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An alternate binding site for PPARγ ligands

Academic Article
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Overview

related to degree

  • Marciano, David, Ph.D. in Biology, Scripps Research 2010 - 2014

authors

  • Hughes, T. S.
  • Giri, P. K.
  • de Vera, I. M. S.
  • Marciano, David
  • Kuruvilla, D. S.
  • Shin, Y.
  • Blayo, A. L.
  • Kamenecka, Theodore
  • Burris, Thomas
  • Griffin, Patrick
  • Kojetin, Douglas

publication date

  • April 2014

journal

  • Nature Communications  Journal

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.

subject areas

  • Binding Sites
  • Ligands
  • PPAR gamma
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Identity

PubMed Central ID

  • PMC4070320

International Standard Serial Number (ISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/ncomms4571

PubMed ID

  • 24705063
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Additional Document Info

start page

  • 3571

volume

  • 5

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