An alternate binding site for PPARγ ligands.
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.
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
Travis S
TS
Hughes
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
Pankaj Kumar
PK
Giri
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
Ian Mitchelle S
IM
de Vera
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
David P
DP
Marciano
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
Dana S
DS
Kuruvilla
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
Youseung
Y
Shin
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
Anne-Laure
AL
Blayo
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
Theodore M
TM
Kamenecka
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
Thomas P
TP
Burris
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
Patrick R
PR
Griffin
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
Douglas J
DJ
Kojetin
D001665:Binding Sites; D008024:Ligands; D047495:PPAR gamma / Q000737:chemistry / Q000378:metabolism*
D008024:Ligands; D047495:PPAR gamma