Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1

Ian Mitchelle S. de Vera; Paola Munoz-Tello; Jie Zheng; Venkatasubramanian Dharmarajan; David P. Marciano; Edna Matta-Camacho; Pankaj Kumar Giri; Jinsai Shang; Travis S. Hughes; Mark Rance; Patrick R. Griffin; Douglas J. Kojetin

doi:10.1016/j.str.2018.10.002

Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1

Ian Mitchelle S. de Vera
, Paola Munoz-Tello
, Jie Zheng
, Venkatasubramanian Dharmarajan
, David P. Marciano
, Edna Matta-Camacho
, Pankaj Kumar Giri
, Jinsai Shang
, Travis S. Hughes
, Mark Rance
, Patrick R. Griffin
, Douglas J. Kojetin

Research output: Contribution to journal › Article › peer-review

42 Scopus citations

Abstract

Nuclear receptor-related 1 protein (Nurr1/NR4A2) is an orphan nuclear receptor (NR) that is considered to function without a canonical ligand-binding pocket (LBP). A crystal structure of the Nurr1 ligand-binding domain (LBD) revealed no physical space in the conserved region where other NRs with solvent accessible apo-protein LBPs bind synthetic and natural ligands. Using solution nuclear magnetic resonance spectroscopy, hydrogen/deuterium exchange mass spectrometry, and molecular dynamics simulations, we show that the putative canonical Nurr1 LBP is dynamic with high solvent accessibility, exchanges between two or more conformations on the microsecond-to-millisecond timescale, and can expand from the collapsed crystallized conformation to allow binding of unsaturated fatty acids. These findings should stimulate future studies to probe the ligandability and druggability of Nurr1 for both endogenous and synthetic ligands, which could lead to new therapeutics for Nurr1-related diseases, including Parkinson's disease and schizophrenia.

Original language	English
Pages (from-to)	66-77.e5
Journal	Structure
Volume	27
Issue number	1
DOIs	https://doi.org/10.1016/j.str.2018.10.002
State	Published - Jan 2 2019

Funding

This work was supported in part by NIH grants R01GM114420 (to D.J.K.), K99DK103116 (to T.S.H.); National Science Foundation (NSF) funding to the Summer Undergraduate Research Fellows (SURF) program at The Scripps Research Institute (grant 1659594); and the Academic Year Research Internship for Undergraduates (AYRIU) program at The Scripps Research Institute. A portion of this work was performed at the National High Magnetic Field Laboratory (NHMFL/MagLab), which is supported by NSF Cooperative Agreement No. DMR-1157490 and the State of Florida; we thank Mr. Ashley Blue at the NHMFL for assistance with NMR experiments. NMR data presented herein were collected in part at the City University of New York Advanced Science Research Center (CUNY ASRC) Biomolecular NMR Facility; we thank Dr. James Aramini at the ASRC for assistance with NMR experiments. This work was supported in part by NIH grants R01GM114420 (to D.J.K.), K99DK103116 (to T.S.H.); National Science Foundation (NSF) funding to the Summer Undergraduate Research Fellows (SURF) program at The Scripps Research Institute (grant 1659594 ); and the Academic Year Research Internship for Undergraduates (AYRIU) program at The Scripps Research Institute. A portion of this work was performed at the National High Magnetic Field Laboratory (NHMFL/MagLab), which is supported by NSF Cooperative Agreement No. DMR-1157490 and the State of Florida; we thank Mr. Ashley Blue at the NHMFL for assistance with NMR experiments. NMR data presented herein were collected in part at the City University of New York Advanced Science Research Center (CUNY ASRC) Biomolecular NMR Facility; we thank Dr. James Aramini at the ASRC for assistance with NMR experiments.

Funders	Funder number
Digital Surf
K99DK103116
R01GM114420
Scripps Research Institute	1659594
DMR-1157490

Keywords

NMR spectroscopy
NR4A2
Nurr1
dynamic pocket
hydrogen deuterium exchange mass spectrometry
ligand binding
molecular dynamics simulations
orphan nuclear receptor
unsaturated fatty acids

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10.1016/j.str.2018.10.002

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title = "Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1",

abstract = "Nuclear receptor-related 1 protein (Nurr1/NR4A2) is an orphan nuclear receptor (NR) that is considered to function without a canonical ligand-binding pocket (LBP). A crystal structure of the Nurr1 ligand-binding domain (LBD) revealed no physical space in the conserved region where other NRs with solvent accessible apo-protein LBPs bind synthetic and natural ligands. Using solution nuclear magnetic resonance spectroscopy, hydrogen/deuterium exchange mass spectrometry, and molecular dynamics simulations, we show that the putative canonical Nurr1 LBP is dynamic with high solvent accessibility, exchanges between two or more conformations on the microsecond-to-millisecond timescale, and can expand from the collapsed crystallized conformation to allow binding of unsaturated fatty acids. These findings should stimulate future studies to probe the ligandability and druggability of Nurr1 for both endogenous and synthetic ligands, which could lead to new therapeutics for Nurr1-related diseases, including Parkinson's disease and schizophrenia.",

keywords = "NMR spectroscopy, NR4A2, Nurr1, dynamic pocket, hydrogen deuterium exchange mass spectrometry, ligand binding, molecular dynamics simulations, orphan nuclear receptor, unsaturated fatty acids",

author = "\{de Vera\}, \{Ian Mitchelle S.\} and Paola Munoz-Tello and Jie Zheng and Venkatasubramanian Dharmarajan and Marciano, \{David P.\} and Edna Matta-Camacho and Giri, \{Pankaj Kumar\} and Jinsai Shang and Hughes, \{Travis S.\} and Mark Rance and Griffin, \{Patrick R.\} and Kojetin, \{Douglas J.\}",

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doi = "10.1016/j.str.2018.10.002",

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AU - Dharmarajan, Venkatasubramanian

AU - Marciano, David P.

AU - Matta-Camacho, Edna

AU - Giri, Pankaj Kumar

AU - Shang, Jinsai

AU - Hughes, Travis S.

AU - Rance, Mark

AU - Griffin, Patrick R.

AU - Kojetin, Douglas J.

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AB - Nuclear receptor-related 1 protein (Nurr1/NR4A2) is an orphan nuclear receptor (NR) that is considered to function without a canonical ligand-binding pocket (LBP). A crystal structure of the Nurr1 ligand-binding domain (LBD) revealed no physical space in the conserved region where other NRs with solvent accessible apo-protein LBPs bind synthetic and natural ligands. Using solution nuclear magnetic resonance spectroscopy, hydrogen/deuterium exchange mass spectrometry, and molecular dynamics simulations, we show that the putative canonical Nurr1 LBP is dynamic with high solvent accessibility, exchanges between two or more conformations on the microsecond-to-millisecond timescale, and can expand from the collapsed crystallized conformation to allow binding of unsaturated fatty acids. These findings should stimulate future studies to probe the ligandability and druggability of Nurr1 for both endogenous and synthetic ligands, which could lead to new therapeutics for Nurr1-related diseases, including Parkinson's disease and schizophrenia.

KW - NMR spectroscopy

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KW - hydrogen deuterium exchange mass spectrometry

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KW - orphan nuclear receptor

KW - unsaturated fatty acids

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JO - Structure

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Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1

Abstract

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Keywords

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