PPARα Ligand-Binding Domain Structures with Endogenous Fatty Acids and Fibrates
Summary: 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, b...
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Elsevier
2020-11-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S258900422030924X |
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doaj-019e9a2e669140bd9f38f82355fbf3542020-11-25T04:07:13ZengElsevieriScience2589-00422020-11-012311101727PPARα Ligand-Binding Domain Structures with Endogenous Fatty Acids and FibratesShotaro Kamata0Takuji Oyama1Kenta Saito2Akihiro Honda3Yume Yamamoto4Keisuke Suda5Ryo Ishikawa6Toshimasa Itoh7Yasuo Watanabe8Takahiro Shibata9Koji Uchida10Makoto Suematsu11Isao Ishii12Laboratory of Health Chemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, JapanFaculty of Life and Environmental Sciences, University of Yamanashi, Kofu, Yamanashi 400-8510, JapanLaboratory of Health Chemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, JapanLaboratory of Health Chemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, JapanLaboratory of Health Chemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, JapanLaboratory of Health Chemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, JapanLaboratory of Health Chemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, JapanLaboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, JapanLaboratory of Pharmacology, Showa Pharmaceutical University, Machida, Tokyo 194-8543, JapanGraduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Aichi 464-8601, JapanGraduate School of Agricultural and Life Sciences, the University of Tokyo, Bunkyo, Tokyo 113-8657, JapanDepartment of Biochemistry, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, JapanLaboratory of Health Chemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S258900422030924XBiochemistryMolecular PhysiologyStructural BiologyProtein Structure Aspects |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 PPARα Ligand-Binding Domain Structures with Endogenous Fatty Acids and Fibrates iScience Biochemistry Molecular Physiology Structural Biology Protein Structure Aspects |
| author_facet |
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 |
| author_sort |
Shotaro Kamata |
| title |
PPARα Ligand-Binding Domain Structures with Endogenous Fatty Acids and Fibrates |
| title_short |
PPARα Ligand-Binding Domain Structures with Endogenous Fatty Acids and Fibrates |
| title_full |
PPARα Ligand-Binding Domain Structures with Endogenous Fatty Acids and Fibrates |
| title_fullStr |
PPARα Ligand-Binding Domain Structures with Endogenous Fatty Acids and Fibrates |
| title_full_unstemmed |
PPARα Ligand-Binding Domain Structures with Endogenous Fatty Acids and Fibrates |
| title_sort |
pparα ligand-binding domain structures with endogenous fatty acids and fibrates |
| publisher |
Elsevier |
| series |
iScience |
| issn |
2589-0042 |
| publishDate |
2020-11-01 |
| description |
Summary: 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. |
| topic |
Biochemistry Molecular Physiology Structural Biology Protein Structure Aspects |
| url |
http://www.sciencedirect.com/science/article/pii/S258900422030924X |
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