近日來(lái)自中科院上海藥物所的研究人員在新研究中首次解析了無(wú)配體的人源維甲酸X受體（RXR）與共抑制因子SMRT2的復(fù)合物晶體結(jié)構(gòu),，揭示了RXR受到拮抗劑抑制的分子機(jī)制,。這一研究成果在線發(fā)表在國(guó)際重要學(xué)術(shù)期刊《生物化學(xué)期刊》（J Biol Chem）上。
這項(xiàng)研究由藥物所沈旭課題組與蔣華良課題組合作完成,，沈旭課題組博士研究生張海濤是論文的第一作者,，這項(xiàng)研究得到了國(guó)家自然科學(xué)基金委及上海市科委基金資助。
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(xì)胞發(fā)育和代謝調(diào)節(jié)等眾多生理過(guò)程，被認(rèn)為是治療癌癥和代謝性疾病的重要藥物靶標(biāo),。
在這篇文章中,，研究人員首次解析了無(wú)配體的人源RXR與共抑制因子SMRT2的復(fù)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(dǎo)RXR四聚體的構(gòu)象變化,，通過(guò)增大四聚體相互作用界面，來(lái)穩(wěn)定無(wú)活性的RXR,。為了進(jìn)一步研究RXR如何被其拮抗劑抑制的分子機(jī)理,，該研究工作同時(shí)解析了RXR與其拮抗劑rhein和共抑制因子SMRT2的三元復(fù)合物結(jié)構(gòu)。通過(guò)對(duì)無(wú)配體的RXR四聚體,、激動(dòng)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(jī)制,。
該項(xiàng)成果不僅為基于RXR靶點(diǎn)的藥物設(shè)計(jì)研究提供了重要的研究策略,，而且為RXR介導(dǎo)的重大疾病（如腫瘤,、代謝性疾病,、老年性癡呆等）的病理機(jī)制探索提供了富有價(jià)值的線索。
此外,，這一研究小組近期在同一期刊上發(fā)表的另一篇論文中證實(shí)天然產(chǎn)物Danthron是RXRa特異性拮抗劑,，并獲得了RXRa-LBD/Danthron復(fù)合物晶體，成功解析了其結(jié)構(gòu),，這是國(guó)際上RXR與其拮抗劑復(fù)合物晶體結(jié)構(gòu)的首例報(bào)道,，研究發(fā)現(xiàn)Danthron采用穩(wěn)定無(wú)活性RXR受體四聚體構(gòu)象方式拮抗RXRa的轉(zhuǎn)錄激活,。這一成果為RXR拮抗劑的設(shè)計(jì)篩選提供了新的重要研究思路。（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,etc
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.
