ligands for this receptor. These structures reveal that the receptor can (i) simultaneously bind two fatty acids and (ii) couple covalently with conjugated oxo fatty acids. Thermal stability and gene expression analyses suggest that such covalent ligands are particularly effective activators of PPAR gamma and thus may serve as potent and biologically relevant ligands.

引用

页码：924 / 931

页数：8

共 37 条

[1] THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].