PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function.
Alprostadil
/ metabolism
Animals
Cell Line, Tumor
Crystallography, X-Ray
Dopamine
/ metabolism
Humans
Ligands
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Neurons
/ metabolism
Neuroprotective Agents
/ pharmacology
Nuclear Receptor Subfamily 4, Group A, Member 2
/ chemistry
Prostaglandins A
/ metabolism
Protein Binding
Rats
Signal Transduction
Transcription, Genetic
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
22
08
2019
accepted:
22
04
2020
pubmed:
27
5
2020
medline:
24
11
2020
entrez:
27
5
2020
Statut:
ppublish
Résumé
The orphan nuclear receptor Nurr1 is critical for the development, maintenance and protection of midbrain dopaminergic (mDA) neurons. Here we show that prostaglandin E1 (PGE1) and its dehydrated metabolite, PGA1, directly interact with the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional function. We also report the crystallographic structure of Nurr1-LBD bound to PGA1 at 2.05 Å resolution. PGA1 couples covalently to Nurr1-LBD by forming a Michael adduct with Cys566, and induces notable conformational changes, including a 21° shift of the activation function-2 helix (H12) away from the protein core. Furthermore, PGE1/PGA1 exhibit neuroprotective effects in a Nurr1-dependent manner, prominently enhance expression of Nurr1 target genes in mDA neurons and improve motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse models of Parkinson's disease. Based on these results, we propose that PGE1/PGA1 represent native ligands of Nurr1 and can exert neuroprotective effects on mDA neurons, via activation of Nurr1's transcriptional function.
Identifiants
pubmed: 32451509
doi: 10.1038/s41589-020-0553-6
pii: 10.1038/s41589-020-0553-6
pmc: PMC7405943
mid: NIHMS1598692
doi:
Substances chimiques
Ligands
0
NR4A2 protein, human
0
Neuroprotective Agents
0
Nuclear Receptor Subfamily 4, Group A, Member 2
0
Prostaglandins A
0
Alprostadil
F5TD010360
Dopamine
VTD58H1Z2X
prostaglandin A1
VYR271N44P
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
876-886Subventions
Organisme : NINDS NIH HHS
ID : R01 NS070577
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS084869
Pays : United States
Organisme : NIH HHS
ID : R24 OD024622
Pays : United States
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