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In here the authors described a new class of PPAR agonists, the 5…


Biology Articles » Biochemistry » A New Class of Peroxisome Proliferator-activated Receptor Agonists with a Novel Binding Epitope Shows Antidiabetic Effects* » Figures

Figures
- A New Class of Peroxisome Proliferator-activated Receptor Agonists with a Novel Binding Epitope Shows Antidiabetic Effects*

mcith_BC-peroxisomeF01.jpg Figure 1 Molecular basis for 2-BABA interaction with PPAR{gamma} a, chemical structures of BVT.13, BVT.762, and BVT.763. b, ribbons drawing of PPAR-gamma LBD in complex with BVT.13 (light blue), BVT.762 (magenta), and BVT.763 (yellow). The GRIP-1 coactivator peptide is depicted in orange. c, close-up of the PPAR-gamma ligand binding pocket with BVT.13 (light blue), BVT.762 (magenta), BVT.763 (yellow), and rosiglitazone (red). d, amino acid residues involved in BVT.13 binding. A Fo - Fc omit map is shown contoured at 2.5 sigma.

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mcith_BC-peroxisomeF02.gif Figure 2 Transcriptional activation of PPAR{gamma} by BVT.13, BVT.762, BVT.763, and rosiglitazone. CaCo-2/TC7 cells were transiently transfected with a 4xGAL4-RE luciferase reporter and a GAL4-PPAR{gamma} LBD fusion construct and subsequently treated with BVT.13, BVT.762, BVT.763, and rosiglitazone in optimized serial dilutions (a) or BVT.13, BVT.762, and BVT.763 in optimized serial dilutions in the presence of 30 nM rosiglitazone (b), as indicated in the figures. Data are shown as the -fold inductions of agonist-induced luciferase activity divided by the luciferase activity of the vehicle.

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mcith_BC-peroxisomeF03.jpg Figure 3 Selectivity of BVT.13 determined for a set of NR LBDs. Data are shown as the -fold inductions of agonist-induced luciferase activity divided by the luciferase activity of the vehicle. The following reference compounds were used as positive controls at the indicated concentrations, for hPPAR-alpha and mPPAR-alpha, 10 µM WY14643; for hPPAR-delta and mPPAR-delta, 10 µM GW2331; for hPPAR{gamma} and mPPAR-gamma, 1 µM rosiglitazone; for PXR and FXR 1 µM SR12813; for LXR{alpha} and LXR-beta, 10 µM 22(R)-hydroxycholesterol.

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mcith_BC-peroxisomeF04.jpg Figure 4 Effects of BVT.13 administration to ob/ob mice after 7 days of treatment. Fasting plasma levels of glucose (a), insulin (b), trigycerides (c), and free fatty acids (d). Ten mice/dose group were used. A statistical analysis of the plasma glucose levels was performed by one-way analysis of variance followed by Bonferroni's multiple comparison test. A statistical analysis of plasma insulin, triglyceride, and free fatty acid levels was performed by the Kruskal-Wallis test followed by Dunn's multiple comparison test. The corresponding p values for comparison with the vehicle group are indicated in the figures. {alpha}, analytes were below the detection limit of the standard protocol in four samples and therefore were not included in the statistical analysis.

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mcith_BC-peroxisomeF05.gif Figure 5 Ribbons representation of superpositioned PPAR{gamma} structures. Coordinates are from 1WM0 (light blue), 1PRG (dark blue), 2PR

G (green), 4PRG (a subunit, yellow), 1FM6 (red), 1fm9 (pink), 1K74 (light gray), 1KNU (black), and 1NYX (gold). Selected secondary elements are annotated with numbers positioned at their N-terminal ends.

 

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