Open AccessAnalogs of the Dopamine Metabolite 5,6-Dihydroxyindole Bind Directly to and Activate the Nuclear Receptor Nurr1
Author(s) -
Svetlana A. Kholodar,
Geoffrey Lang,
Wilian A. Cortopassi,
Yoshie Iizuka,
Harman S. Brah,
Matthew P. Jacobson,
Pamela M. England
Publication year - 2021
Publication title -
acs chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.899
H-Index - 111
eISSN - 1554-8937
pISSN - 1554-8929
DOI - 10.1021/acschembio.1c00326
Subject(s) - dopamine , substantia nigra , pars compacta , transcription factor , metabolite , nuclear receptor , microbiology and biotechnology , chemistry , dopamine receptor , population , biology , biochemistry , dopaminergic , neuroscience , gene , medicine , environmental health
The nuclear receptor-related 1 protein, Nurr1, is a transcription factor critical for the development and maintenance of dopamine-producing neurons in the substantia nigra pars compacta, a cell population that progressively loses the ability to make dopamine and degenerates in Parkinson's disease. Recently, we demonstrated that Nurr1 binds directly to and is regulated by the endogenous dopamine metabolite 5,6-dihydroxyindole (DHI). Unfortunately, DHI is an unstable compound, and thus a poor tool for studying Nurr1 function. Here, we report that 5-chloroindole, an unreactive analog of DHI, binds directly to the Nurr1 ligand binding domain with micromolar affinity and stimulates the activity of Nurr1, including the transcription of genes governing the synthesis and packaging of dopamine.