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PDBsum entry 6dda
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Transcription
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PDB id
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6dda
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References listed in PDB file
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Key reference
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Title
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Covalent modification and regulation of the nuclear receptor nurr1 by a dopamine metabolite.
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Authors
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J.M.Bruning,
Y.Wang,
F.Oltrabella,
B.Tian,
S.A.Kholodar,
H.Liu,
P.Bhattacharya,
S.Guo,
J.M.Holton,
R.J.Fletterick,
M.P.Jacobson,
P.M.England.
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Ref.
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Cell Chem Biol, 2019,
26,
674.
[DOI no: ]
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PubMed id
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Abstract
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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.
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