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.

Details

Title
Defining a conformational ensemble that directs activation of PPARγ
Author
Chrisman, Ian M 1 ; Nemetchek, Michelle D 2 ; Ian Mitchelle S de Vera 3 ; Shang, Jinsai 4 ; Heidari, Zahra 5 ; Long, Yanan 6   VIAFID ORCID Logo  ; Reyes-Caballero, Hermes 4 ; Galindo-Murillo, Rodrigo 7   VIAFID ORCID Logo  ; Cheatham, Thomas E, III 7 ; Blayo, Anne-Laure 8 ; Shin, Youseung 8 ; Fuhrmann, Jakob 4 ; Griffin, Patrick R 9 ; Kamenecka, Theodore M 8 ; Kojetin, Douglas J 9   VIAFID ORCID Logo  ; Hughes, Travis S 5   VIAFID ORCID Logo 

 Biochemistry and Biophysics Graduate Program, The University of Montana, Missoula, MT, USA; Center for Biomolecular Structure and Dynamics, The University of Montana, Missoula, MT, USA 
 Biochemistry and Biophysics Graduate Program, The University of Montana, Missoula, MT, USA; Center for Biomolecular Structure and Dynamics, The University of Montana, Missoula, MT, USA; Department of Biomedical and Pharmaceutical Sciences, The University of Montana, Missoula, MT, USA 
 Department of Integrative Structural and Computational Biology, Scripps Florida, The Scripps Research Institute, Jupiter, FL, USA; Department of Pharmacology & Physiology, Saint Louis University School of Medicine, Saint Louis, MO, USA 
 Department of Integrative Structural and Computational Biology, Scripps Florida, The Scripps Research Institute, Jupiter, FL, USA 
 Center for Biomolecular Structure and Dynamics, The University of Montana, Missoula, MT, USA; Department of Biomedical and Pharmaceutical Sciences, The University of Montana, Missoula, MT, USA 
 Department of Integrative Structural and Computational Biology, Scripps Florida, The Scripps Research Institute, Jupiter, FL, USA; Summer Undergraduate Research Fellows (SURF) Program, Scripps Florida, The Scripps Research Institute, Jupiter, FL, USA 
 Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT, USA 
 Department of Molecular Medicine, Scripps Florida, The Scripps Research Institute, Jupiter, FL, USA 
 Department of Integrative Structural and Computational Biology, Scripps Florida, The Scripps Research Institute, Jupiter, FL, USA; Department of Molecular Medicine, Scripps Florida, The Scripps Research Institute, Jupiter, FL, USA 
Pages
1-16
Publication year
2018
Publication date
May 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2034682720
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.