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

Most triacylglycerol-lowering fibrates have been developed in the 1960s-1980s before their molecular target, peroxisome proliferator-activated receptor alpha (PPAR alpha), was identified. Twenty-one ligand-bound PPAR alpha structures have been deposited in the Protein Data Bank since 2001; however, binding modes of fibrates and physiological ligands remain unknown. Here we showthirty-four X-ray crystallographic structures of the PPAR alpha ligand-binding domain, which are composed of a Center'' and four Arm'' regions, in complexes with five endogenous fatty acids, sixfibrates in clinical use, and six synthetic PPAR alpha 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 ArmIII is important for high PPAR alpha 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 alpha ligand recognition andcontribute to the molecular design of next-generation PPAR-targeted drugs.