Structural basis for PPAR partial or full activation revealed by a novel ligand binding mode

Area of Science:

• Molecular biology
• Pharmacology
• Structural biology

Background:

• Peroxisome proliferator-activated receptors (PPARs) are crucial nuclear receptors regulating metabolic homeostasis.
• PPARs are significant therapeutic targets for metabolic diseases.
• Current PPARγ agonists cause side effects, necessitating the development of balanced drugs.

Purpose of the Study:

• To identify novel PPAR pan-agonists with improved activity profiles.
• To overcome the limitations of existing PPARγ agonists.
• To provide a structural basis for designing balanced PPAR-modulating drugs.

Main Methods:

• Employed a structure-based virtual screening approach.
• Determined the crystal structure of a novel ligand complexed with PPARα and PPARγ.
• Analyzed ligand-induced conformational changes in PPARα.

Main Results:

• Identified a novel PPAR pan-agonist with a promising activity profile.
• The crystal structure revealed the ligand binding to a unique pocket in PPARα, involving an F273 side chain switch.
• Structural comparison between PPARα and PPARγ pockets elucidated differential ligand activation.

Conclusions:

• The novel pan-agonist presents a potential therapeutic candidate for metabolic diseases.
• The identified ligand-binding pocket and conformational changes offer new insights for designing balanced PPAR drugs.
• This study provides a structural rationale for developing safer and more effective PPAR-targeting therapeutics.