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Structural basis for GL479 a dual Peroxisome Proliferator-Activated Receptor alpha agonistStructural basis for GL479 a dual Peroxisome Proliferator-Activated Receptor alpha agonist
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) are ligand-dependent transcription factors that control various functions in human organism, including the control of glucose and lipid metabolism. PPARgamma is a target of TZD agonists, clinically used to improve insulin sensitivity whereas fibrates, PPARalpha ligands, lower serum triglyceride levels. We report here the structural studies of GL479, a synthetic dual PPARalpha/gamma agonist, designed by a combination of clofibric acid skeleton and a phenyldiazenyl moiety, as bioisosteric replacement of stilbene group, in complex with both PPARalpha and PPARgamma receptors. GL479 was previously reported as a partial agonist of PPARgamma and a full agonist of PPARalpha with high affinity for both PPARs. Our structural studies reveal different binding modes of GL479 to PPARalpha and PPARgamma, which may explain the distinct activation behaviors observed for each receptor. In both cases the ligand interacts with a Tyr located at helix 12 (H12), resulting in the receptor active conformation. In the complex with PPARalpha, GL479 occupies the same region of the ligand-binding pocket (LBP) observed for other full agonists, whereas GL479 bound to PPARgamma displays a new binding mode. Our results indicate a novel region of PPARs LBP that may be explored for the design of partial agonists as well dual PPARalpha/gamma agonists that combine, simultaneously, the therapeutic effects of the treatment of insulin resistance and dyslipidemia. Different binding and recognition modes of GL479, a dual agonist of Peroxisome Proliferator-Activated Receptor alpha/gamma.,Dos Santos JC, Bernardes A, Giampietro L, Ammazzalorso A, De Filippis B, Amoroso R, Polikarpov I J Struct Biol. 2015 Jul 14. pii: S1047-8477(15)30031-9. doi:, 10.1016/j.jsb.2015.07.006. PMID:26185032[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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