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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
Published on: November 15, 2013
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An alternate binding site for PPARγ ligands.
Travis S Hughes1, Pankaj Kumar Giri1, Ian Mitchelle S de Vera1
1Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
Nature Communications
|April 8, 2014
Summary
Synthetic PPARγ ligands bind to a novel alternate site, causing unique conformational changes. This discovery impacts understanding of diabetes drug mechanisms and adverse effects, suggesting new therapeutic strategies.
Area of Science:
- Molecular biology
- Pharmacology
- Endocrinology
Background:
- Peroxisome proliferator-activated receptor gamma (PPARγ) is a key target for insulin-sensitizing drugs like glitazones used in diabetes management.
- Synthetic ligands typically aim to mimic endogenous ligands for hyperactivation of PPARγ via its canonical binding pocket.
Purpose of the Study:
- To investigate the binding mechanisms of synthetic PPARγ ligands beyond the canonical binding pocket.
- To elucidate the functional consequences of alternate site binding on PPARγ activity and gene expression.
Main Methods:
- Structure-function studies utilizing synthetic and endogenous ligands, as well as antagonists.
- Analysis of receptor conformational changes, coregulator binding, and transactivation activity.
Main Results:
- Synthetic PPARγ ligands bind to a previously unidentified alternate allosteric site.
- This alternate binding induces unique conformational changes affecting coregulator interactions and transactivation.
- Alternate site binding occurs at pharmacologically relevant concentrations and is independent of canonical pocket occupancy.
Conclusions:
- Alternate site binding contributes to PPARγ hyperactivation and may explain shared adverse effects of different PPARγ agonists.
- Findings suggest a new paradigm for PPARγ ligand interaction, distinct from canonical activation.
- This opens avenues for designing allosteric modulators for precise tuning of PPARγ activity without endogenous ligand interference.
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