Elucidation of Molecular Mechanism of a Selective PPARα Modulator, Pemafibrate, through Combinational Approaches of X-ray Crystallography, Thermodynamic Analysis, and First-Principle Calculations
Elucidation of Molecular Mechanism of a Selective PPARα Modulator, Pemafibrate, through Combinational Approaches of X-ray Crystallography, Thermodynamic Analysis, and First-Principle Calculations
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DOI：
10.3390/ijms21010361
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发表时间：
2020-01-01
影响因子：
5.6
通讯作者：
Shimano, Hitoshi
中科院分区：
文献类型：
--
作者：
Kawasaki, Mayu;Kambe, Akira;Shimano, Hitoshi
选择性PPARα调节剂(SPPARMα)有望在治疗血脂异常的同时将不良反应降至最低。最近，培马贝特被从配体库中筛选出具有较强效力的SPPARMα。一些临床证据已经证明了培马贝特作为一种药物的有效性；然而，培马贝特如何在分子水平上作为SPPARMα发挥作用还不完全清楚。在这项研究中，我们通过X射线结晶学、等温滴定量热(ITC)和碎片分子轨道(FMO)分析相结合的方法，研究了其新的SPPARMα特征背后的分子机制。ITC的测量表明，培马贝特与PPARα的结合比与PPAR伽马的结合更强。在3.2埃分辨率下测定的PPARα配体结合域(LBD)/培马贝特/类固醇受体辅活化子-1肽(SRC1)的晶体结构表明，培马贝特以Y形形式与PPARα的配体结合口袋(LBP)结合。该结构还揭示了在没有与PPARα结合的SRC1共激活剂的情况下，培马贝特中苯氧基烷基的构象是灵活的，这使得苯氧基烷基可以自由地采用由辅激活剂结合而引起的结构变化。FMO计算表明，与非诺贝特和PPARα之间的相互作用相比，LBP残基提供的疏水相互作用的积累改善了培马贝特和PPARα之间的相互作用。
The selective PPAR alpha modulator (SPPARM alpha) is expected to medicate dyslipidemia with minimizing adverse effects. Recently, pemafibrate was screened from the ligand library as an SPPARM alpha bearing strong potency. Several clinical pieces of evidence have proved the usefulness of pemafibrate as a medication; however, how pemafibrate works as a SPPARM alpha at the molecular level is not fully known. In this study, we investigate the molecular mechanism behind its novel SPPARM alpha 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 PPAR alpha than to PPAR gamma. The crystal structure of PPAR alpha-ligand binding domain (LBD)/pemafibrate/steroid receptor coactivator-1 peptide (SRC1) determined at 3.2 angstrom resolution indicates that pemafibrate binds to the ligand binding pocket (LBP) of PPAR alpha 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 PPAR alpha; 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 PPAR alpha compared with the interaction between fenofibrate and PPAR alpha.