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Dynamics, Gating and Opening in Enzyme Catalysis

酶催化的动力学、门控和开放

基本信息

批准号：
BB/K016245/1
负责人：
Jon Waltho
金额：
$ 48.81万
依托单位：
University of Manchester
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FK016245%2F1
关键词：
Dynamics Gating Opening Enzyme Catalysis

项目摘要

The present application aims to get to the heart of fundamental, yet unanswered, questions that are critical to developing our understanding of how enzymes work. Enzymes, which are normally protein-based, control the rate at which almost all chemistry occurs in living systems. Understanding enzyme activity is a high priority - it is at the core of therapeutic intervention, industrial biotechnology, and synthetic biology. The controlled manipulation of enzyme activity is one of the key elements targeted in each of these areas of research. Enzyme activity has been studied for many decades and many paradigms have evolved but, very recently, tools have been developed that allow the testing of those paradigms with unprecedented levels of detail. Arguably foremost among these tools is NMR spectroscopy, which allows the observation of the structure, electronics and dynamics within enzymes at the level of individual atoms. A proper understanding of all of these elements and their interplay is crucial to manipulating enzyme activity, and with observation powers at this level of detail, paradigms are shifting. In this study we will address questions that are fundamental to the activity of almost all enzymes, namely what controls how fast the chemistry occurs, what makes an enzyme carry out one reaction against another, and what determines how well it binds to the chemicals on which it acts. To achieve this we will study the behaviour of an enzyme that moves phosphate groups around glucose. Enzymes that move phosphate groups lie at the heart of every system in living organisms - in the storage, maintenance and expression of genetic information, in metabolism, communication, cell architecture, differentiation, and homeostasis. We will develop new models based on the behaviour an archetypal enzyme that delivers very high quality measurements, which can then be translated to the enzymes that are common targets in therapeutic, industrial biotechnology and synthetic biology programmes.

本申请旨在触及基本但尚未回答的问题的核心，这些问题对于发展我们对酶如何工作的理解至关重要。酶通常是以蛋白质为基础的，它控制着生命系统中几乎所有化学反应发生的速率。了解酶的活性是一个高度优先事项-它是治疗干预，工业生物技术和合成生物学的核心。酶活性的受控操纵是这些研究领域中每个领域的关键目标之一。酶的活性已经研究了几十年，许多范式已经发展，但最近，已经开发了工具，允许测试这些范式与前所未有的细节水平。在这些工具中，可以说最重要的是NMR光谱学，它允许在单个原子的水平上观察酶的结构，电子和动力学。正确理解所有这些元素及其相互作用对于操纵酶活性至关重要，并且随着观察能力在这种细节水平上的提高，范式正在发生变化。在这项研究中，我们将解决几乎所有酶活性的基本问题，即是什么控制了化学反应发生的速度，是什么使酶进行一种反应对抗另一种反应，以及是什么决定了它与其作用的化学物质结合的程度。为了实现这一目标，我们将研究一种酶的行为，这种酶可以使磷酸基团围绕葡萄糖移动。移动磷酸基团的酶位于生物体中每个系统的核心-在遗传信息的存储，维护和表达，新陈代谢，通信，细胞结构，分化和稳态中。我们将开发基于行为的新模型，这种原型酶可以提供非常高质量的测量，然后可以将其转化为治疗，工业生物技术和合成生物学计划中的常见靶标酶。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regional conformational flexibility couples substrate specificity and scissile phosphate diester selectivity in human flap endonuclease 1.

DOI：
10.1093/nar/gky293
发表时间：
2018-06-20
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Bennet IA;Finger LD;Baxter NJ;Ambrose B;Hounslow AM;Thompson MJ;Exell JC;Shahari NNBM;Craggs TD;Waltho JP;Grasby JA
通讯作者：
Grasby JA

Supplementary material to "High Affinity Tamoxifen Analogues Retain Extensive Positional Disorder when Bound to Calmodulin"

补充材料