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Nature:组蛋白脱乙酰基酶可作为抗癌药物新靶点

2012/01/12 来源:esciencenews
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导读
英国莱斯特大学的研究人员肌醇磷脂信号传递(此处为IP4)与组蛋白脱乙酰基酶及后续的转录抑制(或基因沉默)之间发现了一种全新的、出人意料的联系。将有助于针对多种癌症进行全新的药物开发。

莱斯特大学的科学家揭示了针对一组抗癌药物靶标的治疗新方法,该方法得益于一项全新的、出乎意料的发现。Schwabe教授和他的同事们在本周的Nature杂志上发表了他们的研究结果,详细描述了他们对转录抑制复合物起作用方式的全新理解。他们的这项工作进行了6年,主要围绕测定具有重要医学意义的生物分子复合物的原子分辨结构开展。

转录调节复合物在发育调节、分化、癌症及体内平衡中发挥着重要的作用。转录是产生DNA的互补RNA拷贝的过程,是基因表达过程中的第一步。

该图为组蛋白脱乙酰基酶3(暗灰色表面)的原子分辨结构,组蛋白脱乙酰基酶3是SMRT(亮灰色条状/带状)的及关键信号分子IP4(绿色/橙色条状)的辅助抑制物。(莱斯特大学)

莱斯特大学生物化学学院的John Schwabe教授说:“我们发现了在肌醇磷脂信号传递(此处为IP4)与组蛋白脱乙酰基酶之间一种全新的、出人意料的关联以及转录抑制或基因沉默。”

“简单的说,我们发现,IP4作为自然的信号分子对在基因表达调节中起重要作用的组蛋白脱乙酰基酶起着调节作用。抑制性复合物除了对了解转录的调节有重要的学术意义外,还是许多癌症包括几种类型白血病的重要治疗靶标。”

“我们的研究确定了新的方法,出于治疗目的而以组蛋白脱乙酰基酶为靶标:要么使用药物阻止IP4对酶的结合,要么干扰身体产生IP4的途径。因此,这项工作打开了一个全新的研究领域,针对组蛋白脱乙酰基酶进行新药及新方法的开发。”


Structure of HDAC3 bound to co-repressor and inositol tetraphosphate

Peter J. Watson, Louise Fairall, Guilherme M. Santos & John W. R. Schwabe

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.

文献链接:http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10728.html

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