Selective allosteric ligand activation of the retinoid X receptor heterodimers of NGFI-B and Nurr1
Selective allosteric ligand activation of the retinoid X receptor heterodimers of NGFI-B and Nurr1
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DOI：
10.1016/j.bcp.2005.10.017
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发表时间：
2005-12-19
影响因子：
5.8
通讯作者：
Makishima, M
中科院分区：
文献类型：
--
作者：
Morita, K;Kawana, K;Makishima, M
NGFI-B是核受体NR4A亚家族的孤儿成员，作为单体识别神经元靶基因启动子中的特定序列。虽然NGFI-B也与9-顺式维甲酸（9CRA）的受体类维甲酸X受体（RXR）形成异源二聚体，但该异源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活化中的作用，发现二苯二氮平衍生的配体，如弱RXR激动剂HX600，选择性地激活NGFI-B/RXR异源二聚体。HX600还激活了RXR和另一个NR4A亚家族受体Nurr1形成的异源二聚体。在检测配体结合域的配体依赖性重建的组装试验中，HX600而不是9CRA通过RXR α结合诱导NGFI-B的变构配体效应。结果表明，NGFI-B和Nurr1的RXR异源二聚体被RXR配体HX600选择性激活，HX600等化合物将成为研究NGFI-B和Nurr1功能的有价值的工具。(c) 2005爱思唯尔公司版权所有。
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 RXR alpha 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. (c) 2005 Elsevier Inc. All rights reserved.