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Structural basis for telmisartan-mediated partial activation of PPAR gamma
Yasushi Amano1, Tomohiko Yamaguchi, Kazuki Ohno
1Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
Summary
Telmisartan partially activates peroxisome proliferator-activated receptor gamma (PPARγ) by binding in a unique way. This binding mode destabilizes a key region, leading to reduced coactivator interaction and explaining its partial agonist activity.
Area of Science:
- Molecular biology
- Structural biology
- Pharmacology
Background:
- Telmisartan is an angiotensin II type 1 receptor blocker.
- Telmisartan exhibits partial agonism for peroxisome proliferator-activated receptor gamma (PPARγ).
Purpose of the Study:
- To elucidate the structural mechanism behind telmisartan's partial activation of PPARγ.
- To understand how telmisartan's binding affects coactivator recruitment.
Main Methods:
- Determined the ternary complex structure of PPARγ, telmisartan, and a coactivator peptide using X-ray crystallography.
- Analyzed the binding mode and hydrogen-bonding interactions at a resolution of 2.18 Å.
Main Results:
- Telmisartan binds to PPARγ via an unexpected mode, utilizing a non-canonical hydrogen-bonding network around helix 12 (H12).
- This network differs significantly from that induced by full agonists, leading to a less stable H12.
- The destabilized H12 results in attenuated coactivator binding.
Conclusions:
- The unique binding of telmisartan to PPARγ explains its partial agonist activity.
- Structural insights reveal how suboptimal interactions lead to reduced coactivator recruitment and partial activation.
- This study provides a molecular basis for telmisartan's pharmacological profile concerning PPARγ.
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