Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive...

Area of Science:

• Molecular Biology
• Structural Biology
• Pharmacology

Background:

• Nuclear receptors (NRs) dynamically shift between active and repressive states, influenced by ligand binding.
• Existing NR ligand series often lack repressive inverse agonists, limiting the exploration of the full conformational ensemble.
• Understanding the complete conformational spectrum of NRs is crucial for drug development and biological insights.

Purpose of the Study:

• To develop a novel ligand series for peroxisome proliferator-activated receptor gamma (PPARγ) with a broad pharmacological spectrum.
• To investigate how subtle structural modifications in ligands influence PPARγ activity, including inverse agonism.
• To elucidate the impact of these ligands on the dynamic conformational ensemble of PPARγ.

Main Methods:

• Design and synthesis of a focused ligand series targeting PPARγ.
• Utilized Nuclear Magnetic Resonance (NMR) spectroscopy to analyze dynamic conformational changes.
• Employed conformation-activity relationship (CAR) analysis to correlate structural changes with functional outcomes.

Main Results:

• A PPARγ ligand series was identified that spans from inverse agonism (repression) to agonism (activation).
• Subtle structural modifications within the ligand series were shown to effectively switch compound activity.
• NMR and CAR analyses revealed that these ligands modulate the PPARγ conformational ensemble, shifting it towards states observed in the apo/ligand-free receptor.

Conclusions:

• Established a molecular framework for achieving enhanced PPARγ inverse agonism through minimal chemical modifications.
• Demonstrated the ability to dynamically control the PPARγ conformational ensemble using a tailored ligand series.
• Provides new avenues for understanding NR function and developing biased modulators with precise pharmacological profiles.