6DDA

Nurr1 Covalently Modified by a Dopamine Metabolite

Summary for 6DDA

• Entry DOI: 10.2210/pdb6dda/pdb
• Descriptor: Nuclear receptor subfamily 4 group A member 2, POTASSIUM ION, 5-hydroxy-1,2-dihydro-6H-indol-6-one, ... (5 entities in total)
• Functional Keywords: nurr1, dopamine, cysteine adduct, dihydroxyindole, transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 93240.25

Authors

Bruning, J.M.,Wang, Y.,Otrabella, F.,Boxue, T.,Liu, H.,Bhattacharya, P.,Guo, S.,Holton, J.M.,Fletterick, R.J.,Jacobson, M.P.,England, P.M. (deposition date: 2018-05-09, release date: 2019-03-20, Last modification date: 2024-12-25)

Primary citation

Bruning, J.M.,Wang, Y.,Oltrabella, F.,Tian, B.,Kholodar, S.A.,Liu, H.,Bhattacharya, P.,Guo, S.,Holton, J.M.,Fletterick, R.J.,Jacobson, M.P.,England, P.M.
Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite.
Cell Chem Biol, 26:674-685.e6, 2019

PubMed 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.

PubMed: 30853418
DOI: 10.1016/j.chembiol.2019.02.002

Experimental method

X-RAY DIFFRACTION (3.2 Å)