Defining a conformational ensemble that directs activation of PPARγ

Ian M. Chrisman, Michelle D. Nemetchek, Ian Mitchelle S. De Vera, Jinsai Shang, Zahra Heidari, Yanan Long, Hermes Reyes-Caballero, Rodrigo Galindo-Murillo, Thomas E. Cheatham, Anne Laure Blayo, Youseung Shin, Jakob Fuhrmann, Patrick R. Griffin, Theodore M. Kamenecka, Douglas J. Kojetin, Travis S. Hughes

Research output: Contribution to journalArticlepeer-review

Abstract

The nuclear receptor ligand-binding domain (LBD) is a highly dynamic entity. Crystal structures have defined multiple low-energy LBD structural conformations of the activation function-2 (AF-2) co-regulator-binding surface, yet it remains unclear how ligand binding influences the number and population of conformations within the AF-2 structural ensemble. Here, we present a nuclear receptor co-regulator-binding surface structural ensemble in solution, viewed through the lens of fluorine-19 (19F) nuclear magnetic resonance (NMR) and molecular simulations, and the response of this ensemble to ligands, co-regulator peptides and heterodimerization. We correlate the composition of this ensemble with function in peroxisome proliferator-activated receptor-γ (PPARγ) utilizing ligands of diverse efficacy in co-regulator recruitment. While the co-regulator surface of apo PPARγ and partial-agonist-bound PPARγ is characterized by multiple thermodynamically accessible conformations, the full and inverse-agonist-bound PPARγ co-regulator surface is restricted to a few conformations which favor coactivator or corepressor binding, respectively.

Original languageEnglish (US)
Article number1794
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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