Structural highlights
6dda is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Ligands: | , , |
| NonStd Res: | |
| Gene: | NR4A2, NOT, NURR1, TINUR (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[NR4A2_HUMAN] Transcriptional regulator which is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development. It is crucial for expression of a set of genes such as SLC6A3, SLC18A2, TH and DRD2 which are essential for development of mdDA neurons (By similarity).
Publication Abstract from PubMed
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.
Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite.,Bruning JM, Wang Y, Oltrabella F, Tian B, Kholodar SA, Liu H, Bhattacharya P, Guo S, Holton JM, Fletterick RJ, Jacobson MP, England PM Cell Chem Biol. 2019 Feb 16. pii: S2451-9456(19)30036-4. doi:, 10.1016/j.chembiol.2019.02.002. PMID:30853418[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bruning JM, Wang Y, Oltrabella F, Tian B, Kholodar SA, Liu H, Bhattacharya P, Guo S, Holton JM, Fletterick RJ, Jacobson MP, England PM. Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite. Cell Chem Biol. 2019 Feb 16. pii: S2451-9456(19)30036-4. doi:, 10.1016/j.chembiol.2019.02.002. PMID:30853418 doi:http://dx.doi.org/10.1016/j.chembiol.2019.02.002
