CCP4 Grant Renewal 2014-2019: Question-driven crystallographic data collection and advanced structure solution
CCP4 资助续签 2014-2019:问题驱动的晶体学数据收集和高级结构解决方案
基本信息
- 批准号:BB/L008777/1
- 负责人:
- 金额:$ 1.49万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2014
- 资助国家:英国
- 起止时间:2014 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Proteins, DNA and RNA are the active machines of the cells which make up living organisms, and are collectively known as macromolecules. They carry out all of the functions that sustain life, from metabolism through replication to the exchange of information between a cell and its environment. They are coded for by a 'blueprint' in the form of the DNA sequence in the genome, which describes how to make them as linear strings of building blocks. In order to function, however, most macromolecules fold into a precise 3D structure, which in turn depends primarily on the sequence of building blocks from which they are made. Knowledge of the molecule's 3D structure allows us both to understand its function, and to design chemicals to interfere with it.Due to advances in molecular biology, a number of projects, including the Human Genome Project, have led to the determination of the complete DNA sequences of many organisms, from which we can now read the linear blueprints for many macromolecules. As yet, however, the 3D structure cannot be predicted from knowledge of the sequence alone. One way to "see" macromolecules, and so to determine their 3D structure, involves initially crystallising the molecule under investigation, and subsequently imaging it with suitable radiation. Macromolecules are too small to see with normal light, and so a different approach is required. With an optical microscope we cannot see objects which are smaller than the wavelength of light, roughly 1 millionth of a metre: Atoms are about 1000 times smaller than this. However X-rays have a wavelength about the same as the size of the atoms. For this reason, in order to resolve the atomic detail of macromolecular structure, we image them with X-rays rather than with visible light. The process of imaging the structures of macromolecules that have been crystallised is known as X-ray crystallography. X-ray crystallography is like using a microscope to magnify objects that are too small to be seen with visible light. Unfortunately X-ray crystallography is complicated because, unlike a microscope, there is no lens system for X-rays and so additional information and complex computation are required to reconstruct the final image. This information may come from known protein structures using the Molecular Replacement (MR) method, or from other sources including Electron Microscopy (EM).Once the structure is known, it is easier to pinpoint how macromolecules contribute to the living cellular machinery. Pharmaceutical research uses this as the basis for designing drugs to turn the molecules on or off when required. Drugs are designed to interact with the target molecule to either block or promote the chemical processes which they perform within the body. Other applications include protein engineering and carbohydrate engineering.The aim of this project is to improve the key computational tools needed to extract a 3D structure from X-ray crystallography experiments. It will provide continuing support to a Collaborative Computing Project (CCP4 first established in 1979), which has become one of the leading sources of software for this task. The project will help efficient and effective use to be made of the synchrotrons that make the X-rays that are used in most crystallographic experiments. It will provide more powerful tools to allow users to exploit information from known protein structures when the match to the unknown structure is very poor. It will also automate the use of information from electron microscopy, even when the crystal structure has been distorted by the process of growing the protein crystal. Finally, it will allow structures to be solved, even when poor quality and very small crystals are obtained.
蛋白质、DNA和RNA是构成生物体的细胞的活性机器,统称为大分子。它们执行维持生命的所有功能,从新陈代谢到复制,再到细胞与环境之间的信息交换。它们是由基因组中DNA序列形式的“蓝图”编码的,该蓝图描述了如何使它们成为构建模块的线性字符串。然而,为了发挥作用,大多数大分子折叠成精确的3D结构,这反过来又主要取决于制造它们的构建块的序列。分子三维结构的知识使我们既能理解其功能,又能设计化学物质来干扰它。由于分子生物学的进步,包括人类基因组计划在内的许多项目已经确定了许多生物体的完整DNA序列,我们现在可以从中阅读许多大分子的线性蓝图。然而,到目前为止,3D结构不能仅从序列的知识来预测。一种“看到”大分子并因此确定其3D结构的方法包括首先使所研究的分子结晶,然后用合适的辐射对其成像。大分子太小,用普通光看不到,所以需要一种不同的方法。用光学显微镜,我们不能看到比光波长小的物体,大约是百万分之一米:原子比这个小1000倍。然而,X射线的波长大约与原子的大小相同。出于这个原因,为了解决大分子结构的原子细节,我们用X射线而不是可见光对其进行成像。对已结晶的大分子结构成像的过程称为X射线晶体学。X射线晶体学就像是用显微镜来放大用可见光看不到的太小的物体。不幸的是,X射线晶体学是复杂的,因为与显微镜不同,X射线没有透镜系统,因此需要额外的信息和复杂的计算来重建最终的图像。这些信息可能来自使用分子置换(MR)方法的已知蛋白质结构,或来自包括电子显微镜(EM)在内的其他来源。一旦结构已知,就更容易确定大分子如何对活细胞机器做出贡献。药物研究将此作为设计药物的基础,以便在需要时打开或关闭分子。药物被设计为与靶分子相互作用,以阻止或促进它们在体内执行的化学过程。其他应用包括蛋白质工程和碳水化合物工程。该项目的目的是改进从X射线晶体学实验中提取3D结构所需的关键计算工具。它将继续支持协作计算项目(1979年首次建立的CCP4),该项目已成为这项任务的主要软件来源之一。该项目将有助于高效和有效地利用同步加速器,使大多数晶体学实验中使用的X射线。它将提供更强大的工具,允许用户在与未知结构的匹配非常差时利用已知蛋白质结构的信息。它还将自动使用来自电子显微镜的信息,即使晶体结构已被蛋白质晶体生长过程扭曲。最后,它将允许解决结构,即使当获得质量差和非常小的晶体。
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)
Exploring the speed and performance of molecular replacement with AMPLE using QUARK ab initio protein models.
- DOI:10.1107/s1399004714025784
- 发表时间:2015-02
- 期刊:
- 影响因子:0
- 作者:Keegan RM;Bibby J;Thomas J;Xu D;Zhang Y;Mayans O;Winn MD;Rigden DJ
- 通讯作者:Rigden DJ
A revised partiality model and post-refinement algorithm for X-ray free-electron laser data.
- DOI:10.1107/s1399004715006902
- 发表时间:2015-06
- 期刊:
- 影响因子:0
- 作者:Ginn HM;Brewster AS;Hattne J;Evans G;Wagner A;Grimes JM;Sauter NK;Sutton G;Stuart DI
- 通讯作者:Stuart DI
TakeTwo: an indexing algorithm suited to still images with known crystal parameters.
- DOI:10.1107/s2059798316010706
- 发表时间:2016-08
- 期刊:
- 影响因子:0
- 作者:Ginn HM;Roedig P;Kuo A;Evans G;Sauter NK;Ernst OP;Meents A;Mueller-Werkmeister H;Miller RJ;Stuart DI
- 通讯作者:Stuart DI
Macromolecular refinement by model morphing using non-atomic parameterizations.
- DOI:10.1107/s205979831701350x
- 发表时间:2018-02-01
- 期刊:
- 影响因子:0
- 作者:Cowtan K;Agirre J
- 通讯作者:Agirre J
Recovery of data from perfectly twinned virus crystals revisited.
- DOI:10.1107/s2059798316007117
- 发表时间:2016-06
- 期刊:
- 影响因子:0
- 作者:Ginn HM;Stuart DI
- 通讯作者:Stuart DI
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Martin Noble其他文献
Martin Noble的其他文献
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{{ truncateString('Martin Noble', 18)}}的其他基金
Cells to Molecules: Structural EM at Newcastle University
细胞到分子:纽卡斯尔大学的结构电磁学
- 批准号:
BB/R013942/1 - 财政年份:2018
- 资助金额:
$ 1.49万 - 项目类别:
Research Grant
Structure-function study of CDK complexes
CDK复合物的结构-功能研究
- 批准号:
G0800014/2 - 财政年份:2011
- 资助金额:
$ 1.49万 - 项目类别:
Research Grant
Structure-function study of CDK complexes
CDK复合物的结构-功能研究
- 批准号:
G0800014/1 - 财政年份:2009
- 资助金额:
$ 1.49万 - 项目类别:
Research Grant
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