Peroxisome proliferator-activated receptor-alpha (PPAR alpha) is a ligand-activated transcription factor involved in the regulation of lipid homeostasis and improves hypertriglyceridemia. Pemafibrate is a novel selective PPAR alpha modulator (SPPARM alpha) that activates PPAR alpha transcriptional activity. Here, we computationally constructed the structure of the human PPAR alpha in a complex with pemafibrate, along with that of hPPAR alpha 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 SPPARM alpha. 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 PPAR alpha. Importantly, this selective modulator allosterically changes PPAR alpha conformation to form a brand-new interface, which in turn binds to PPAR alpha co-activator, PGC-l alpha, resulting in the full activation of PPAR alpha. The structural basis for the potent effects of pemafibrate on PPAR alpha 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. (C) 2018 Elsevier Inc. All rights reserved.