9hx2
X-ray crystal structure of PPAR gamma Ligand Binding Domain in complex with CZ58
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 PubMedInsulin resistance (IR) is a pathological condition in which tissues exhibit a reduced response to normal or elevated levels of insulin. Type 2 diabetes mellitus (T2DM) and Metabolic Syndrome are the most prevalent disorders associated with IR. Most of the glitazones, traditional anti-diabetic drugs acting as Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) agonists, have been withdrawn from the market. To mitigate the serious adverse effects associated with PPARgamma agonism, a new opportunity is represented by the inhibitors of PPARgamma phosphorylation by the Cyclin-Dependent Kinase 5 (CDK5). Their mechanism of action is mediated by the stabilization of the PPARgamma beta-sheet containing Ser245. Recently, we identified 4-(4-bromophenyl)-3-hydroxy-5-(3-hydroxyphenyl)furan-2(5H)-one (I) as a PPARgamma non-agonist, capable of blocking the phosphorylation of the enzyme without direct effects on either CDK5 or PPARgamma. Here, we isolated the two enantiomers of I, unambiguously defined their absolute configuration through single crystal X-ray diffraction and demonstrated by Grating-Coupled Interferometry binding assays that both (S)-I and (R)-I exhibited comparable affinity for PPARgamma. Then, a library of 12 analogs was designed through structure-based modifications, optimizing the interactions within the ligand-binding domain. GCI analysis identified derivative 11, featuring an oxyacetic group in place of the initial hydroxyl function of the reference compound I, as the most promising candidate (K(D) = 186 nM). The crystal structure of the PPARgamma-LBD/11 complex revealed a hydrogen bond interaction with Arg280, further stabilizing the binding conformation. These findings highlight the potential of gamma-hydroxy lactone derivatives as PPARgamma modulators and provide a foundation for future drug development targeting IR. Enhancing the activity of gamma-hydroxy lactone derivatives as innovative peroxisome proliferator-activated receptor gamma non-agonists inhibiting cyclin-dependent kinase 5-mediated phosphorylation.,Cazzaniga G, Capelli D, Montanari R, Fassi EMA, Grazioso G, Tresoldi A, Rinaldi F, Calleri E, Bassanini I, Romeo S, Garofalo M, Mori M, Meneghetti F, Villa S Eur J Med Chem. 2025 Aug 5;292:117657. doi: 10.1016/j.ejmech.2025.117657. Epub , 2025 Apr 18. PMID:40318479[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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