An alternate binding site for PPARÎ 3 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; Douglas J. Kojetin

doi:10.1038/ncomms4571

Scripps Research Institute

Research output: Contribution to journal › Article › peer-review

162 Scopus citations

Abstract

PPARγ 3 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 3. Here we reveal that synthetic PPARγ 3 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 3 hyperactivation in vivo, perhaps explaining why PPARγ 3 full and partial or weak agonists display similar adverse effects. These findings expand our understanding of PPARγ 3 activation by ligands and suggest that allosteric modulators could be designed to fine tune PPARγ 3 activity without competing with endogenous ligands.

Original language	English
Article number	3571
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms4571
State	Published - Apr 7 2014

Funding

We thank Wolfgang Bermel (Bruker Biospin) for providing CHD2-detected NMR pulse sequences; Mark Rance (University of Cincinnati), Donna Baldisseri (Bruker Biospin) and Clemens Anklin (Bruker Biospin) for NMR assistance and discussions; Laura Solt (Scripps) and Anutosh Chakraborty (Scripps) for assistance with cell lines. This work was supported with start-up funds from The Scripps Research Institute, the James and Esther King Biomedical Research Program, Florida Department of Health (1KN-09) and NIH/NIDDK (DK101871). T.S.H. was supported by an NIH F32 NRSA award from NIH/NIDDK (DK097890).

Funders	Funder number
DK097890
R01DK101871, F32DK097890
S10RR027270
Florida Department of Health	1KN-09
Scripps Research Institute

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Access to Document

10.1038/ncomms4571

Cite this

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abstract = "PPARγ 3 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 3. Here we reveal that synthetic PPARγ 3 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 3 hyperactivation in vivo, perhaps explaining why PPARγ 3 full and partial or weak agonists display similar adverse effects. These findings expand our understanding of PPARγ 3 activation by ligands and suggest that allosteric modulators could be designed to fine tune PPARγ 3 activity without competing with endogenous ligands.",

author = "Hughes, \{Travis S.\} and Giri, \{Pankaj Kumar\} and \{De Vera\}, \{Ian Mitchelle S.\} and Marciano, \{David P.\} and Kuruvilla, \{Dana S.\} and Youseung Shin and Blayo, \{Anne Laure\} and Kamenecka, \{Theodore M.\} and Burris, \{Thomas P.\} and Griffin, \{Patrick R.\} and Kojetin, \{Douglas J.\}",

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AU - Hughes, Travis S.

AU - Giri, Pankaj Kumar

AU - De Vera, Ian Mitchelle S.

AU - Marciano, David P.

AU - Kuruvilla, Dana S.

AU - Shin, Youseung

AU - Blayo, Anne Laure

AU - Kamenecka, Theodore M.

AU - Burris, Thomas P.

AU - Griffin, Patrick R.

AU - Kojetin, Douglas J.

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N2 - PPARγ 3 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 3. Here we reveal that synthetic PPARγ 3 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 3 hyperactivation in vivo, perhaps explaining why PPARγ 3 full and partial or weak agonists display similar adverse effects. These findings expand our understanding of PPARγ 3 activation by ligands and suggest that allosteric modulators could be designed to fine tune PPARγ 3 activity without competing with endogenous ligands.

AB - PPARγ 3 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 3. Here we reveal that synthetic PPARγ 3 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 3 hyperactivation in vivo, perhaps explaining why PPARγ 3 full and partial or weak agonists display similar adverse effects. These findings expand our understanding of PPARγ 3 activation by ligands and suggest that allosteric modulators could be designed to fine tune PPARγ 3 activity without competing with endogenous ligands.

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