Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite
Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite
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DOI：
10.1016/j.chembiol.2019.02.002
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发表时间：
2019-05-16
影响因子：
8.6
通讯作者：
England, Pamela M.
中科院分区：
文献类型：
--
作者：
Bruning, John M.;Wang, Yan;England, Pamela M.
Nurr 1是中脑多巴胺能神经元发育、维持和存活所必需的核受体，是帕金森病的潜在治疗靶点，帕金森病是一种以这些相同神经元变性为特征的神经系统疾病。鉴定Nurr 1激动剂的努力由于认识到它缺乏核受体功能的几个经典调节元件而受到阻碍，包括典型的配体结合口袋。在这里，我们报告说，多巴胺代谢产物5，6-二羟基吲哚（DHI）直接结合，并调节Nurr 1的活性。使用生物物理分析和X射线晶体学，我们表明，DHI结合到配体结合结构域内的非典型口袋，形成共价加合物与Cys 566。在培养的细胞和斑马鱼中，DHI刺激Nurr 1活性，包括多巴胺稳态的靶基因转录。这些发现为开发合成Nurr 1配体以改善帕金森病的症状和进展提供了途径。
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 beenhampered 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.