3r5n | pdb_00003r5n
Crystal structure of PPARgammaLBD complexed with the agonist magnolol
Structural highlights
Disease[PPARG_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. Function[PPARG_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 PubMedNuclear receptors retinoic X receptor alpha (RXRalpha) and peroxisome proliferator activated receptor gamma (PPARgamma) function potently in metabolic diseases, and are both important targets for anti-diabetic drugs. Coactivation of RXRalpha and PPARgamma is believed to synergize their effects on glucose and lipid metabolism. Here we identify the natural product magnolol as a dual agonist targeting both RXRalpha and PPARgamma. Magnolol was previously reported to enhance adipocyte differentiation and glucose uptake, ameliorate blood glucose level and prevent development of diabetic nephropathy. Although magnolol can bind and activate both of these two nuclear receptors, the transactivation assays indicate that magnolol exhibits biased agonism on the transcription of PPAR-response element (PPRE) mediated by RXRalpha:PPARgamma heterodimer, instead of RXR-response element (RXRE) mediated by RXRalpha:RXRalpha homodimer. To further elucidate the molecular basis for magnolol agonism, we determine both the co-crystal structures of RXRalpha and PPARgamma ligand-binding domains (LBDs) with magnolol. Structural analyses reveal that magnolol adopts its two 5-allyl-2-hydroxyphenyl moieties occupying the acidic and hydrophobic cavities of RXRalpha L-shaped ligand-binding pocket, respectively. While, two magnolol molecules cooperatively accommodate into PPARgamma Y-shaped ligand-binding pocket. Based on these two complex structures, the key interactions for magnolol activating RXRalpha and PPARgamma are determined. As the first report on the dual agonist targeting RXRalpha and PPARgamma with receptor-ligand complex structures, our results are thus expected to help inspect the potential pharmacological mechanism for magnolol functions, and supply useful hits for nuclear receptor multi-target ligand design. Molecular determinants of magnolol targeting both RXRalpha and PPARgamma.,Zhang H, Xu X, Chen L, Chen J, Hu L, Jiang H, Shen X PLoS One. 2011;6(11):e28253. Epub 2011 Nov 29. PMID:22140563[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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