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

doi:10.1038/s41467-018-04176-x

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 journal › Article › peer-review

55 Scopus citations

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 language	English
Article number	1794
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04176-x
State	Published - Dec 1 2018

Funding

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.

Funders	Funder number
Digital Surf
1359369
DK105825, P20GM103546, DK101871
K99DK103116

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Chrisman, I. M., Nemetchek, M. D., De Vera, I. M. S., Shang, J., Heidari, Z., Long, Y., Reyes-Caballero, H., Galindo-Murillo, R., Cheatham, T. E., Blayo, A. L., Shin, Y., Fuhrmann, J., Griffin, P. R., Kamenecka, T. M., Kojetin, D. J., & Hughes, T. S. (2018). Defining a conformational ensemble that directs activation of PPARγ. Nature Communications, 9(1), Article 1794. https://doi.org/10.1038/s41467-018-04176-x

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title = "Defining a conformational ensemble that directs activation of PPARγ",

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.",

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

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doi = "10.1038/s41467-018-04176-x",

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Chrisman, IM, Nemetchek, MD, De Vera, IMS, Shang, J, Heidari, Z, Long, Y, Reyes-Caballero, H, Galindo-Murillo, R, Cheatham, TE, Blayo, AL, Shin, Y, Fuhrmann, J, Griffin, PR, Kamenecka, TM, Kojetin, DJ & Hughes, TS 2018, 'Defining a conformational ensemble that directs activation of PPARγ', Nature Communications, vol. 9, no. 1, 1794. https://doi.org/10.1038/s41467-018-04176-x

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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.

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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DO - 10.1038/s41467-018-04176-x

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SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1794

ER -

Defining a conformational ensemble that directs activation of PPARγ

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