한빛사 논문
Sreekanth Rajan1,15, Yongwoo Jang2,3,15, Chun-Hyung Kim2,4,15, Woori Kim2,15, 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 Yoon1,6,* and Kwang-Soo Kim2,14,*
1School of Biological Sciences, Nanyang Technological University, Singapore, Singapore. 2Molecular Neurobiology Laboratory, Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA. 3Department of Biomedical Engineering, Hanyang University, Seoul, Korea. 4Paean Biotechnology, Daejeon, Korea. 5Nanyang Institute of Technology in Health and Medicine, Interdisciplinary Graduate School, Nanyang Technological University, Singapore, Singapore. 6NTU Institute of Structural Biology, Nanyang Technological University, Singapore, Singapore. 7Experimental Drug Development Centre, Agency for Science, Technology and Research, Nanos, Singapore, Singapore. 8Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, Singapore. 9National Neuroscience Institute, Singapore, Singapore. 10Lee Kong Chian School of Medicine, Singapore, Singapore. 11Department of Bioscience and Biotechnology, Konkuk University, Gwangjin-gu, Seoul, Republic of Korea. 12Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. 13Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. 14Program in Neuroscience and Harvard Stem Cell Institute, McLean Hospital, Harvard Medical School, Belmont, MA, USA. 15These authors contributed equally: Sreekanth Rajan, Yongwoo Jang, Chun-Hyung Kim, Woori Kim.
*Corresponding authors
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.
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