7c6q
Novel natural PPARalpha agonist with a unique binding mode
Structural highlights
FunctionPPARA_HUMAN Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety (By similarity). Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2.[1] [2] [3] [4] Publication Abstract from PubMedPeroxisome proliferator-activated receptors (PPARs) play crucial roles in glucose and lipid metabolism and inflammation. Sanguinarine is a natural product that is isolated from Sanguinaria Canadensis, a potential therapeutic agent for intervention in chronic diseases. In this study, biochemical and cell-based promoter-reporter gene assays revealed that sanguinarine activated both PPARalpha and PPARgamma, and enhanced their transcriptional activity; thus, sanguinarine was identified as a dual agonist of PPARalpha/gamma. Similar to fenofibrate, sanguinarine upregulates the expression of PPARalpha-target genes in hepatocytes. Sanguinarine also modulates the expression of key PPARgamma-target genes and promotes adipocyte differentiation, but with a lower adipogenic activity compared with rosiglitazone. We report the crystal structure of sanguinarine bound to PPARalpha, which reveals a unique ligand-binding mode of sanguinarine, dissimilar to the classic Y-shaped binding pocket, which may represent a new pharmacophore that can be optimized for selectively targeting PPARalpha. Further structural and functional studies uncover the molecular basis for the selectivity of sanguinarine toward PPARalpha/gamma among all three PPARs. In summary, our study identifies a PPARalpha/gamma dual agonist with a unique ligand-binding mode, and provides a promising and viable novel template for the design of dual-targeting PPARs ligands. Structural Basis for PPARs Activation by The Dual PPARalpha/gamma Agonist Sanguinarine: A Unique Mode of Ligand Recognition.,Tian S, Wang R, Chen S, He J, Zheng W, Li Y Molecules. 2021 Oct 3;26(19):6012. doi: 10.3390/molecules26196012. PMID:34641558[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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