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Analogs of the Dopamine Metabolite 5,6-Dihydroxyindole Bind Directly to and Activate the Nuclear Receptor Nurr1 (NR4A2)

Svetlana A. Kholodar, Geoffrey Lang, Wilian A. Cortopassi, Yoshie Iizuka, Harman S. Brah, Matthew P. Jacobson, View ORCID ProfilePamela M. England
doi: https://doi.org/10.1101/2021.05.09.442997
Svetlana A. Kholodar
Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158
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Geoffrey Lang
Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158
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Wilian A. Cortopassi
Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158
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Yoshie Iizuka
Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158
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Harman S. Brah
Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158
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Matthew P. Jacobson
Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158
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Pamela M. England
Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158
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  • ORCID record for Pamela M. England
  • For correspondence: Pamela.england@ucsf.edu
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ABSTRACT

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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 10, 2021.
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Analogs of the Dopamine Metabolite 5,6-Dihydroxyindole Bind Directly to and Activate the Nuclear Receptor Nurr1 (NR4A2)
Svetlana A. Kholodar, Geoffrey Lang, Wilian A. Cortopassi, Yoshie Iizuka, Harman S. Brah, Matthew P. Jacobson, Pamela M. England
bioRxiv 2021.05.09.442997; doi: https://doi.org/10.1101/2021.05.09.442997
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Analogs of the Dopamine Metabolite 5,6-Dihydroxyindole Bind Directly to and Activate the Nuclear Receptor Nurr1 (NR4A2)
Svetlana A. Kholodar, Geoffrey Lang, Wilian A. Cortopassi, Yoshie Iizuka, Harman S. Brah, Matthew P. Jacobson, Pamela M. England
bioRxiv 2021.05.09.442997; doi: https://doi.org/10.1101/2021.05.09.442997

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