Novel tools to map allosteric networks in proteins.

绘制蛋白质变构网络的新工具。

• 批准号: BB/I023291/1
• 负责人: Franca Fraternali
• 金额: $ 12.13万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI023291%2F1
• 关键词: Novel; tools; map; allosteric; networks

Proteins are a class of molecules that provides the majority of essential cellular functions such as catalysis, recognition and transport. These functions require binding of the protein to a 'target' molecule. Binding and the activity of the associated function are largely regulated by the concentration of the involved molecules. However, there are additional regulatory mechanisms in proteins; an important one is 'allostery', in which binding of an (additional) 'effector' molecule changes the activity of the protein towards the target molecule. Binding of target and effector molecule occurs at different sites on the protein surface. The allosteric effect can modulate (enhance/reduce) either target molecule binding or subsequent processing (e.g. enzymatic reaction). The detailed mechanism of allosteric regulation in proteins is largely unknown. We know that the information (signal) of the effector binding event has to cross the protein structure to affect the target site. A plausible assumption is that effector binding induces a 'chain' of conformational changes. The aim of the present project is to detect those pathways within protein structures that transmit the effector signal. Owing to the dynamic nature of proteins, we will run molecular simulations to sample a large number of protein conformations. We will analyse correlated conformational changes within the conformational ensembles to follow the signal transmission at the atomistic level.

蛋白质是一类提供大部分基本细胞功能如催化、识别和运输的分子。这些功能需要蛋白质与“靶”分子结合。结合和相关功能的活性在很大程度上受所涉及分子的浓度调节。然而，在蛋白质中存在另外的调节机制;重要的一个是“变构”，其中（另外的）“效应”分子的结合改变蛋白质对靶分子的活性。靶分子和效应分子的结合发生在蛋白质表面上的不同位点。变构效应可以调节（增强/减少）靶分子结合或后续加工（例如酶促反应）。蛋白质变构调节的详细机制在很大程度上是未知的。我们知道效应子结合事件的信息（信号）必须穿过蛋白质结构才能影响靶位点。一个合理的假设是效应物结合诱导构象变化的“链”。本项目的目的是检测蛋白质结构内传递效应信号的那些通路。由于蛋白质的动态性质，我们将运行分子模拟来对大量蛋白质构象进行采样。我们将分析相关的构象变化的构象合奏遵循在原子水平上的信号传输。

项目成果

Pathogenic missense protein variants affect different functional pathways and proteomic features than healthy population variants.

• DOI: 10.1371/journal.pbio.3001207
• 发表时间: 2021-04
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Laddach A;Ng JCF;Fraternali F
• 通讯作者: Fraternali F

Short loop functional commonality identified in leukaemia proteome highlights crucial protein sub-networks.

• DOI: 10.1093/nargab/lqab010
• 发表时间: 2021-03
• 期刊: NAR genomics and bioinformatics
• 影响因子: 4.6
• 作者: Chung SS;Ng JCF;Laddach A;Thomas NSB;Fraternali F
• 通讯作者: Fraternali F

Tumor-Infiltrating B Lymphocyte Profiling Identifies IgG-Biased, Clonally Expanded Prognostic Phenotypes in Triple-Negative Breast Cancer.

• DOI: 10.1158/0008-5472.can-20-3773
• 发表时间: 2021-08-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Harris RJ;Cheung A;Ng JCF;Laddach R;Chenoweth AM;Crescioli S;Fittall M;Dominguez-Rodriguez D;Roberts J;Levi D;Liu F;Alberts E;Quist J;Santaolalla A;Pinder SE;Gillett C;Hammar N;Irshad S;Van Hemelrijck M;Dunn-Walters DK;Fraternali F;Spicer JF;Lacy KE;Tsoka S;Grigoriadis A;Tutt ANJ;Karagiannis SN
• 通讯作者: Karagiannis SN

Assembly of Influenza Hemagglutinin Fusion Peptides in a Phospholipid Bilayer by Coarse-grained Computer Simulations.

• DOI: 10.3389/fmolb.2015.00066
• 发表时间: 2015
• 期刊: Frontiers in molecular biosciences
• 影响因子: 5
• 作者: Collu F;Spiga E;Lorenz CD;Fraternali F
• 通讯作者: Fraternali F

Anatomy of protein disorder, flexibility and disease-related mutations.

• DOI: 10.3389/fmolb.2015.00047
• 发表时间: 2015
• 期刊: Frontiers in molecular biosciences
• 影响因子: 5
• 作者: Lu HC;Chung SS;Fornili A;Fraternali F
• 通讯作者: Fraternali F