Atomic structure of mutant PPARgamma LBD complexed with 15d-PGJ2: novel modulation mechanism of PPARgamma/RXRalpha function by covalently bound ligands.
15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) activates a nuclear receptor heterodimer, peroxisome proliferators-activated receptor gamma (PPARgamma)/ retinoid X receptor (RXRalpha) through covalent binding to Cys285 in PPARgamma ligand-binding domain (LBD). Here, we present the 1.9A 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 PPARgamma 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 PPARgamma/RXRalpha function through conformational changes of the loop following helix H2' and the beta-sheet.
Waku
Tsuyoshi
T
The Takara-Bio Endowed Division, Department of Biomolecular Recognition, Institute for Protein Research, Osaka University, Open Laboratories of Advanced Bioscience and Biotechnology, 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan.
Shiraki
Takuma
T
Oyama
Takuji
T
Morikawa
Kosuke
K
D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D008024:Ligands; D047495:PPAR gamma / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000737:chemistry; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D047490:Retinoid X Receptor alpha / Q000378:metabolism
C477819:15-deoxyprostaglandin J2; D008024:Ligands; D047495:PPAR gamma; D047490:Retinoid X Receptor alpha; D015230:Prostaglandin D2