Different binding and recognition modes of GL479, a dual agonist of Peroxisome Proliferator-Activated Receptor α/γ

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• Peroxisome Proliferator-Activated Receptors (PPARs) are crucial transcription factors regulating glucose and lipid metabolism.
• PPARγ agonists (TZDs) improve insulin sensitivity, while PPARα ligands (fibrates) reduce triglycerides.
• GL479 is a synthetic dual PPARα/γ agonist with high affinity for both receptors.

Purpose of the Study:

• To elucidate the structural basis of GL479's dual agonism by studying its complexes with PPARα and PPARγ.
• To understand how GL479's distinct binding modes influence its activation of PPARα versus PPARγ.
• To identify novel regions within the PPAR ligand-binding pocket for future drug design.

Main Methods:

• X-ray crystallography was used to determine the structures of GL479 in complex with PPARα and PPARγ.
• Comparative analysis of the ligand-binding pocket occupancy and interactions in both receptor complexes.
• Assessment of GL479's previously reported partial PPARγ and full PPARα agonist activities.

Main Results:

• GL479 exhibits different binding modes when complexed with PPARα and PPARγ.
• In both receptors, GL479 interacts with a tyrosine residue in helix 12, stabilizing the active conformation.
• GL479 occupies a canonical pocket in PPARα but a novel region in PPARγ.

Conclusions:

• The distinct structural interactions of GL479 with PPARα and PPARγ explain its differential activation profiles.
• The findings reveal a previously unexplored region of the PPAR ligand-binding pocket.
• This structural understanding can inform the design of novel partial and dual PPAR agonists for treating metabolic disorders.