Crystal structure of the human RXRα ligand-binding domain bound to its natural ligand:: 9-cis retinoic acid
Crystal structure of the human RXRα ligand-binding domain bound to its natural ligand:: 9-cis retinoic acid
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DOI：
10.1093/emboj/19.11.2592
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发表时间：
2000-06-01
期刊：
影响因子：
11.4
通讯作者：
Moras, D
中科院分区：
文献类型：
--
作者：
Egea, PF;Mitschler, A;Moras, D
活性类视黄醇的多效性作用由其同源核受体、类视黄醇 X 受体 (RXR) 和视黄酸受体 (RAR) 转导，它们充当由视黄酸 (RA) 的两种立体异构体激活的转录调节因子：9-顺式 RA (9-cRA) 和全反式 RA (a-tRA)。在核受体中，RXR 占据中心位置，并在许多细胞内信号传导途径中发挥着至关重要的作用，作为与该超家族的许多其他成员的普遍存在的异二聚化伙伴，而 RAR 结合两种异构体，RXR 专门结合 9-cRA，与 9-cRA 结合的人 RXR α 的配体结合结构域 (LBD) 的晶体结构揭示了这种配体选择性的分子基础，并允许比较相同的核受体。在晶体中，受体是单体的，并表现出典型的激动剂构象，配体和反式激活螺旋 H12 之间没有直接接触。与未配体的 RXR α LED 结构的比较揭示了配体诱导的构象变化的分子机制，并使我们能够在原子水平上描述这些变化如何产生参与核受体-共激活剂相互作用的适当的蛋白质界面。
The pleiotropic effects of active retinoids are transduced by their cognate nuclear receptors, retinoid X receptors (RXRs) and retinoic acid receptors (RARs), which act as transcriptional regulators activated by two stereoisomers of retinoic acid (RA): 9-cis RA (9-cRA) and all-trans RA (a-tRA). Among nuclear receptors, RXR occupies a central position and plays a crucial role in many intracellular signalling pathways as a ubiquitous heterodimerization partner with numerous other members of this superfamily, Whereas RARs bind both isomers, RXRs exclusively bind 9-cRA, The crystal structure of the ligand-binding domain (LBD) of human RXR alpha bound to 9-cRA reveals the molecular basis of this ligand selectivity and allows a comparison of both apo and hole forms of the same nuclear receptor. In the crystal, the receptor is monomeric and exhibits a canonical agonist conformation without direct contacts between the ligand and the transactivation helix H12. Comparison with the unliganded RXR alpha LED structure reveals the molecular mechanisms of ligand-induced conformational changes and allows us to describe at the atomic level how these changes generate the proper protein interface involved in nuclear receptor-coactivator interaction.