PMC

Typical structural features of PPAR agonists are displayed. Carbon, fluoride, sulfur, oxygen and nitrogen atoms are colored white, light grey, grey, dark grey and black, respectively.

PPAR activation induced by (A) the δ-selective agonist GW0742; (B) the pan-agonist benzafibrate; (C) the α-selective agonist GW7647 and (D) the γ-selective agonist rosiglitazone. All data were normalized by the level of Renilla luciferase activity. ▪/# wtPPARδ, ▴/xx PPARδVal312Met, •///PPARδIle328M, <$>\vskip -1\scale 80%\raster="rg1"<$>/ = PPARα and ◂/<$>\vskip -1\scale 70%\raster="rg2"<$>PPARγ.

Residues placed in arm I (A), arm II (B) and arm III (C) are shown. Residues involved in the hPPARδ-LBD:GW0742 interactions are underscored. Residues in black, bold and gray represent identical residues, residues with same chemical character and residues with different chemical character, respectively.

Helices from PPAR are shown as yellow, magenta and green cartoons for PPARα, δ and γ, respectively. The α selective ligand, GW735 (PDBid: 2P54), the δ selective ligand, GW0742, and the γ selective ligand, rosiglitazone (PDBid: 2PRG), are shown as yellow, magenta and green sticks, respectively. Oxygen, nitrogen, sulfur and fluoride atoms are shown in red, blue, yellow and light blue, respectively. A) Upper vision of the binding site. B) Stereoscopic view of the PPAR binding sites, highlighting the importance of Val312 and Ile328 in GW0742 accommodation and GW735 and rosiglitazone displacement, presumably due to the presence of bulky substitutions. Ligands GW735, GW0742, rosiglitazone are painted in yellow, magenta and green, respectively.

(A) The ligand (magenta sticks) occupies the PPARδ-LBD (grey cartoon) and performs interactions with residues belonging to the arm I (yellow), arm II (green) and arm III (orange). (B) Stereo view of the binding site, showing the electron density calculated for the ligand (omit map, contoured at σ = 1.0) and the PPARδ residues that stabilize the ligand. Polar interactions between hPPARδ-LBD and the GW0742 ligand are shown as dashed lines. Nitrogen, oxygen, sulfur and fluoride atoms are colored blue, red, yellow and light blue, respectively. The residues from arms I, II and III are colored in yellow, green and orange, respectively. Figures were generated with the Pymol software (Schrödinger).