TY - JOUR
T1 - PPARα Ligand-Binding Domain Structures with Endogenous Fatty Acids and Fibrates
AU - Kamata, Shotaro
AU - Oyama, Takuji
AU - Saito, Kenta
AU - Honda, Akihiro
AU - Yamamoto, Yume
AU - Suda, Keisuke
AU - Ishikawa, Ryo
AU - Itoh, Toshimasa
AU - Watanabe, Yasuo
AU - Shibata, Takahiro
AU - Uchida, Koji
AU - Suematsu, Makoto
AU - Ishii, Isao
N1 - Funding Information:
We thank Prof. Jerold Chun (Sanford Burnham Prebys Medical Discovery Institute) for helpful comments. S.K. and I.I. acknowledge fundings from Grants-in-Aid for Scientific Research from Japan Society for the Promotion of Sciences ( JSPS ), Japan (grant numbers: 19K16359 and 16H05107 ), Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research [BINDS]) from AMED , Japan (grant number: JP19am0101071 ; support number: 1407), and Showa Pharmaceutical University , Japan. T.O. acknowledges fundings from a Grant-in-Aid for Scientific Research from JSPS (grant number: 18K06081 ) and Adaptable and Seamless Technology Transfer Program through Target-driven R&D (A-STEP) from Japan Science and Technology Agency , Japan (grant number: JPMJTM19AT ). This work was performed under the approval of the Photon Factory Program Advisory Committee, Japan (proposal number: 2018G658).
PY - 2020/11/20
Y1 - 2020/11/20
N2 - 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.
AB - 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.
KW - Biochemistry
KW - Molecular Physiology
KW - Protein Structure Aspects
KW - Structural Biology
UR - http://www.scopus.com/inward/record.url?scp=85095415802&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85095415802&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2020.101727
DO - 10.1016/j.isci.2020.101727
M3 - Article
AN - SCOPUS:85095415802
VL - 23
JO - iScience
JF - iScience
SN - 2589-0042
IS - 11
M1 - 101727
ER -