Atomic structure of mutant PPAR gamma LBD complexed with 15d-PGJ(2): Novel modulation mechanism of PPAR gamma/RXR alpha function by covalently bound ligands

作者：Waku Tsuyoshi; Shiraki Takuma; Oyama Takuji; Morikawa Kosuke^*

来源：FEBS LETTERS, 2009, 583(2): 320-324.

DOI：10.1016/j.febslet.2008.12.017

• PPAR gamma
• covalently bound ligand
• PPAR gamma/RXR alpha
• activating process
• modulation mechanism
• Crystal structure

15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) activates a nuclear receptor heterodimer, peroxisome proliferators-activated receptor gamma (PPAR gamma)/retinoid X receptor (RXR alpha) through covalent binding to Cys285 in PPAR gamma ligand-binding domain (LBD). Here, we present the 1.9 angstrom 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 beta-sheet. Comparisons with previous structures clarified the relationships between PPAR gamma 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 PPAR gamma/RXR alpha function through conformational changes of the loop following helix H2' and the beta-sheet.

• 出版日期2009-1-22