Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/155280
Title: PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function
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
Keywords: Science::Chemistry
Issue Date: 2020
Source: Rajan, S., Jang, Y., Kim, C., Kim, W., Toh, H. T., Jeon, J., Song, B., Serra, A., Lescar, J., Yoo, J. Y., Beldar, S., Ye, H., Kang, C., Liu, X., Feitosa, M., Kim, Y., Hwang, D., Goh, G., Lim, K., ...Kim, K. (2020). PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function. Nature Chemical Biology, 16(8), 876-886. https://dx.doi.org/10.1038/s41589-020-0553-6
Project: NS070577 
NS084869 
NRF-2018M3A9B5023055 
ARC55/16 
TCR/013-NNI/2014 
Journal: Nature Chemical Biology 
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.
URI: https://hdl.handle.net/10356/155280
ISSN: 1552-4450
DOI: 10.1038/s41589-020-0553-6
Rights: © 2020 The Author(s), under exclusive licence to Springer Nature America, Inc. All rights reserved.
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:IGS Journal Articles
LKCMedicine Journal Articles
SBS Journal Articles
SPMS Journal Articles

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