This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.
Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.
6dha
From Proteopedia
Crystal Structure of Human PPARgamma Ligand Binding Domain in Complex with Hydroxy Pioglitazone (M-IV)
Structural highlights
DiseasePPARG_HUMAN Note=Defects in PPARG can lead to type 2 insulin-resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer. Defects in PPARG may be associated with susceptibility to obesity (OBESITY) [MIM:601665. It is a condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.[1] Defects in PPARG are the cause of familial partial lipodystrophy type 3 (FPLD3) [MIM:604367. Familial partial lipodystrophies (FPLD) are a heterogeneous group of genetic disorders characterized by marked loss of subcutaneous (sc) fat from the extremities. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia.[2] [3] Genetic variations in PPARG can be associated with susceptibility to glioma type 1 (GLM1) [MIM:137800. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility. FunctionPPARG_HUMAN Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses.[4] [5] [6] Publication Abstract from PubMedPioglitazone (Pio) is a Food and Drug Administration-approved drug for type-2 diabetes that binds and activates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma), yet it remains unclear how in vivo Pio metabolites affect PPARgamma 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 PPARgamma 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 PPARgamma 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 PPARgamma agonist contributes to our understanding of PPARgamma-drug metabolite interactions. Structural Basis of Altered Potency and Efficacy Displayed by a Major in Vivo Metabolite of the Antidiabetic PPARgamma Drug Pioglitazone.,Mosure SA, Shang J, Eberhardt J, Brust R, Zheng J, Griffin PR, Forli S, Kojetin DJ J Med Chem. 2019 Feb 28;62(4):2008-2023. doi: 10.1021/acs.jmedchem.8b01573. Epub , 2019 Feb 7. PMID:30676741[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
