PDBsum entry 6dda

Transcription

PDB id: 6dda

Contents

Protein chains

236 a.a.

224 a.a.

Ligands

G7J ×3

Metals

__K ×5

_BR ×7

PDB id:

6dda

Name:

Transcription

Title:

Nurr1 covalently modified by a dopamine metabolite

Structure:

Nuclear receptor subfamily 4 group a member 2. Chain: b, c. Synonym: immediate-early response protein not,orphan nuclear receptor nurr1,transcriptionally-inducible nuclear receptor. Engineered: yes. Nuclear receptor subfamily 4 group a member 2. Chain: a. Synonym: immediate-early response protein not,orphan nuclear receptor nurr1,transcriptionally-inducible nuclear receptor.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: nr4a2, not, nurr1, tinur. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562

Resolution:

3.20Å R-factor: 0.250 R-free: 0.295

Authors:

J.M.Bruning,Y.Wang,F.Otrabella,T.Boxue,H.Liu,P.Bhattacharya,S.Guo, J.M.Holton,R.J.Fletterick,M.P.Jacobson,P.M.England

Key ref:

J.M.Bruning et al. (2019). Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite. Cell Chem Biol, 26, 674. PubMed id: 30853418 DOI: 10.1016/j.chembiol.2019.02.002

Date:

09-May-18 Release date: 20-Mar-19

Protein chain

P43354  (NR4A2_HUMAN) -  Nuclear receptor subfamily 4 group A member 2 from Homo sapiens

Seq: 598 a.a.

Struc: 236 a.a.

Protein chains

P43354  (NR4A2_HUMAN) -  Nuclear receptor subfamily 4 group A member 2 from Homo sapiens

Seq: 598 a.a.

Struc: 224 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1016/j.chembiol.2019.02.002

Cell Chem Biol 26:674 (2019)

PubMed id: 30853418

Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite.

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.

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.