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 and Travis S. Hughes ()
Additional contact information
Ian M. Chrisman: The University of Montana
Michelle D. Nemetchek: The University of Montana
Ian Mitchelle S. de Vera: The Scripps Research Institute
Jinsai Shang: The Scripps Research Institute
Zahra Heidari: The University of Montana
Yanan Long: The Scripps Research Institute
Hermes Reyes-Caballero: The Scripps Research Institute
Rodrigo Galindo-Murillo: University of Utah
Thomas E. Cheatham: University of Utah
Anne-Laure Blayo: The Scripps Research Institute
Youseung Shin: The Scripps Research Institute
Jakob Fuhrmann: The Scripps Research Institute
Patrick R. Griffin: The Scripps Research Institute
Theodore M. Kamenecka: The Scripps Research Institute
Douglas J. Kojetin: The Scripps Research Institute
Travis S. Hughes: The University of Montana

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04176-x

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