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

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 sol...

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Veröffentlicht in:Structure (London) 2019-01, Vol.27 (1), p.66-77.e5
Hauptverfasser: de Vera, Ian Mitchelle S., Munoz-Tello, Paola, Zheng, Jie, Dharmarajan, Venkatasubramanian, Marciano, David P., Matta-Camacho, Edna, Giri, Pankaj Kumar, Shang, Jinsai, Hughes, Travis S., Rance, Mark, Griffin, Patrick R., Kojetin, Douglas J.
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Sprache:eng
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Zusammenfassung: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. [Display omitted] •A previous crystal structure indicated Nurr1 lacks a canonical ligand-binding pocket•Solution NMR and HDX-MS uncover a dynamic putative pocket•NMR exposes a similar binding epitope for fatty acids and a synthetic Nurr1 agonist•MD simulations and HDX-MS implicate pocket expansion after ligand binding The orphan nuclear receptor Nurr1 is thought to lack a canonical ligand-binding pocket for natural ligands. Solution structural analyses of the Nurr1 ligand-binding domain (LBD) show that its putative ligand-binding pocket is dynamic, solvent accessible, and expands to bind unsaturated fatty acids.
ISSN:0969-2126
1878-4186
DOI:10.1016/j.str.2018.10.002