PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function

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 trans...

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Published inNature chemical biology Vol. 16; no. 8; pp. 876 - 886
Main Authors Rajan, Sreekanth, Jang, Yongwoo, Kim, Chun-Hyung, Kim, Woori, Toh, Hui Ting, Jeon, Jeha, Song, Bin, Serra, Aida, Lescar, Julien, Yoo, Jun Yeob, Beldar, Serap, Ye, Hong, Kang, Congbao, Liu, Xue-Wei, Feitosa, Melissa, Kim, Yeahan, Hwang, Dabin, Goh, Geraldine, Lim, Kah-Leong, Park, Hye Min, Lee, Choong Hwan, Oh, Sungwhan F., Petsko, Gregory A., Yoon, Ho Sup, Kim, Kwang-Soo
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.08.2020
Nature Publishing Group
Subjects
631/378
631/92
631/92/287
631/92/612/822
Alprostadil - metabolism
Animal models
Animals
Binding
Biochemical Engineering
Biochemistry
Bioorganic Chemistry
Cell Biology
Cell Line, Tumor
Chemistry
Chemistry and Materials Science
Chemistry/Food Science
Crystal structure
Crystallography
Crystallography, X-Ray
Dehydration
Domains
Dopamine - metabolism
Dopamine receptors
Gene expression
Genes
Humans
Ligands
Male
Mesencephalon
Metabolites
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Movement disorders
MPTP
Neurodegenerative diseases
Neurons
Neurons - metabolism
Neuroprotection
Neuroprotective Agents - pharmacology
Nuclear Receptor Subfamily 4, Group A, Member 2 - chemistry
Nuclear Receptor Subfamily 4, Group A, Member 2 - genetics
Nuclear Receptor Subfamily 4, Group A, Member 2 - metabolism
Nuclear receptors
Nurr1 protein
Parkinson's disease
Prostaglandin E1
Prostaglandins
Prostaglandins A - metabolism
Protein Binding
Rats
Signal Transduction
Transcription activation
Transcription, Genetic
Online AccessGet full text

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Abstract 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. Prostaglandins PGE1 and PGA1 have neuroprotective effects by enhancing the transcriptional activity of Nurr1 by directly binding to its ligand-binding domain and upregulating their target genes implicated in Parkinson’s disease.
AbstractList 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.
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. Prostaglandins PGE1 and PGA1 have neuroprotective effects by enhancing the transcriptional activity of Nurr1 by directly binding to its ligand-binding domain and upregulating their target genes implicated in Parkinson’s disease.
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.Prostaglandins PGE1 and PGA1 have neuroprotective effects by enhancing the transcriptional activity of Nurr1 by directly binding to its ligand-binding domain and upregulating their target genes implicated in Parkinson’s disease.
Author Beldar, Serap
Jeon, Jeha
Kim, Woori
Petsko, Gregory A.
Lee, Choong Hwan
Yoon, Ho Sup
Yoo, Jun Yeob
Jang, Yongwoo
Ye, Hong
Hwang, Dabin
Liu, Xue-Wei
Song, Bin
Feitosa, Melissa
Lescar, Julien
Oh, Sungwhan F.
Park, Hye Min
Rajan, Sreekanth
Kim, Chun-Hyung
Kim, Kwang-Soo
Toh, Hui Ting
Lim, Kah-Leong
Kim, Yeahan
Serra, Aida
Kang, Congbao
Goh, Geraldine
AuthorAffiliation 4 Paean Biotechnology, Daejeon, Korea
1 School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
13 Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
14 Program in Neuroscience and Harvard Stem Cell Institute, McLean Hospital, Harvard Medical School, Belmont, MA, USA
15 These authors contributed equally: Sreekanth Rajan, Yongwoo Jang, Chun-Hyung Kim, Woori Kim
7 Experimental Drug Development Centre, Agency for Science, Technology and Research, Nanos, Singapore, Singapore
5 Nanyang Institute of Technology in Health and Medicine, Interdisciplinary Graduate School, Nanyang Technological University, Singapore, Singapore
11 Department of Bioscience and Biotechnology, Konkuk University, Gwangjin-gu, Seoul, Republic of Korea
3 Department of Biomedical Engineering, Hanyang University, Seoul, Korea
9 National Neuroscience Institute, Singapore, Singapore
8 Division of Chemistry and Biologic
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/32451509$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright The Author(s), under exclusive licence to Springer Nature America, Inc. 2020
The Author(s), under exclusive licence to Springer Nature America, Inc. 2020.
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content type line 23
K.-S.K. and H.S.Y. initiated and supervised the project. S.R., Y.J., C.H.K. and W.K. were responsible for the overall design and performance of experiments. S.R., H.T.T., H.Y., C.K., A.S., J.L., J.Y.Y., S.B., H.Y., C.K., X.L., G.G. and K.L.L. performed and analyzed structural studies. Y.J., C.H.K., W.K, J.J., B.S., M.F., Y.K., D.H., H.M.P., S.F.O. and C.H.L. performed and analyzed functional and biological studies. K.-S.K., H.S.Y., S.R., Y.J., C.H.K., W.K. and G.A.P. analyzed the data and wrote the paper. All authors contributed to the discussion and final approval of the paper.
Author contributions
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SSID ssj0036618
Score 2.580962
Snippet The orphan nuclear receptor Nurr1 is critical for the development, maintenance and protection of midbrain dopaminergic (mDA) neurons. Here we show that...
SourceID pubmedcentral
proquest
crossref
pubmed
springer
SourceType Open Access Repository
Aggregation Database
Index Database
Publisher
StartPage 876
SubjectTerms 631/378
631/92
631/92/287
631/92/612/822
Alprostadil - metabolism
Animal models
Animals
Binding
Biochemical Engineering
Biochemistry
Bioorganic Chemistry
Cell Biology
Cell Line, Tumor
Chemistry
Chemistry and Materials Science
Chemistry/Food Science
Crystal structure
Crystallography
Crystallography, X-Ray
Dehydration
Domains
Dopamine - metabolism
Dopamine receptors
Gene expression
Genes
Humans
Ligands
Male
Mesencephalon
Metabolites
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Movement disorders
MPTP
Neurodegenerative diseases
Neurons
Neurons - metabolism
Neuroprotection
Neuroprotective Agents - pharmacology
Nuclear Receptor Subfamily 4, Group A, Member 2 - chemistry
Nuclear Receptor Subfamily 4, Group A, Member 2 - genetics
Nuclear Receptor Subfamily 4, Group A, Member 2 - metabolism
Nuclear receptors
Nurr1 protein
Parkinson's disease
Prostaglandin E1
Prostaglandins
Prostaglandins A - metabolism
Protein Binding
Rats
Signal Transduction
Transcription activation
Transcription, Genetic
Title PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function
URI https://link.springer.com/article/10.1038/s41589-020-0553-6
https://www.ncbi.nlm.nih.gov/pubmed/32451509
https://www.proquest.com/docview/2425719827
https://www.proquest.com/docview/2476741313
https://search.proquest.com/docview/2406951172
https://pubmed.ncbi.nlm.nih.gov/PMC7405943
Volume 16
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