Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition
Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition
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DOI：
10.1016/s0092-8674(02)00817-6
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发表时间：
2002-07-12
期刊：
影响因子：
64.5
通讯作者：
Xu, HE
中科院分区：
文献类型：
--
作者：
Bledsoe, RK;Montana, VG;Xu, HE
糖皮质激素受体（GR）的转录调控是通过激素结合、受体二聚化以及辅激活因子招募来介导的。在此，我们报道了人糖皮质激素受体配体结合域（LBD）与地塞米松以及源自转录中介因子2的一个辅激活因子基序相结合的晶体结构。尽管与其他类固醇受体具有结构相似性，但糖皮质激素受体配体结合域呈现出一种令人惊讶的二聚体构象，涉及一个分子间的β折叠的形成。功能研究表明，这种新的二聚体界面对于糖皮质激素受体介导的激活非常重要。该结构还揭示了一个额外的电荷钳，它决定了辅激活因子的结合选择性，以及一个独特的配体结合口袋，这解释了它对内源性类固醇激素的选择性。这些结果为理解蛋白质 - 激素和蛋白质 - 蛋白质相互作用在糖皮质激素受体信号通路中的作用建立了一个框架。
Transcriptional regulation by the glucocorticoid receptor (GR) is mediated by hormone binding, receptor dimerization, and coactivator recruitment. Here, we report the crystal structure of the human GR ligand binding domain (LBD) bound to dexamethasone and a coactivator motif derived from the transcriptional intermediary factor 2. Despite structural similarity to other steroid receptors, the GR LBD adopts a surprising dimer configuration involving formation of an intermolecular P sheet. Functional studies demonstrate that the novel dimer interface is important for GR-mediated activation. The structure also reveals an additional charge clamp that determines the binding selectivity of a coactivator and a distinct ligand binding pocket that explains its selectivity for endogenous steroid hormones. These results establish a framework for understanding the roles of protein-hormone and protein-protein interactions in GR signaling pathways.