維甲酸X受體（RXR）是核受體家族蛋白中的一員，在核受體調(diào)控信號(hào)通路中發(fā)揮重要作用,。RXR能與三分之一的核受體家族蛋白形成異源二聚體,，參與了包括細(xì)胞生長,、分化、代謝和胚胎發(fā)育等許多重要生理過程的調(diào)節(jié),。因此,，RXR被認(rèn)為是治療癌癥和代謝性疾病的重要藥物作用靶標(biāo)之一。RXR主要由DNA結(jié)合結(jié)構(gòu)域(DBD)和配體結(jié)合結(jié)構(gòu)域(LBD)組成,。多功能的LBD負(fù)責(zé)調(diào)控RXR二聚化,、四聚化以及配體依賴的受體激活。RXR同源四聚體的解離被認(rèn)為是RXR激活的第一步,，而四聚體的形成也可以將細(xì)胞內(nèi)過量的RXR以無活性的狀態(tài)儲(chǔ)存起來,。一般認(rèn)為,，RXR配體誘導(dǎo)RXR發(fā)生劇烈構(gòu)象變化后將起始下游基因的轉(zhuǎn)錄，因此從結(jié)構(gòu)上闡明RXR與其配體的作用將具有重要的理論意義,。然而迄今為止,，仍未見RXR與其拮抗劑形成的復(fù)合物晶體結(jié)構(gòu)報(bào)道。
最近,，中科院上海藥物研究所沈旭課題組與蔣華良及胡立宏課題組合作,，博士研究生張海濤與周蓉（華東理工大學(xué)藥學(xué)院聯(lián)合培養(yǎng)碩博生）等發(fā)現(xiàn)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)定無活性RXR受體四聚體構(gòu)象方式拮抗RXRa的轉(zhuǎn)錄激活,。
研究所取得的成果將為RXR拮抗劑的設(shè)計(jì)篩選提供了新的重要研究思路,。此外,，由于Danthron是中藥大黃的主要成分之一,，大黃曾被發(fā)現(xiàn)具有抗糖尿病和抗癌的作用,，但其作用機(jī)理尚不明確，因此該項(xiàng)研究還為中藥大黃有效成分的相應(yīng)藥理作用提供了相關(guān)作用靶點(diǎn)信息,。（生物谷Bioon.com）
生物谷推薦原文出處：
J. Biol. Chem. DOI 10.1074/jbc.M110.166215
Danthron functions as an RXR antagonist by stabilizing the receptor's tetramers
Haitao Zhang1, Rong Zhou2, Li Li2, Jing Chen1, Lili Chen1, Chenjing Li1, Hong Ding1, Liang Yu1, Lihong Hu1, Hualiang Jiang1 and Xu Shen1,*
Abstract
Retinoic X receptor (RXR) is a promising target for drug discovery against cancer and metabolic syndromes. Here we identified a specific RXRα antagonist danthron from the traditional Chinese medicine rhubarb. Danthron repressed all the tested RXRα-involved response elements transcription, including RXRE, PPRE, FXRE and LXRE. Results from native PAGE and isothermal titration calorimetry (ITC) based assays indicated that danthron bound to the tetrameric RXRα-LBD in a specific stoichimetric ratio, and such a binding could influence the corepressor SMRT affinity to the receptor. Additionally, a unique tetrameric structure of apo RXRα ligand-binding domain (LBD) was determined, which exhibited a larger tetramer interface and different ligand-binding pocket size compared with the previously reported one. Together with the biochemical and biophysical results, the determined crystal structure of danthron-soaked RXRα-LBD suggested a new mechanism for danthron antagonism to tetrameric RXRα. Moreover, the in vivo efficient improvement of insulin sensitivity by danthron was observed in diet-induced obese (DIO) mice. Thus our findings were expected to supply new insights into the structural basis of RXRα antagonist for its further potential therapeutic application.
