萊斯特大學(xué)的科學(xué)家因?yàn)橐粋€(gè)全新的意外發(fā)現(xiàn),，開辟了一種全新的方法，此方法用于一個(gè)抗癌藥物靶標(biāo)家族的治療性干預(yù),。
Schwabe教授和他的同事,，即Watson博士、Fairall博士和Santos博士,，已將他們的研究結(jié)果發(fā)表在本周的Nature上,，詳細(xì)地報(bào)道了對(duì)轉(zhuǎn)錄抑制復(fù)合物如何工作的一種新理解。他們的工作以測(cè)定醫(yī)學(xué)重要生物分子復(fù)合物的原子分辨率結(jié)構(gòu)為基礎(chǔ),，已經(jīng)持續(xù)進(jìn)行了六年,，目前由韋爾科姆基金會(huì)資助，資助額為140萬(wàn)英磅,。
轉(zhuǎn)錄調(diào)節(jié)復(fù)合物在發(fā)育,、分化、癌癥與平衡中發(fā)揮重要作用,。轉(zhuǎn)錄是一個(gè)創(chuàng)造與DNA序列拷貝互補(bǔ)的RNA的過(guò)程,，是基因表達(dá)過(guò)程的第一步。
萊斯特大學(xué)生物化學(xué)系的John Schwabe教授說(shuō)："我們已經(jīng)發(fā)現(xiàn)了一個(gè)全新的意想不到的聯(lián)系,，這個(gè)聯(lián)系是磷酸肌醇信號(hào)（在這里為IP4）和組蛋白脫乙?；刚{(diào)節(jié)間的聯(lián)系，因此便轉(zhuǎn)錄抑制或基因沉默,。
簡(jiǎn)單地說(shuō),，我們已經(jīng)指出，IP4充當(dāng)一種調(diào)節(jié)組蛋白去乙酰酶的天然信號(hào)分子,，這個(gè)酶在基因表達(dá)調(diào)控中發(fā)揮關(guān)鍵作用,。除了對(duì)轉(zhuǎn)錄如何調(diào)控的理解的大量知識(shí)重要性外，抑制復(fù)合物是包括幾種類型白血病的許多癌癥的重要治療靶標(biāo),。
我們的研究確定了若干在治療上潛在靶向組蛋白脫乙?；傅男率侄危阂赐ㄟ^(guò)使用藥物阻止IP4結(jié)合到酶上或通過(guò)干擾機(jī)體制備IP4的途徑,。因此，這項(xiàng)工作開辟了一個(gè)全新的研究領(lǐng)域,，這個(gè)領(lǐng)域具有靶向組蛋白去乙酰酶的新藥物和新方法的,。"
Schwabe教授表示，這項(xiàng)研究不僅是此領(lǐng)域一個(gè)令人興奮的突破,，也是一個(gè)技術(shù)壯舉,，它既依賴于萊斯特大學(xué)的良好科研設(shè)施，又依賴于牛津在鉆石光源上的微焦點(diǎn)X射線源,。（生物谷bioon.com）
doi:10.1038/nature10728
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Structure of HDAC3 bound to co-repressor and inositol tetraphosphate
Peter J. Watson, Louise Fairall, Guilherme M. Santos, John W. R. Schwabe
Abstract Histone deacetylase enzymes (HDACs) are emerging cancer drug targets. They regulate gene expression by removing acetyl groups from lysine residues in histone tails, resulting in chromatin condensation. The enzymatic activity of most class I HDACs requires recruitment into multi-subunit co-repressor complexes, which are in turn recruited to chromatin by repressive transcription factors. Here we report the structure of a complex between an HDAC and a co-repressor, namely, human HDAC3 with the deacetylase activation domain (DAD) from the human SMRT co-repressor (also known as NCOR2). The structure reveals two remarkable features. First, the SMRT-DAD undergoes a large structural rearrangement on forming the complex. Second, there is an essential inositol tetraphosphate molecule-D-myo-inositol-(1,4,5,6)-tetrakisphosphate (Ins(1,4,5,6)P4)-acting as an 'intermolecular glue' between the two proteins. Assembly of the complex is clearly dependent on the Ins(1,4,5,6)P4, which may act as a regulator-potentially explaining why inositol phosphates and their kinases have been found to act as transcriptional regulators. This mechanism for the activation of HDAC3 appears to be conserved in class I HDACs from yeast to humans, and opens the way to novel therapeutic opportunities.
