Small molecule keys (SMK) for functional assignments in post-translational protein modification

用于翻译后蛋白质修饰中功能分配的小分子键 (SMK)

• 批准号: BB/D005949/1
• 负责人: Hagan Bayley
• 金额: $ 204.5万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FD005949%2F1
• 关键词: Small; molecule; keys; SMK; functional

The human genome, which catalogues the initial DNA sequences that go to make up genes, is just a starting point in new realms of science that will make use of the virtually untapped data that lies within. A major bottleneck in the exploitation of this genomic data is the assignment of function for gene products, at the molecular, cellular and physiological levels. Recent developments, including 'transgenic' and 'RNAinterference' (RNAi) technologies directly interfere with the DNA coding or the processes by which the coding is 'read'. These have enabled advances to be made at an increasing pace, however, they suffer from significant limitations, such as difficulties of delivery inside organisms and imperfect control of the timing of their effect. In addition, these changes are often too 'far' (in terms of relating biological pathways) from the biochemical event under study and so the effect or information gained is then less clear. For many decades, small molecules have proven to be invaluable tools in biological systems. Methodology now exists for the efficient chemical synthesis and analysis of logically-designed collections (so-called 'focused libraries') of small molecules. Using this chemical synthetic methodology we will attempt to generate cell-penetrating molecules designed to selectively change the process of protein targets. These small molecule keys (SMKs) are chosen to target for each member of a family or related proteins. Using these chemical 'keys' we 'unlock or lock' their function and that of the family and so examine and exploit the resulting effects. Our initial target proteins are challenging and exciting ones. These are proteins involved in so-called post-translational modifications (PTMs) - changes that are made to protein structures after their genetically-encoded construction. Since these processes are not under direct genetic control, their study has until now been difficult - the little we do know shows that the effect of PTMs on biological processes can be profound. We aim to see just how profound in the first stage of the SMK centre - a site that we aim to create to act as a local, national and international resource for the generation and application of small molecules for a wide range of biological processes in a cooperative manner.

人类基因组对组成基因的初始DNA序列进行了分类，它只是新科学领域的一个起点，它将利用隐藏在其中的几乎未开发的数据。利用这些基因组数据的一个主要瓶颈是基因产物在分子、细胞和生理水平上的功能分配。最近的发展，包括“转基因”和“RNA干扰”(RNAi)技术，直接干扰DNA编码或编码被“读取”的过程。这使得进展的速度越来越快，然而，它们受到了巨大的限制，例如在生物体内传递的困难和对其作用时间的不完善控制。此外，这些变化往往与正在研究的生化事件相距太远(就相关的生物途径而言)，因此所获得的影响或信息不太清楚。几十年来，小分子已被证明是生物系统中无价的工具。现在已经有了有效的化学合成和分析逻辑设计的小分子集合(所谓的“聚焦文库”)的方法。使用这种化学合成方法，我们将尝试产生穿透细胞的分子，旨在选择性地改变蛋白质靶标的过程。这些小分子键(SMK)被选为针对家族或相关蛋白质的每个成员。使用这些化学“钥匙”，我们解锁或锁定它们的功能和家庭的功能，从而检查和利用由此产生的影响。我们最初的目标蛋白质是具有挑战性和激动人心的蛋白质。这些蛋白质参与了所谓的翻译后修饰(PTM)--在其基因编码结构之后对蛋白质结构进行的改变。由于这些过程不受直接的基因控制，所以到目前为止，他们的研究一直很困难--我们所知的很少，这表明PTMS对生物过程的影响可能是深远的。我们的目标是看看SMK中心的第一阶段有多深远--我们的目标是创建一个地点，作为一个地方、国家和国际资源，以合作的方式为广泛的生物过程产生和应用小分子。

项目成果

Saturation transfer difference NMR reveals functionally essential kinetic differences for a sugar-binding repressor protein.

饱和转移差异 NMR 揭示了糖结合阻遏蛋白功能上必需的动力学差异。

• DOI: 10.1039/b913489a
• 发表时间: 2009
• 期刊: Chemical communications (Cambridge, England)
• 作者: Pérez-Victoria I