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Atomic structure of mutant PPARγ LBD complexed with 15d‐PGJ 2 : Novel modulation mechanism of PPARγ/RXRα function by covalently bound ligands
Author(s) -
Waku Tsuyoshi,
Shiraki Takuma,
Oyama Takuji,
Morikawa Kosuke
Publication year - 2009
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2008.12.017
Subject(s) - retinoid x receptor , peroxisome proliferator activated receptor , covalent bond , chemistry , nuclear receptor , ligand (biochemistry) , receptor , function (biology) , mutant , stereochemistry , transcription factor , biophysics , biochemistry , biology , microbiology and biotechnology , gene , organic chemistry
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.