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Biochem Biophys Res Commun. 2018 May 5;499(2):239-245. doi: 10.1016/j.bbrc.2018.03.135. Epub 2018 Mar 22.

Molecular association model of PPARα and its new specific and efficient ligand, pemafibrate: Structural basis for SPPARMα.

Author information

1
Department of Chemistry, Rikkyo University, Nishi-Ikebukuro, Toshima, Tokyo 171-8501, Japan.
2
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
3
Department of Chemistry, Rikkyo University, Nishi-Ikebukuro, Toshima, Tokyo 171-8501, Japan; Research Center for Smart Molecules, Rikkyo University, Nishi-Ikebukuro, Toshima, Tokyo 171-8501, Japan.
4
Department of Chemistry, Rikkyo University, Nishi-Ikebukuro, Toshima, Tokyo 171-8501, Japan; Institute of Chemistry - Centre for Glycomics, Slovak Academy of Sciences, 845 38 Bratislava, Slovakia; AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda, Tokyo 100-0004, Japan.
5
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda, Tokyo 100-0004, Japan.
6
Graduate School of Pure and Applied Sciences, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8571, Japan; Department of Chemistry, Graduate School of Science, Tohoku University, Aramaki, Aoba, Sendai, Miyagi 980-8578, Japan.
7
Center for Computational Sciences, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8577, Japan.
8
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
9
Department of Chemistry, Rikkyo University, Nishi-Ikebukuro, Toshima, Tokyo 171-8501, Japan; Research Center for Smart Molecules, Rikkyo University, Nishi-Ikebukuro, Toshima, Tokyo 171-8501, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda, Tokyo 100-0004, Japan. Electronic address: tokiwa@rikkyo.ac.jp.
10
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda, Tokyo 100-0004, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba 305-8577, Japan. Electronic address: hshimano@md.tsukuba.ac.jp.

Abstract

Peroxisome proliferator-activated receptor-α (PPARα) is a ligand-activated transcription factor involved in the regulation of lipid homeostasis and improves hypertriglyceridemia. Pemafibrate is a novel selective PPARα modulator (SPPARMα) that activates PPARα transcriptional activity. Here, we computationally constructed the structure of the human PPARα in a complex with pemafibrate, along with that of hPPARα complexed with the classical fenofibrate, and studied their interactions quantitatively by using the first-principles calculations-based fragment molecular orbital (FMO) method. Comprehensive structural and protein-ligand binding elucidation along with the in vitro luciferase analysis let us to identify pemafibrate as a novel SPPARMα. Unlike known fibrate ligands, which bind only with the arm I of the Y-shaped ligand binding pocket, the Y-shaped pemafibrate binds to the entire cavity region. This lock and key nature causes enhanced induced fit in pemafibrate-ligated PPARα. Importantly, this selective modulator allosterically changes PPARα conformation to form a brand-new interface, which in turn binds to PPARα co-activator, PGC-1α, resulting in the full activation of PPARα. The structural basis for the potent effects of pemafibrate on PPARα transcriptional activity predicted by the in silico FMO methods was confirmed by in vitro luciferase assay for mutants. The unique binding mode of pemafibrate reveals a new pattern of nuclear receptor ligand recognition and suggests a novel basis for ligand design, offering cues for improving the binding affinity and selectivity of ligand for better clinical consequences. The findings explain the high affinity and efficacy of pemafibrate, which is expected to be in the clinical use soon.

KEYWORDS:

Fenofibrate; Fragment molecular orbital theory; Luciferase assay; Pemafibrate; Peroxisome proliferator-activated receptors; Protein-ligand interaction

PMID:
29567478
DOI:
10.1016/j.bbrc.2018.03.135
[Indexed for MEDLINE]

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