Structural basis for telmisartan-mediated partial activation of PPAR gamma

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Abstract

Telmisartan, a selective angiotensin II type 1 receptor blocker, has recently been shown to act as a partial agonist for peroxisome proliferator-activated receptor gamma (PPARγ). To understand how telmisartan partially activates PPARγ, we determined the ternary complex structure of PPARγ, telmisartan, and a coactivator peptide from steroid receptor coactivator-1 at a resolution of 2.18 Å. Crystallographic analysis revealed that telmisartan exhibits an unexpected binding mode in which the central benzimidazole ring is engaged in a non-canonical-and suboptimal-hydrogen-bonding network around helix 12 (H12). This network differs greatly from that observed when full-agonists bind with PPARγ and prompt high-coactivator recruitment through H12 stabilized by multiple hydrogen bonds. Binding with telmisartan results in a less stable H12 that in turn leads to attenuated coactivator binding, thus explaining the mechanism of partial activation. © 2012 The Japanese Society of Hypertension All rights reserved.

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Amano, Y., Yamaguchi, T., Ohno, K., Niimi, T., Orita, M., Sakashita, H., & Takeuchi, M. (2012). Structural basis for telmisartan-mediated partial activation of PPAR gamma. Hypertension Research, 35(7), 715–719. https://doi.org/10.1038/hr.2012.17

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