維甲酸X受體（RXR）是核受體蛋白家族的核心成員,。作為一種配體調(diào)節(jié)的轉(zhuǎn)錄因子，RXR參與了細胞發(fā)育和代謝調(diào)節(jié)等眾多生理過程,，被認為是治療癌癥和代謝性疾病的重要藥物靶標,。
2011年1月，國際重要學術(shù)期刊《生物化學期刊》（J Biol Chem. 2011, 286(3):1868-75）曾刊登了由中科院上海藥物研究所沈旭課題組博士研究生張海濤等完成的天然產(chǎn)物danthron拮抗RXR機理及RXR和danthron復合物晶體結(jié)構(gòu)的研究成果,，這是國際上RXR與其拮抗劑復合物晶體結(jié)構(gòu)的首例報道,。
在已取得的研究成果的基礎上，該課題組針對RXR拮抗機理開展了進一步的系統(tǒng)研究,。5月24日,，《生物化學期刊》又一次在線發(fā)表了上海藥物所沈旭課題組與蔣華良課題組關于RXR抑制機制的最新研究成果（J. Biol. Chem. May 24, 2011, doi:10.1074/jbc.M111.245498）。該研究工作首次解析了無配體的人源RXR與共抑制因子SMRT2的復合物晶體結(jié)構(gòu),，發(fā)現(xiàn)SMRT2結(jié)合在RXR四聚體上,，并能誘導RXR四聚體的構(gòu)象變化，通過增大四聚體相互作用界面,，來穩(wěn)定無活性的RXR,。
為了進一步研究RXR如何被其拮抗劑抑制的分子機理，該研究工作同時解析了RXR與其拮抗劑rhein和共抑制因子SMRT2的三元復合物結(jié)構(gòu),。通過對無配體的RXR四聚體,、激動劑結(jié)合的RXR二聚體和拮抗劑結(jié)合的RXR四聚體的結(jié)構(gòu)比較，研究人員發(fā)現(xiàn)RXR末端的AF-2模塊在不同結(jié)構(gòu)中采用了不同的構(gòu)象并發(fā)揮不同的功能,，并首次闡明了RXR的四聚體抑制機制,。
該項成果不僅為基于RXR靶點的藥物設計研究提供了重要的研究策略，而且為RXR介導的重大疾?。ㄈ缒[瘤,、代謝性疾病,、老年性癡呆等）的病理機制探索提供了富有價值的線索。（生物谷Bioon.com）
生物谷推薦原文出處：
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.
