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

• Published in: Biochemical and biophysical research communications 2018-05, Vol.499 (2), p.239-245
• Main Authors: Yamamoto, Yuta, Takei, Kenta, Arulmozhiraja, Sundaram, Sladek, Vladimir, Matsuo, Naoya, Han, Song-iee, Matsuzaka, Takashi, Sekiya, Motohiro, Tokiwa, Takaki, Shoji, Mitsuo, Shigeta, Yasuteru, Nakagawa, Yoshimi, Tokiwa, Hiroaki, Shimano, Hitoshi
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Fenofibrate; Fragment molecular orbital theory; HOMEOSTASIS; LIPIDS; LUCIFERASE; Luciferase assay; MOLECULAR ORBITAL METHOD; Pemafibrate; Peroxisome proliferator-activated receptors; Protein-ligand interaction; RECEPTORS; TRANSCRIPTION FACTORS
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2018.03.135

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. •Computationally constructed the structure of hPPARα in a complex with pemafibrate.•Structural basis for potent effects of pemafibrate predicted by in silico FMO method.•Computational results were confirmed by in vitro luciferase assay analysis.•Unlike fibrates, pemafibrate binds efficiently that makes it as a novel SPPARMα.