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Cell Chem Biol. 2019 May 16;26(5):674-685.e6. doi: 10.1016/j.chembiol.2019.02.002. Epub 2019 Mar 7.

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

Author information

1
Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California San Francisco, San Francisco, CA 94158, USA.
2
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA.
3
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA.
4
Bioengineering Graduate Program, University of California San Francisco, San Francisco, CA 94158, USA.
5
Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94158, USA.
6
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.
7
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.

Abstract

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.

KEYWORDS:

5,6-dihydroxyindole; 5,6-dihydroxyindolequinone; 5,6-indolequinone; DHI; DHICA; IQ; Nr4A2; Nurr1; Parkinson's disease; cysteine adduct; dopamine homeostasis; dopamine metabolite; dopamine oxidation; ligand-binding domain; ligand-binding pocket; nuclear receptor; nuclear receptor related 1 protein; redox sensor

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