6DHA
Crystal Structure of Human PPARgamma Ligand Binding Domain in Complex with Hydroxy Pioglitazone (M-IV)
Summary for 6DHA
| Entry DOI | 10.2210/pdb6dha/pdb |
| Descriptor | Peroxisome proliferator-activated receptor gamma, Hydroxy Pioglitazone (M-IV), nonanoic acid, ... (4 entities in total) |
| Functional Keywords | nuclear receptors, tzds, drug design, therapeutic targets, transcription, transcription-transcription inhibitor complex, transcription/transcription inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 63055.39 |
| Authors | Shang, J.,Mosure, S.A.,Kojetin, D.J. (deposition date: 2018-05-18, release date: 2019-03-13, Last modification date: 2023-10-11) |
| Primary citation | Mosure, S.A.,Shang, J.,Eberhardt, J.,Brust, R.,Zheng, J.,Griffin, P.R.,Forli, S.,Kojetin, D.J. Structural Basis of Altered Potency and Efficacy Displayed by a Major in Vivo Metabolite of the Antidiabetic PPAR gamma Drug Pioglitazone. J. Med. Chem., 62:2008-2023, 2019 Cited by PubMed 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. PubMed: 30676741DOI: 10.1021/acs.jmedchem.8b01573 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.88 Å) |
Structure validation
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