莱斯特大学的科学家因为一个全新的意外发现，开辟了一种全新的方法，此方法用于一个抗癌药物靶标家族的治疗性干预。
Schwabe教授和他的同事，即Watson博士、Fairall博士和Santos博士，已将他们的研究结果发表在本周的Nature上，详细地报道了对转录抑制复合物如何工作的一种新理解。他们的工作以测定医学重要生物分子复合物的原子分辨率结构为基础，已经持续进行了六年，目前由韦尔科姆基金会资助，资助额为140万英磅。
转录调节复合物在发育、分化、癌症与平衡中发挥重要作用。转录是一个创造与DNA序列拷贝互补的RNA的过程，是基因表达过程的第一步。
莱斯特大学生物化学系的John Schwabe教授说："我们已经发现了一个全新的意想不到的联系，这个联系是磷酸肌醇信号（在这里为IP4）和组蛋白脱乙酰基酶调节间的联系，因此便转录抑制或基因沉默。
简单地说，我们已经指出，IP4充当一种调节组蛋白去乙酰酶的天然信号分子，这个酶在基因表达调控中发挥关键作用。除了对转录如何调控的理解的大量知识重要性外，抑制复合物是包括几种类型白血病的许多癌症的重要治疗靶标。
我们的研究确定了若干在治疗上潜在靶向组蛋白脱乙酰基酶的新手段：要么通过使用药物阻止IP4结合到酶上或通过干扰机体制备IP4的途径。因此，这项工作开辟了一个全新的研究领域，这个领域具有靶向组蛋白去乙酰酶的新药物和新方法的。"
Schwabe教授表示，这项研究不仅是此领域一个令人兴奋的突破，也是一个技术壮举，它既依赖于莱斯特大学的良好科研设施，又依赖于牛津在钻石光源上的微焦点X射线源。（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.
