| Literature DB >> 32451509 |
Sreekanth Rajan1, Yongwoo Jang2,3, Chun-Hyung Kim2,4, Woori Kim2, Hui Ting Toh1,5, Jeha Jeon2, Bin Song2, Aida Serra1, Julien Lescar1,6, Jun Yeob Yoo1, Serap Beldar1, Hong Ye1, Congbao Kang7, Xue-Wei Liu8, Melissa Feitosa2, Yeahan Kim2, Dabin Hwang2, Geraldine Goh9, Kah-Leong Lim9,10, Hye Min Park11, Choong Hwan Lee11, Sungwhan F Oh12, Gregory A Petsko13, Ho Sup Yoon14,15, Kwang-Soo Kim16,17.
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.Entities:
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Year: 2020 PMID： 32451509 PMCID： PMC7405943 DOI： 10.1038/s41589-020-0553-6
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 15.040