6DDA

Nurr1 Covalently Modified by a Dopamine Metabolite

6DDA の概要

• エントリーDOI: 10.2210/pdb6dda/pdb
• 分子名称: Nuclear receptor subfamily 4 group A member 2, POTASSIUM ION, 5-hydroxy-1,2-dihydro-6H-indol-6-one, ... (5 entities in total)
• 機能のキーワード: nurr1, dopamine, cysteine adduct, dihydroxyindole, transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 93240.25

構造登録者

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. (登録日: 2018-05-09, 公開日: 2019-03-20, 最終更新日: 2024-12-25)

主引用文献

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

実験手法

X-RAY DIFFRACTION (3.2 Å)