8rce
From Proteopedia
Crystal structure of PPAR alfa Ligand Binding Domain in complex with the ligand LBB78
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 PubMedNew analogs of the PPAR pan agonist AL29-26 encompassed ligand (S)-7 showing potent activation of PPARalpha and -gamma subtypes as a partial agonist. In vitro experiments and docking studies in the presence of PPAR antagonists were performed to help interpretation of biological data and investigate the main interactions at the binding sites. Further in vitro experiments showed that (S)-7 induced anti-steatotic effects and enhancement of the glucose uptake. This latter effect could be partially ascribed to a significant inhibition of the mitochondrial pyruvate carrier demonstrating that (S)-7 also acted through insulin-independent mechanisms. In vivo experiments showed that this compound reduced blood glucose and lipid levels in a diabetic mice model displaying no toxicity on bone, kidney, and liver. To our knowledge, this is the first example of dual PPARalpha/gamma partial agonist showing these combined effects representing, therefore, the potential lead of new drugs for treatment of dyslipidemic type 2 diabetes. A chemical modification of a peroxisome proliferator-activated receptor pan agonist produced a shift to a new dual alpha/gamma partial agonist endowed with mitochondrial pyruvate carrier inhibition and antidiabetic properties.,Laghezza A, Cerchia C, Genovese M, Montanari R, Capelli D, Wackerlig J, Simic S, Falbo E, Pecora L, Leuci R, Brunetti L, Piemontese L, Tortorella P, Biswas A, Singh RP, Tambe S, Sudeep CA, Pattnaik AK, Jayaprakash V, Paoli P, Lavecchia A, Loiodice F Eur J Med Chem. 2024 Sep 5;275:116567. doi: 10.1016/j.ejmech.2024.116567. Epub , 2024 Jun 9. PMID:38865743[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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