3VN2

Crystal Structure of PPARgamma complexed with Telmisartan

Summary for 3VN2

• Entry DOI: 10.2210/pdb3vn2/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, Nuclear receptor coactivator 1, 4'-[(1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-bibenzimidazol-3'-yl)methyl]biphenyl-2-carboxylic acid, ... (4 entities in total)
• Functional Keywords: signaling protein
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P37231; Nucleus (By similarity): Q15788
• Total number of polymer chains: 2
• Total formula weight: 34913.44

Authors

Amano, Y. (deposition date: 2011-12-21, release date: 2012-03-07, Last modification date: 2024-03-20)

Primary citation

Amano, Y.,Yamaguchi, T.,Ohno, K.,Niimi, T.,Orita, M.,Sakashita, H.,Takeuchi, M.
Structural basis for telmisartan-mediated partial activation of PPAR gamma
Hypertens Res, 35:715-719, 2012

PubMed 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.

PubMed: 22357520
DOI: 10.1038/hr.2012.17

Experimental method

X-RAY DIFFRACTION (2.18 Å)