Structural Basis of Altered Potency and Efficacy Displayed by a Major in Vivo Metabolite of the Antidiabetic PPARγ Drug Pioglitazone
- Sarah A. MosureSarah A. MosureSkaggs Graduate School of Chemical and Biological Sciences and Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, Florida 33458, United StatesMore by Sarah A. Mosure
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- Jinsai ShangJinsai ShangDepartment of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, Florida 33458, United StatesMore by Jinsai Shang
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- Jerome EberhardtJerome EberhardtDepartment of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, United StatesMore by Jerome Eberhardt
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- Richard BrustRichard BrustDepartment of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, Florida 33458, United StatesMore by Richard Brust
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- Jie ZhengJie ZhengDepartment of Molecular Medicine, The Scripps Research Institute, Jupiter, Florida 33458, United StatesMore by Jie Zheng
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- Patrick R. GriffinPatrick R. GriffinDepartment of Integrative Structural and Computational Biology and Department of Molecular Medicine, The Scripps Research Institute, Jupiter, Florida 33458, United StatesMore by Patrick R. Griffin
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- Stefano ForliStefano ForliDepartment of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92037, United StatesMore by Stefano Forli
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- Douglas J. Kojetin*Douglas J. Kojetin*E-mail: [email protected]. Tel: (561) 228-2298. Fax: (561) 228-2297.Department of Integrative Structural and Computational Biology and Department of Molecular Medicine, The Scripps Research Institute, Jupiter, Florida 33458, United StatesMore by Douglas J. Kojetin
Abstract
Pioglitazone (Pio) is a Food and Drug Administration-approved drug for type-2 diabetes that binds and activates the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), yet it remains unclear how in vivo Pio metabolites affect PPARγ structure and function. Here, we present a structure–function comparison of Pio and its most abundant in vivo metabolite, 1-hydroxypioglitazone (PioOH). PioOH displayed a lower binding affinity and reduced potency in co-regulator recruitment assays. X-ray crystallography and molecular docking analysis of PioOH-bound PPARγ ligand-binding domain revealed an altered hydrogen bonding network, including the formation of water-mediated bonds, which could underlie its altered biochemical phenotype. NMR spectroscopy and hydrogen/deuterium exchange mass spectrometry analysis coupled to activity assays revealed that PioOH better stabilizes the PPARγ activation function-2 (AF-2) co-activator binding surface and better enhances co-activator binding, affording slightly better transcriptional efficacy. These results indicating that Pio hydroxylation affects its potency and efficacy as a PPARγ agonist contributes to our understanding of PPARγ–drug metabolite interactions.
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