PPAR? Ligand-Binding Domain Structures with Endogenous Fatty Acids and Fibrates.

ABSTRACT: Most triacylglycerol-lowering fibrates have been developed in the 1960s-1980s before their molecular target, peroxisome proliferator-activated receptor alpha (PPAR?), was identified. Twenty-one ligand-bound PPAR? 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 PPAR? 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 PPAR? 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 PPAR? 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 PPAR? ligand recognition and contribute to the molecular design of next-generation PPAR-targeted drugs.

SUBMITTER: Kamata S 

PROVIDER: S-EPMC7653058 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature