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

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• Fibrates, developed before their target discovery, are used to lower triacylglycerol levels.
• The binding modes of fibrates and physiological ligands to peroxisome proliferator-activated receptor alpha (PPARα) remain largely unknown despite available structural data.

Purpose of the Study:

• To elucidate the binding mechanisms of fibrates and endogenous ligands to the PPARα ligand-binding domain.
• To provide structural insights for the development of novel PPARα-targeted therapeutics.

Main Methods:

• X-ray crystallography was used to determine 34 high-resolution structures of the PPARα ligand-binding domain complexed with various ligands.
• Coactivator recruitment and thermostability assays were performed to assess ligand-induced functional changes.

Main Results:

• Stearic and palmitic acids are identified as likely physiological ligands for PPARα.
• Coordination within the Arm III region is crucial for the high potency and selectivity of pemafibrate and GW7647.
• The partial agonist GW9662 was found to enhance the agonistic activities of four clinical fibrates.

Conclusions:

• The study provides a renewed understanding of PPARα ligand recognition through detailed structural analysis.
• Findings contribute to the rational molecular design of next-generation drugs targeting PPARα for metabolic disorders.