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

doi:10.1016/j.isci.2020.101727

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

iScience. 2020 Oct 23;23(11):101727. doi: 10.1016/j.isci.2020.101727. eCollection 2020 Nov 20.

Authors

Affiliations

¹ Laboratory of Health Chemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
² Faculty of Life and Environmental Sciences, University of Yamanashi, Kofu, Yamanashi 400-8510, Japan.
³ Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
⁴ Laboratory of Pharmacology, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
⁵ Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi 464-8601, Japan.
⁶ Graduate School of Agricultural and Life Sciences, the University of Tokyo, Bunkyo, Tokyo 113-8657, Japan.
⁷ Department of Biochemistry, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan.

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.

Keywords: Biochemistry; Molecular Physiology; Protein Structure Aspects; Structural Biology.