RT Journal Article
SR Electronic
T1 Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 368399
DO 10.1101/368399
A1 John M. Bruning
A1 Yan Wang
A1 Francesca Oltrabella
A1 Boxue Tian
A1 Svetlana A. Kholodar
A1 Harrison Liu
A1 Paulomi Bhattacharya
A1 Su Guo
A1 James M. Holton
A1 Robert J. Fletterick
A1 Matthew P. Jacobson
A1 Pamela M. England
YR 2018
UL http://biorxiv.org/content/early/2018/11/07/368399.abstract
AB 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.