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Elucidation of Molecular Mechanism of a Selective PPARα Modulator, Pemafibrate, through Combinational Approaches of X-ray Crystallography, Thermodynamic Analysis, and First-Principle Calculations

The selective PPARα modulator (SPPARMα) is expected to medicate dyslipidemia with minimizing adverse effects. Recently, pemafibrate was screened from the ligand library as an SPPARMα bearing strong potency. Several clinical pieces of evidence have proved the usefulness of pemafibrate as a medication...

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Autores principales: Kawasaki, Mayu, Kambe, Akira, Yamamoto, Yuta, Arulmozhiraja, Sundaram, Ito, Sohei, Nakagawa, Yoshimi, Tokiwa, Hiroaki, Nakano, Shogo, Shimano, Hitoshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981837/
https://www.ncbi.nlm.nih.gov/pubmed/31935812
http://dx.doi.org/10.3390/ijms21010361
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author Kawasaki, Mayu
Kambe, Akira
Yamamoto, Yuta
Arulmozhiraja, Sundaram
Ito, Sohei
Nakagawa, Yoshimi
Tokiwa, Hiroaki
Nakano, Shogo
Shimano, Hitoshi
author_facet Kawasaki, Mayu
Kambe, Akira
Yamamoto, Yuta
Arulmozhiraja, Sundaram
Ito, Sohei
Nakagawa, Yoshimi
Tokiwa, Hiroaki
Nakano, Shogo
Shimano, Hitoshi
author_sort Kawasaki, Mayu
collection PubMed
description The selective PPARα modulator (SPPARMα) is expected to medicate dyslipidemia with minimizing adverse effects. Recently, pemafibrate was screened from the ligand library as an SPPARMα bearing strong potency. Several clinical pieces of evidence have proved the usefulness of pemafibrate as a medication; however, how pemafibrate works as a SPPARMα at the molecular level is not fully known. In this study, we investigate the molecular mechanism behind its novel SPPARMα 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 PPARα than to PPARγ. The crystal structure of PPARα-ligand binding domain (LBD)/pemafibrate/steroid receptor coactivator-1 peptide (SRC1) determined at 3.2 Å resolution indicates that pemafibrate binds to the ligand binding pocket (LBP) of PPARα 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 PPARα; 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 PPARα compared with the interaction between fenofibrate and PPARα.
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spelling pubmed-69818372020-02-07 Elucidation of Molecular Mechanism of a Selective PPARα Modulator, Pemafibrate, through Combinational Approaches of X-ray Crystallography, Thermodynamic Analysis, and First-Principle Calculations Kawasaki, Mayu Kambe, Akira Yamamoto, Yuta Arulmozhiraja, Sundaram Ito, Sohei Nakagawa, Yoshimi Tokiwa, Hiroaki Nakano, Shogo Shimano, Hitoshi Int J Mol Sci Article The selective PPARα modulator (SPPARMα) is expected to medicate dyslipidemia with minimizing adverse effects. Recently, pemafibrate was screened from the ligand library as an SPPARMα bearing strong potency. Several clinical pieces of evidence have proved the usefulness of pemafibrate as a medication; however, how pemafibrate works as a SPPARMα at the molecular level is not fully known. In this study, we investigate the molecular mechanism behind its novel SPPARMα 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 PPARα than to PPARγ. The crystal structure of PPARα-ligand binding domain (LBD)/pemafibrate/steroid receptor coactivator-1 peptide (SRC1) determined at 3.2 Å resolution indicates that pemafibrate binds to the ligand binding pocket (LBP) of PPARα 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 PPARα; 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 PPARα compared with the interaction between fenofibrate and PPARα. MDPI 2020-01-06 /pmc/articles/PMC6981837/ /pubmed/31935812 http://dx.doi.org/10.3390/ijms21010361 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kawasaki, Mayu
Kambe, Akira
Yamamoto, Yuta
Arulmozhiraja, Sundaram
Ito, Sohei
Nakagawa, Yoshimi
Tokiwa, Hiroaki
Nakano, Shogo
Shimano, Hitoshi
Elucidation of Molecular Mechanism of a Selective PPARα Modulator, Pemafibrate, through Combinational Approaches of X-ray Crystallography, Thermodynamic Analysis, and First-Principle Calculations
title Elucidation of Molecular Mechanism of a Selective PPARα Modulator, Pemafibrate, through Combinational Approaches of X-ray Crystallography, Thermodynamic Analysis, and First-Principle Calculations
title_full Elucidation of Molecular Mechanism of a Selective PPARα Modulator, Pemafibrate, through Combinational Approaches of X-ray Crystallography, Thermodynamic Analysis, and First-Principle Calculations
title_fullStr Elucidation of Molecular Mechanism of a Selective PPARα Modulator, Pemafibrate, through Combinational Approaches of X-ray Crystallography, Thermodynamic Analysis, and First-Principle Calculations
title_full_unstemmed Elucidation of Molecular Mechanism of a Selective PPARα Modulator, Pemafibrate, through Combinational Approaches of X-ray Crystallography, Thermodynamic Analysis, and First-Principle Calculations
title_short Elucidation of Molecular Mechanism of a Selective PPARα Modulator, Pemafibrate, through Combinational Approaches of X-ray Crystallography, Thermodynamic Analysis, and First-Principle Calculations
title_sort elucidation of molecular mechanism of a selective pparα modulator, pemafibrate, through combinational approaches of x-ray crystallography, thermodynamic analysis, and first-principle calculations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981837/
https://www.ncbi.nlm.nih.gov/pubmed/31935812
http://dx.doi.org/10.3390/ijms21010361
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