Structural Basis for Retinoic X Receptor Repression on the Tetramer
Structural Basis for Retinoic X Receptor Repression on the Tetramer
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四聚体上视黄酸 X 受体抑制的结构基础
DOI：
10.1074/jbc.m111.245498
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发表时间：
2011-07-15
影响因子：
4.8
通讯作者：
Shen, Xu
中科院分区：
文献类型：
--
作者：
Zhang, Haitao;Chen, Lili;Shen, Xu
视黄酸X受体（Retinoic X receptor，RXR）是细胞发育和稳态过程中的主要核受体。未配体的RXR存在于自阻遏的四聚体中，激动剂可以诱导RXR二聚化和共激活因子募集以激活。然而，涉及辅阻遏物募集和拮抗剂介导的RXR抑制的分子机制仍然是难以捉摸的。在这里，我们报告的晶体结构的RXR α配体结合域（LBD）与沉默介质维甲酸和甲状腺激素受体（SMRT）辅阻遏基序。作为第一个关于与辅阻遏物基序结合的无配体核受体的结构报告，与apoRXR alpha LBD四聚体相比，RXR alpha LBD-SMRT表现出显着的结构重排。为了进一步阐明其拮抗剂抑制RXR的分子决定因素，我们还确定了与已鉴定的拮抗剂大黄酸复合的RXR alpha LBD-SMRT的晶体结构。在该结构中，两个大黄酸分子和两个SMRT肽在RXR alpha LBD四聚体中，这与RXR alpha LBD-SMRT结构中的情况不同，其中四个SMRT肽与RXR alpha LBD四聚体结合。大黄酸诱导SMRT基序被AF-2基序取代。结合我们目前的工作与已发表的结果，RXR α LBD在不同状态下的结构叠加表明，RXR使用共激活因子，共阻遏因子和AF-2基序的重叠结合位点，而AF-2基序采用不同的构象进行激动剂或拮抗剂相互作用和共激活因子或共阻遏因子的招募。综上所述，我们提出了RXR阻遏四聚体的分子模型。
Retinoic X receptor (RXR) is a master nuclear receptor in the processes of cell development and homeostasis. Unliganded RXR exists in an autorepressed tetramer, and agonists can induce RXR dimerization and coactivator recruitment for activation. However, the molecular mechanisms involving the corepressor recruitment and antagonist-mediated repression of RXR are still elusive. Here we report the crystal structure of RXR alpha ligand-binding domain (LBD) complexed with silencing mediator for retinoid and thyroid hormone receptors (SMRT) corepressor motif. As the first structural report on the unliganded nuclear receptor bound to the corepressor motif, RXR alpha LBD-SMRT exhibits a significant structural rearrangement, compared with apoRXR alpha LBD tetramer. To elucidate further the molecular determinants for RXR repression by its antagonist, we also determine the crystal structure of RXR alpha LBD-SMRT complexed with the identified antagonist rhein. In the structure, two rhein molecules and two SMRT peptides are in the RXR alpha LBD tetramer, different from the case in RXR alpha LBD-SMRT structure, where four SMRT peptides bind to RXR alpha LBD tetramer. It seems that rhein induces a displacement of SMRT motif by activation function 2 (AF-2) motif binding to the receptor. Combining our current work with the published results, structural superposition of RXR alpha LBDs in different states reveals that RXR uses an overlapped binding site for coactivator, corepressor, and AF-2 motifs, whereas the AF-2 motif adopts different conformations for agonist or antagonist interaction and coactivator or corepressor recruitment. Taken together, we thus propose a molecular model of RXR repression on the tetramer.