Morita Kentaro, Kawana Katsuyoshi, Sodeyama Mariko, Shimomura Iichiro, Kagechika Hiroyuki, Makishima Makoto
Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan.
Biochem Pharmacol. 2005 Dec 19;71(1-2):98-107. doi: 10.1016/j.bcp.2005.10.017. Epub 2005 Nov 10.
NGFI-B, an orphan member of the NR4A subfamily of the nuclear receptors, recognizes specific sequences in the promoters of neuronal target genes as a monomer. Although NGFI-B also forms a heterodimer with the retinoid X receptor (RXR), a receptor for 9-cis retinoic acid (9CRA), endogenous targets of the heterodimer have not been identified. We investigated the role of RXR ligand binding in NGFI-B/RXR activation and found that dibenzodiazepine-derived ligands, such as the weak RXR agonist HX600, selectively activate NGFI-B/RXR heterodimers. HX600 also activated the heterodimer formed by RXR and Nurr1, another NR4A subfamily receptor. In an assembly assay that detects ligand-dependent reconstruction of the ligand-binding domain, HX600 and not 9CRA induced an allosteric ligand effect on NGFI-B through RXRalpha binding. The data indicate that the RXR heterodimers of NGFI-B and Nurr1 are selectively activated by the RXR ligand HX600, and that compounds such as HX600 will be valuable tools in investigating NGFI-B and Nurr1 function.
NGFI-B是核受体NR4A亚家族的一个孤儿成员，作为单体识别神经元靶基因启动子中的特定序列。尽管NGFI-B也与视黄酸X受体（RXR，一种9-顺式视黄酸（9CRA）的受体）形成异二聚体，但该异二聚体的内源性靶点尚未确定。我们研究了RXR配体结合在NGFI-B/RXR激活中的作用，发现二苯并二氮卓衍生的配体，如弱RXR激动剂HX600，可选择性激活NGFI-B/RXR异二聚体。HX600还激活了由RXR和另一个NR4A亚家族受体Nurr1形成的异二聚体。在检测配体结合结构域配体依赖性重建的组装试验中，HX600而非9CRA通过RXRα结合对NGFI-B诱导变构配体效应。数据表明，NGFI-B和Nurr1的RXR异二聚体被RXR配体HX600选择性激活，并且诸如HX600之类的化合物将是研究NGFI-B和Nurr1功能的有价值工具。
