title: Structural basis for telmisartan-mediated partial activation of PPAR gamma.
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.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Amano
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Kazuki
authors.initials: K
authors.lastname: Ohno
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Niimi
authors.forename: Masaya
authors.initials: M
authors.lastname: Orita
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sakashita
authors.forename: Makoto
authors.initials: M
authors.lastname: Takeuchi
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry* / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D056920:Nuclear Receptor Coactivator 1 / Q000737:chemistry; D047495:PPAR gamma / Q000819:agonists*; D013329:Structure-Activity Relationship; D000077333:Telmisartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D047495:PPAR gamma; D056920:Nuclear Receptor Coactivator 1; D000077333:Telmisartan