[PPARα-Ligand Binding Modes Revealed by X-ray Crystallography]

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors regulating metabolism, with subtypes α, γ, and β/δ.
• PPARs are therapeutic targets for metabolic diseases; PPARα and PPARγ agonists are approved drugs, while dual/pan agonists are investigated for NASH and fibrosis.
• Structural data for PPARα and PPARδ ligand-binding domains (LBDs) are limited compared to PPARγ.

Purpose of the Study:

• To obtain novel co-crystal structures of PPARα-LBD and various ligands.
• To establish a method for preparing PPARδ-LBD co-crystals.
• To facilitate the molecular design of novel PPAR-targeted therapeutics.

Main Methods:

• X-ray crystallography was employed to determine co-crystal structures.
• Various co-crystallization techniques were utilized.
• Ligand-free apocrystals were prepared for PPARγ, providing a comparative basis.

Main Results:

• 34 novel co-crystal structures of PPARα-LBD with diverse ligands, including fibrates, were successfully obtained.
• The developed co-crystallization procedure is applicable to PPARδ-LBD.
• This work provides structural insights into all three PPAR-LBDs.

Conclusions:

• The study significantly expands the structural knowledge of PPARα-LBD.
• The methodology enables the structural analysis of PPARδ-LBD.
• These findings will accelerate the rational design of new drugs targeting all PPAR subtypes.