Willems Sabine, Kilu Whitney, Ni Xiaomin, Chaikuad Apirat, Knapp Stefan, Heering Jan, Merk Daniel
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.
Structural Genomics Consortium, BMLS, Goethe-University Frankfurt, Max-von-Lause-Str. 15, 60438, Frankfurt, Germany.
Commun Chem. 2020 Jul 3;3(1):85. doi: 10.1038/s42004-020-0331-0.
Nuclear receptor related 1 (Nurr1) is an orphan ligand-activated transcription factor and considered as neuroprotective transcriptional regulator with great potential as therapeutic target for neurodegenerative diseases. However, the collection of available Nurr1 modulators and mechanistic understanding of Nurr1 are limited. Here, we report the discovery of several structurally diverse non-steroidal anti-inflammatory drugs as inverse Nurr1 agonists demonstrating that Nurr1 activity can be regulated bidirectionally. As chemical tools, these ligands enable unraveling the co-regulatory network of Nurr1 and the mode of action distinguishing agonists from inverse agonists. In addition to its ability to dimerize, we observe an ability of Nurr1 to recruit several canonical nuclear receptor co-regulators in a ligand-dependent fashion. Distinct dimerization states and co-regulator interaction patterns arise as discriminating factors of Nurr1 agonists and inverse agonists. Our results contribute a valuable collection of Nurr1 modulators and relevant mechanistic insights for future Nurr1 target validation and drug discovery.
核受体相关蛋白1（Nurr1）是一种孤儿配体激活转录因子，被认为是具有神经保护作用的转录调节因子，作为神经退行性疾病的治疗靶点具有巨大潜力。然而，现有的Nurr1调节剂种类有限，对Nurr1作用机制的了解也较为匮乏。在此，我们报告发现了几种结构各异的非甾体抗炎药可作为Nurr1反向激动剂，这表明Nurr1的活性能够被双向调节。作为化学工具，这些配体有助于揭示Nurr1的共调节网络以及区分激动剂和反向激动剂的作用模式。除了其二聚化能力外，我们还观察到Nurr1能够以配体依赖的方式招募几种典型的核受体共调节因子。不同的二聚化状态和共调节因子相互作用模式是区分Nurr1激动剂和反向激动剂的因素。我们的研究结果为未来Nurr1靶点验证和药物发现提供了宝贵的Nurr1调节剂集合及相关作用机制见解。
