Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite.

Autor:	Bruning JM; Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California San Francisco, San Francisco, CA 94158, USA., Wang Y; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA., Oltrabella F; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA., Tian B; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA., Kholodar SA; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA., Liu H; Bioengineering Graduate Program, University of California San Francisco, San Francisco, CA 94158, USA., Bhattacharya P; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA., Guo S; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA., Holton JM; Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA., Fletterick RJ; Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA., Jacobson MP; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA., England PM; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA. Electronic address: pamela.england@ucsf.edu.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2019 May 16; Vol. 26 (5), pp. 674-685.e6. Date of Electronic Publication: 2019 Mar 07.
DOI:	10.1016/j.chembiol.2019.02.002
Abstrakt:	Nurr1, a nuclear receptor essential for the development, maintenance, and survival of midbrain dopaminergic neurons, is a potential therapeutic target for Parkinson's disease, a neurological disorder characterized by the degeneration of these same neurons. Efforts to identify Nurr1 agonists have been hampered by the recognition that it lacks several classic regulatory elements of nuclear receptor function, including the canonical ligand-binding pocket. Here we report that the dopamine metabolite 5,6-dihydroxyindole (DHI) binds directly to and modulates the activity of Nurr1. Using biophysical assays and X-ray crystallography, we show that DHI binds to the ligand-binding domain within a non-canonical pocket, forming a covalent adduct with Cys566. In cultured cells and zebrafish, DHI stimulates Nurr1 activity, including the transcription of target genes underlying dopamine homeostasis. These findings suggest avenues for developing synthetic Nurr1 ligands to ameliorate the symptoms and progression of Parkinson's disease. (Copyright © 2019 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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