An alternate binding site for PPARγ ligands

Travis S. Hughes, Pankaj Kumar Giri, Ian Mitchelle S. de Vera, David P. Marciano, Dana S. Kuruvilla, Youseung Shin, Anne-Laure Blayo, Theodore M. Kamenecka, Thomas P. Burris, Patrick R. Griffin and Douglas J. Kojetin ()
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Travis S. Hughes: The Scripps Research Institute
Pankaj Kumar Giri: The Scripps Research Institute
Ian Mitchelle S. de Vera: The Scripps Research Institute
David P. Marciano: The Scripps Research Institute
Dana S. Kuruvilla: The Scripps Research Institute
Youseung Shin: The Scripps Research Institute
Anne-Laure Blayo: The Scripps Research Institute
Theodore M. Kamenecka: The Scripps Research Institute
Thomas P. Burris: The Scripps Research Institute
Patrick R. Griffin: The Scripps Research Institute
Douglas J. Kojetin: The Scripps Research Institute

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract PPARγ is a target for insulin-sensitizing drugs such as glitazones, which improve plasma glucose maintenance in patients with diabetes. Synthetic ligands have been designed to mimic endogenous ligand binding to a canonical ligand-binding pocket to hyperactivate PPARγ. Here we reveal that synthetic PPARγ ligands also bind to an alternate site, leading to unique receptor conformational changes that impact coregulator binding, transactivation and target gene expression. Using structure–function studies we show that alternate site binding occurs at pharmacologically relevant ligand concentrations, and is neither blocked by covalently bound synthetic antagonists nor by endogenous ligands indicating non-overlapping binding with the canonical pocket. Alternate site binding likely contributes to PPARγ hyperactivation in vivo, perhaps explaining why PPARγ full and partial or weak agonists display similar adverse effects. These findings expand our understanding of PPARγ activation by ligands and suggest that allosteric modulators could be designed to fine tune PPARγ activity without competing with endogenous ligands.

Date: 2014
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DOI: 10.1038/ncomms4571

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