5gtn
Human PPARgamma ligand binding dmain complexed with R35
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 receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily. It functions as a ligand-activated transcription factor and plays important roles in the regulation of adipocyte differentiation, type 2 diabetes mellitus, and inflammation. Many PPARgamma agonists bind to the canonical ligand-binding pocket near the activation function-2 (AF-2) helix (i.e., helix H12) of the ligand-binding domain (LBD). More recently, an alternate ligand-binding site was identified in PPARgamma LBD; it is located beside the Omega loop between the helices H2' and H3. We reported previously that the chirality of two optimized enantiomeric PPARgamma ligands (S35 and R35) differentiates their PPARgamma transcriptional activity, binding affinity, and inhibitory activity toward Cdk5 (cyclin-dependent kinase 5)-mediated phosphorylation of PPARgamma at Ser245 (in PPARgamma1 numbering; Ser273 in PPARgamma2 numbering). S35 is a PPARgamma phosphorylation inhibitor with promising glucose uptake potential, whereas R35 behaves as a potent conventional PPARgamma agonist. To provide a structural basis for understanding the differential activities of these enantiomeric ligands, we have determined crystal structures of the PPARgamma LBD in complex with either S35 or R35. S35 and R35 bind to the PPARgamma LBD in significantly different manners. The partial agonist S35 occupies the alternate site near the Omega loop, whereas the full agonist R35 binds entirely to the canonical LBP. Alternate site binding of S35 affects the PPARgamma transactivation and the inhibitory effect on PPARgamma Ser245 phosphorylation. This study provides a useful platform for the development of a new generation of PPARgamma ligands as anti-diabetic drug candidates. Structural basis for differential activities of enantiomeric PPARgamma agonists: Binding of S35 to the alternate site.,Jang JY, Koh M, Bae H, An DR, Im HN, Kim HS, Yoon JY, Yoon HJ, Han BW, Park SB, Suh SW Biochim Biophys Acta. 2017 Jun;1865(6):674-681. doi:, 10.1016/j.bbapap.2017.03.008. Epub 2017 Mar 22. PMID:28342850[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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