维甲酸X受体（RXR）是核受体蛋白家族的核心成员。作为一种配体调节的转录因子，RXR参与了细胞发育和代谢调节等众多生理过程，被认为是治疗癌症和代谢性疾病的重要药物靶标。
2011年1月，国际重要学术期刊《生物化学期刊》（J Biol Chem. 2011, 286(3):1868-75）曾刊登了由中科院上海药物研究所沈旭课题组博士研究生张海涛等完成的天然产物danthron拮抗RXR机理及RXR和danthron复合物晶体结构的研究成果，这是国际上RXR与其拮抗剂复合物晶体结构的首例报道。
在已取得的研究成果的基础上，该课题组针对RXR拮抗机理开展了进一步的系统研究。5月24日，《生物化学期刊》又一次在线发表了上海药物所沈旭课题组与蒋华良课题组关于RXR抑制机制的最新研究成果（J. Biol. Chem. May 24, 2011, doi:10.1074/jbc.M111.245498）。该研究工作首次解析了无配体的人源RXR与共抑制因子SMRT2的复合物晶体结构，发现SMRT2结合在RXR四聚体上，并能诱导RXR四聚体的构象变化，通过增大四聚体相互作用界面，来稳定无活性的RXR。
为了进一步研究RXR如何被其拮抗剂抑制的分子机理，该研究工作同时解析了RXR与其拮抗剂rhein和共抑制因子SMRT2的三元复合物结构。通过对无配体的RXR四聚体、激动剂结合的RXR二聚体和拮抗剂结合的RXR四聚体的结构比较，研究人员发现RXR末端的AF-2模块在不同结构中采用了不同的构象并发挥不同的功能，并首次阐明了RXR的四聚体抑制机制。
该项成果不仅为基于RXR靶点的药物设计研究提供了重要的研究策略，而且为RXR介导的重大疾病（如肿瘤、代谢性疾病、老年性痴呆等）的病理机制探索提供了富有价值的线索。（生物谷Bioon.com）
生物谷推荐原文出处：
The Journal of Biological Chemistry DOI:10.1074/jbc.M111.245498
Structural basis for retinoic X receptor repression on the tetramer
Haitao Zhang, Lili Chen, Jing Chen, Hualiang Jiang and Xu Shen
Retinoic X receptor (RXR) is a master nuclear receptor in the processes of cell development and homeostasis. Unliganded RXR exists in an auto-repressed 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 reported the crystal structure of RXRα 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, RXRαLBD-SMRT exhibited a significant structural rearrangement, compared with the apo RXRαLBD tetramer. To further elucidate the molecular determinant for RXR repression by antagonist, we also determined the crystal structure of RXRαLBD-SMRT complexed with the identified antagonist rhein. In the structure, two rhein molecules and two SMRT peptides were in the RXRαLBD tetramer, different from the case in RXRαLBD-SMRT structure, where four SMRT peptides bound to RXR tetramer. It seemed that rhein binding has resulted in a displacement of SMRT motif for activation function-2 (AF-2) motif binding to the receptor. Combining our current work with the published results, structural superposition of RXRαLBDs in different states revealed that RXR used an overlapped binding site for coactivator, corepressor and AF-2 motif, while AF-2 motif adopted different conformations for agonist or antagonist interaction, and coactivator or corepressor recruitment. Taken together, we thus proposed a molecular model of RXR repression on the tetramer.
