Atomic structure of mutant PPARγ LBD complexed with 15d‐PGJ 2 : Novel modulation mechanism of PPARγ/RXRα function by covalently bound ligands
Authors:
- Takuma ShirakiTSTakuma Shiraki
- Takuji OyamaTakuji Oyama
- Kosuke MorikawaKMKosuke Morikawa
- 25 December 2008
- journal article
- research article
- Published by Wiley in FEBS Letters
- Vol. 583 (2) , 320-324
Abstract
15‐deoxy‐Δ 12,14 ‐prostaglandin J 2 (15d‐PGJ 2 ) activates a nuclear receptor heterodimer, peroxisome proliferators‐activated receptor γ (PPARγ)/ retinoid X receptor (RXRα) through covalent binding to Cys285 in PPARγ ligand‐binding domain (LBD). Here, we present the 1.9 Å crystal structure of C285S mutant LBD complexed with 15d‐PGJ 2 , corresponding to the non‐covalently bound state. The ligand lies adjacent to a hydrogen‐bond network around the helix H2 and the nearby β‐sheet. Comparisons with previous structures clarified the relationships between PPARγ function and conformational alterations of LBD during the process of covalently binding ligands, such as 15d‐PGJ 2 , and thus suggested a mechanism, by which these ligands modulate PPARγ/RXRα function through conformational changes of the loop following helix H2′ and the β‐sheet.Keywords
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