Structural basis for telmisartan-mediated partial activation of PPAR gamma

摘要: Telmisartan, a selective angiotensin II type 1 receptor blocker, has recently been shown to act as partial agonist for peroxisome proliferator-activated gamma (PPARγ). To understand how telmisartan partially activates PPARγ, we determined the ternary complex structure of telmisartan, and coactivator peptide from steroid coactivator-1 at resolution 2.18 A. Crystallographic analysis revealed that exhibits an unexpected binding mode in which central benzimidazole ring is engaged non-canonical—and suboptimal—hydrogen-bonding network around helix 12 (H12). This differs greatly observed when full-agonists bind with PPARγ prompt high-coactivator recruitment through H12 stabilized by multiple hydrogen bonds. Binding results less stable turn leads attenuated binding, thus explaining mechanism activation.