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New Drug Targets For Cancer And Other Diseases Revealed By Enzyme Structure
If the genome is the parts list of the human cell, certain proteins are the production managers, activating and deactivating genes as needed. Scientists funded by the National Institute of General Medical Sciences (NIGMS), part of the National Institutes of Health, now have a clearer understanding of how a key protein controls gene activity and how mutations in the protein may cause disease. The work could provide new avenues to design drugs aimed at cancer, diabetes, HIV, and heart disease.
The research appears in the Feb. 14, 2008, issue of the journal Nature. The lead authors include Philip Cole, M.D., Ph.D., of the Johns Hopkins University School of Medicine in Baltimore, Md., and Ronen Marmorstein, Ph.D., of the Wistar Institute in Philadelphia, Pa.
The investigators focused on a protein called p300/CBP that belongs to a family of enzymes known as histone acetyltransferases, or HATs. These enzymes activate genes by attaching chemicals called acetyl groups to histones, the spool-like proteins that hold DNA in a tightly wound form.
Mutations in p300/CBP are linked to a variety of cancers, including those of the colon, breast, pancreas, and prostate. Researchers believe that a substance that selectively inhibits p300/CBP might be the basis for an anticancer agent.
Nearly 10 years ago, Cole and his coworkers designed a p300/CBP inhibitor. But the inhibitor is not active in the human body, so it has been used exclusively as a research tool.
In the new study, the investigators combined X-ray crystallography with detailed enzymology to understand how p300/CBP works.
Their three-dimensional crystal structure provides an image of how a key part of p300/CBP binds to the inhibitor. Their studies of numerous mutant versions of the enzyme reveal which amino acids in p300/CBP are essential for its activity.
The work has a number of clinical implications. Understanding the structure and behavior of p300/CBP will help scientists design a p300/CBP inhibitor that might function in human cells as an anticancer drug.
Proper functioning of p300/CBP is critical for insulin regulation and the health of heart cells. As a result, compounds that can regulate p300/CBP activity might be useful in the treatment of diabetes and heart disease.
In addition, HAT activity is necessary for the multiplication of HIV, leading at least one scientific group to suggest that targeting HATs or similar enzymes might be an new way to thwart the virus.
Finally, the article also shows that some p300/CBP mutations previously linked to certain cancers lie right where p300/CBP contacts the inhibitor. Studying how these mutations alter the enzyme's function should shed light on why the mutations can lead to disease.
\"This work illustrates how enzymology and structural biology can combine to yield both fundamental and practical insights about an important biomedical problem. The studies provide a new framework for understanding p300/CBP in health and disease,\" said Jeremy M. Berg, NIGMS Director.
如果基因组是人类细胞部件的清单，那么某些蛋白质是生产管理者，可以依照需要激活和去活化基因。由美国国立常规医学研究所(NIGMS) ，部分由美国国立卫生研究院资助的科学家，现在更加清楚地理解重要蛋白质怎样控制基因活动并且怎样的蛋白质突变会导致疾病。研究提供了设计药物对癌症，糖尿病，HIV和心脏病靶点的新方法。
研究重点是属于以组蛋白乙酰转移酶为代表的酶蛋白家族的p300/CBP。这些酶通过粘附于所谓的化学剂乙酰组蛋白来激活基因, 像线圈一样的蛋白以紧密创伤形式缠绕着DNA。p300/CBP的突变与大肠，乳房，胰腺和前列腺多种癌症有关。研究员相信，有选择性地抑制p300/CBP 的物质也许是一个抗癌药物的作用机制。在新的研究中，结合X射线晶体学和酶学详细了解p300/CBP怎么运行的。三维晶体结构提供了p300/CBP 的关键部份怎样与抑制剂结合的图像，并且研究了许多突变的酶揭示在p300/CBP活动中哪些氨基酸是必不可少的。
研究有大量的临床意义。了解p300/CBP结构和作用机制将帮助科学家设计在人类细胞里也会起作用的一种抗癌药物：p300/CBP 抑制剂。适当运做p300/CBP 是调节胰岛素和心脏细胞的健康重要的关键。那么，调控p300/CBP活性的化合物对治疗糖尿病和心脏病也许是有用的。此外，组蛋白乙酰转移酶的活性对HIV 的增殖是必要的，至少一个科学小组建议以组蛋白乙酰转移酶或相似的酶做为靶点也许是抑制病毒一个新方式。有证据表明一些p300/CBP 突变前先连接了位于某一癌症右边的p300/CBP接触抑制剂，研究这些突变怎么修改酶的作用应该可以解释为什么突变会导致疾病。
研究结果发表于2008-2-14的自然上，主要作者是巴尔的摩约翰霍普金斯医学院医学博士Philip Cole和费城威斯达(Wistar Institute)研究所的Ronen Marmorstein博士 |
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发表于 2008-2-27 01:00:45