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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.
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1 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
2 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
3 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
4 Department of Integrative Structural and Computational Biology, Scripps Florida, The Scripps Research Institute, Jupiter, FL, USA
5 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
6 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
7 Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT, USA
8 Department of Molecular Medicine, Scripps Florida, The Scripps Research Institute, Jupiter, FL, USA
9 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