5y41
Crystal Structure of LIGAND-BOUND NURR1-LBD
Structural highlights
FunctionNR4A2_HUMAN Transcriptional regulator which is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development. It is crucial for expression of a set of genes such as SLC6A3, SLC18A2, TH and DRD2 which are essential for development of mdDA neurons (By similarity). Publication Abstract from PubMedThe 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 A resolution. PGA1 couples covalently to Nurr1-LBD by forming a Michael adduct with Cys566, and induces notable conformational changes, including a 21 degrees 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. PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function.,Rajan S, Jang Y, Kim CH, Kim W, Toh HT, Jeon J, Song B, Serra A, Lescar J, Yoo JY, Beldar S, Ye H, Kang C, Liu XW, Feitosa M, Kim Y, Hwang D, Goh G, Lim KL, Park HM, Lee CH, Oh SF, Petsko GA, Yoon HS, Kim KS Nat Chem Biol. 2020 May 25. pii: 10.1038/s41589-020-0553-6. doi:, 10.1038/s41589-020-0553-6. PMID:32451509[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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