3sz1
From Proteopedia
Human PPAR gamma ligand binding domain in complex with luteolin and myristic acid
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 PubMedPeroxisome proliferator-activated receptor gamma (PPARgamma) is a target for treatment of type II diabetes and other conditions. PPARgamma full agonists, like thiazolidinediones (TZDs), are effective insulin sensitizers and anti-inflammatories but their use is limited by adverse side effects. Luteolin is flavonoid with anti-inflammatory actions that binds PPARgamma but, unlike TZDs, does not promote adipocyte differentiation. However, previous reports variously suggested that luteolin is a PPARgamma agonist or an antagonist. We show that luteolin exhibits weak partial agonist/antagonist activity in transfections, inhibits several PPARgamma target genes in 3T3-L1 cells (LPL, ORL1 and CBPalpha) and PPARgamma-dependent adipogenesis but activates GLUT4 similarly to rosiglitazone implying gene-specific partial agonism. The crystal structure of the PPARgamma ligand binding domain (LBD) reveals that luteolin occupies buried ligand binding pocket (LBP) but binds an inactive PPARgamma LBD conformer and occupies a space near the beta-sheet region far from activation helix (H12) consistent with partial agonist/antagonist actions. A single myristic acid molecule simultaneously binds the LBP, suggesting that luteolin may cooperate with other ligands to bind PPARgamma, and molecular dynamics simulations show that luteolin and myristic acid cooperate to stabilize the Omega-loop between H2' and 3 and beta-sheet region. Interestingly, luteolin strongly suppresses hypertonicity-induced release of the pro-inflammatory IL-8 from human corneal epithelial cells (HCEC) and reverses reductions in transepithelial electrical resistance (TEER). This effect is PPARgamma dependent. We propose that activities of luteolin are related to its singular binding mode, that anti-inflammatory activity does not require H12 stabilization and that our structure can be useful in developing safe selective PPARgamma modulators. Mode of PPARgamma Activation by Luteolin.,Puhl AC, Bernardes A, Silveira RL, Yuan J, Campos JL, Saidemberg DM, Palma MS, Cvoro A, Ayers SD, Webb P, Reinach PS, Skaf MS, Polikarpov I Mol Pharmacol. 2012 Mar 5. PMID:22391103[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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