Structural and functional insights into nuclear receptor signaling.
Structural and functional insights into nuclear receptor signaling.
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DOI：
10.1016/j.addr.2010.08.007
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发表时间：
2010-10-30
影响因子：
16.1
通讯作者：
Li, Yong
中科院分区：
文献类型：
--
作者：
Jin, Lihua;Li, Yong
核受体是重要的转录因子，具有高度的序列同一性和保守的结构域，包括DNA结合结构域（DBD）和配体结合结构域（LBD）。LBD在配体介导的核受体活性中起着至关重要的作用。数百种不同的核受体晶体结构揭示了配体结合和配体介导的核受体调节的分子基础的一般机制。尽管核受体LBD的保守折叠，配体结合口袋是不同的核受体LBD中最不保守的区域。结构比较和分析表明，口袋的几个特征，如大小和形状，有助于配体结合亲和力和特异性。此外，许多核受体中配体结合口袋的塑性性质提供了更大的灵活性，以进一步容纳具有各种构象的特异性配体。核受体辅激活因子通常含有多个LXXLL基序，用于与核受体相互作用。核受体对不同的配体有不同的反应，并且在不同的环境中容易交换它们的配体。AF-2螺旋的构象灵活性允许核受体感知结合配体（激动剂或拮抗剂）的存在，并募集最终决定核受体的转录激活或抑制的共激活子或共抑制子。
Nuclear receptors are important transcriptional factors that share high sequence identity and conserved domains, including a DNA-binding domain (DBD) and a ligand-binding domain (LBD). The LBD plays a crucial role in ligand-mediated nuclear receptor activity. Hundreds of different crystal structures of nuclear receptors have revealed a general mechanism for the molecular basis of ligand binding and ligand-mediated regulation of nuclear receptors. Despite the conserved fold of nuclear receptor LBDs, the ligand-binding pocket is the least conserved region among different nuclear receptor LBDs. Structural comparison and analysis show that several features of the pocket, like the size and also the shape, have contributed to the ligand binding affinity and specificity. In addition, the plastic nature of the ligand-binding pockets in many nuclear receptors provides greater flexibility to further accommodate specific ligands with a variety of conformations. Nuclear receptor coactivators usually contain multiple LXXLL motifs that are used to interact with nuclear receptors. The nuclear receptors respond differently to distinct ligands and readily exchange their ligands in different environments. The conformational flexibility of the AF-2 helix allows the nuclear receptor to sense the presence of the bound ligands, either an agonist or an antagonist, and to recruit the coactivators or corepressors that ultimately determine the transcriptional activation or repression of nuclear receptors.
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