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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* » Introduction
Crystal structures of PPARα, -δ, and -γ ligand-binding domains (LBDs), in complex with various agonists (5, 21-23), reveal a common binding mode where the ligands form specific hydrogen bonds with residues in, and in the vicinity of, helix 12, also known as activation function 2 (AF2). It is generally believed that agonist binding to NRs induces changes in the dynamics and position of helix 12, which in turn facilitates the recruitment of coactivator proteins resulting in an activation of the transcriptional machinery. The ligand-binding pockets of PPAR LBDs are larger than for other NRs and, as shown for the PPARγ-GW0072 complex (24), allow ligand binding at epitopes distal to helix 12. The GW0072 compound is a poor transactivator and can antagonize TZD-driven adipocyte differentiation (24). Taken together, these observations suggest that the specific hydrogen bonding interactions seen between the agonists and AF2 could act as a necessary molecular switch for transactivation to occur (22, 24).
In opposition to this hypothesis we here describe a new class of PPAR agonists, the 5-substituted 2-benzoylaminobenzoic acids (2-BABAs), which act by binding at the entrance of the ligand pocket and activate the receptor without a direct interaction with helix 12. The 2-BABA compound BVT.13, which selectively activates PPARγ with a similar maximal efficacy as rosiglitazone, was shown to have antidiabetic effects in ob/ob mice.
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