6l96
Structure of PPARalpha-LBD/pemafibrate/SRC1 peptide
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 PubMedThe selective PPARalpha modulator (SPPARMalpha) is expected to medicate dyslipidemia with minimizing adverse effects. Recently, pemafibrate was screened from the ligand library as an SPPARMalpha bearing strong potency. Several clinical pieces of evidence have proved the usefulness of pemafibrate as a medication; however, how pemafibrate works as a SPPARMalpha at the molecular level is not fully known. In this study, we investigate the molecular mechanism behind its novel SPPARMalpha character through a combination of approaches of X-ray crystallography, isothermal titration calorimetry (ITC), and fragment molecular orbital (FMO) analysis. ITC measurements have indicated that pemafibrate binds more strongly to PPARalpha than to PPARgamma. The crystal structure of PPARalpha-ligand binding domain (LBD)/pemafibrate/steroid receptor coactivator-1 peptide (SRC1) determined at 3.2 A resolution indicates that pemafibrate binds to the ligand binding pocket (LBP) of PPARalpha in a Y-shaped form. The structure also reveals that the conformation of the phenoxyalkyl group in pemafibrate is flexible in the absence of SRC1 coactivator peptide bound to PPARalpha; this gives a freedom for the phenoxyalkyl group to adopt structural changes induced by the binding of coactivators. FMO calculations have indicated that the accumulation of hydrophobic interactions provided by the residues at the LBP improve the interaction between pemafibrate and PPARalpha compared with the interaction between fenofibrate and PPARalpha. Elucidation of Molecular Mechanism of a Selective PPARalpha Modulator, Pemafibrate, through Combinational Approaches of X-ray Crystallography, Thermodynamic Analysis, and First-Principle Calculations.,Kawasaki M, Kambe A, Yamamoto Y, Arulmozhiraja S, Ito S, Nakagawa Y, Tokiwa H, Nakano S, Shimano H Int J Mol Sci. 2020 Jan 6;21(1). pii: ijms21010361. doi: 10.3390/ijms21010361. PMID:31935812[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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