PPARα Ligand-Binding Domain Structures with Endogenous Fatty Acids and Fibrates

Shotaro Kamata, Takuji Oyama, Kenta Saito, Akihiro Honda, Yume Yamamoto, Keisuke Suda, Ryo Ishikawa, Toshimasa Itoh, Yasuo Watanabe, Takahiro Shibata, Koji Uchida, Makoto Suematsu, Isao Ishii

Research output: Contribution to journalArticlepeer-review

Abstract

Most triacylglycerol-lowering fibrates have been developed in the 1960s–1980s before their molecular target, peroxisome proliferator-activated receptor alpha (PPARα), was identified. Twenty-one ligand-bound PPARα structures have been deposited in the Protein Data Bank since 2001; however, binding modes of fibrates and physiological ligands remain unknown. Here we show thirty-four X-ray crystallographic structures of the PPARα ligand-binding domain, which are composed of a “Center” and four “Arm” regions, in complexes with five endogenous fatty acids, six fibrates in clinical use, and six synthetic PPARα agonists. High-resolution structural analyses, in combination with coactivator recruitment and thermostability assays, demonstrate that stearic and palmitic acids are presumably physiological ligands; coordination to Arm III is important for high PPARα potency/selectivity of pemafibrate and GW7647; and agonistic activities of four fibrates are enhanced by the partial agonist GW9662. These results renew our understanding of PPARα ligand recognition and contribute to the molecular design of next-generation PPAR-targeted drugs.

Original languageEnglish
Article number101727
JournaliScience
Volume23
Issue number11
DOIs
Publication statusPublished - 2020 Nov 20

Keywords

  • Biochemistry
  • Molecular Physiology
  • Protein Structure Aspects
  • Structural Biology

ASJC Scopus subject areas

  • General

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