TY - JOUR
T1 - Defining a conformational ensemble that directs activation of PPARγ
AU - Chrisman, Ian M.
AU - Nemetchek, Michelle D.
AU - De Vera, Ian Mitchelle S.
AU - Shang, Jinsai
AU - Heidari, Zahra
AU - Long, Yanan
AU - Reyes-Caballero, Hermes
AU - Galindo-Murillo, Rodrigo
AU - Cheatham, Thomas E.
AU - Blayo, Anne Laure
AU - Shin, Youseung
AU - Fuhrmann, Jakob
AU - Griffin, Patrick R.
AU - Kamenecka, Theodore M.
AU - Kojetin, Douglas J.
AU - Hughes, Travis S.
N1 - Funding Information:
We thank James Aramini at the City University of New York Advanced Science Research Center (CUNY ASRC) for assistance in setting up the saturation transfer difference, cpmg, and t1ir experiments and Daniel R. Roe (NIH Laboratory of Computational Biology, NHLBI) for providing the minimization and equilibration script and simulation advice. NMR data presented herein were collected at the CUNY ASRC Biomolecular NMR Facility. This work was supported in part by National Institutes of Health (NIH) grants K99DK103116 (to T.S.H.), R00DK103116 (to T.S.H.), P20GM103546 (to T.H.S.), DK101871 (to D.J.K.), and DK105825 (to P.R.G.); and National Science Foundation (NSF) award 1359369 (PI Karbstein) that funds the SURF program at Scripps Florida.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-018-04176-x
DO - 10.1038/s41467-018-04176-x
M3 - Article
C2 - 29728618
AN - SCOPUS:85046675557
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1794
ER -