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X-ray structure of human PPARgamma ligand binding domain-NCoR2 corepressor peptide co-crystals obtained by co-crystallization
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 PubMedPeroxisome proliferator-activated receptors (PPARs), composed of the alpha/delta/gamma subtypes, are ligand-activated nuclear receptors/transcription factors that sense endogenous fatty acids or therapeutic drugs to regulate lipid/glucose metabolism and oxidative stress. PPAR forms a multiprotein complex with a retinoid X receptor and corepressor complex in an unliganded/inactive state, and ligand binding induces the replacement of the corepressor complex with the coactivator complex to initiate the transcription of various genes, including the metabolic and antioxidant ones. We investigated the processes by which the corepressor is replaced with the coactivator or in which two coactivators compete for the PPARalpha/delta/gamma-ligand-binding domains (LBDs) using single- and dual-emission fluorescence resonance energy transfer (FRET) assays. Single-FRET revealed that the respective PPARalpha/delta/gamma-selective agonists (pemafibrate, seladelpar, and pioglitazone) induced the dissociation of the two corepressor peptides, NCoR1 and NCoR2, from the PPARalpha/delta/gamma-LBDs and the recruitment of the two coactivator peptides, CBP and TRAP220. Meanwhile, dual-FRET demonstrated that these processes are simultaneous and that the four coactivator peptides, CBP, TRAP220, PGC1alpha, and SRC1, were competitively recruited to the PPARalpha/delta/gamma-LBDs with different preferences upon ligand activation. Furthermore, the five newly obtained cocrystal structures using X-ray diffraction, PPARalpha-LBDs-NCoR2/CBP/TRAP220/PGC1alpha and PPARgamma-LBD-NCoR2, were co-analyzed with those from our previous studies. This illustrates that these coactivators bound to the same PPARalpha-LBD loci via their consensus LXXLL motifs in the liganded state; that NCoR1/NCoR2 corepressors bound to the same loci via the IXXXL sequences within their consensus LXXXIXXXL motifs in the unliganded state; and that ligand activation induced AF-2 helix 12 formation that interfered with corepressor binding and created a binding space for the coactivator. These PPARalpha/gamma-related biochemical and physicochemical findings highlight the coregulator dynamics on limited PPARalpha/delta/gamma-LBDs loci. Competitive Ligand-Induced Recruitment of Coactivators to Specific PPARalpha/delta/gamma Ligand-Binding Domains Revealed by Dual-Emission FRET and X-Ray Diffraction of Cocrystals.,Kamata S, Honda A, Yashiro S, Kaneko C, Komori Y, Shimamura A, Masuda R, Oyama T, Ishii I Antioxidants (Basel). 2025 Apr 20;14(4):494. doi: 10.3390/antiox14040494. PMID:40298866[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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