Mapping "missing" conformations of ATP-gated P2X receptor ion channels
绘制 ATP 门控 P2X 受体离子通道“缺失”构象图
基本信息
- 批准号:BB/P001076/1
- 负责人:
- 金额:$ 53.96万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2016
- 资助国家:英国
- 起止时间:2016 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Cells within the body communicate with one-another through the release of chemicals recognised by specific cell surface receptors. One example of such a chemical is ATP that binds to P2X receptors (P2XRs) and activates them. In humans there are at least 13 different types of P2XR (e.g P2X1R and P2X7R) that vary in their properties, for example how long they are able to be "turned-on/activated". P2XRs play an important role in a range of normal bodily functions e.g. in control of blood clotting and taste sensation, as well being drug targets for the treatment of pain and neurodegenerative diseases e.g. Alzheimer's disease. P2XRs are membrane proteins with parts on the outside of the cell (extracellular) that recognize the ATP molecule, a channel region that passes through the cell wall (a valve/tap that regulates the movement of positively charged ions) and a region inside the cell (intracellular) that regulates how long the receptor is "ON" for (dependent on the receptor type). In the absence of ATP the P2XR channel is closed and "OFF". ATP binding to the extracellular region leads to a change in the shape of the receptor; an "ON" signal opening the channel (movement of positive ions through it excites the cell). Recent studies have shown the 3D structure of a P2XR in the "OFF" and "ATP-ON" states and this has provided a major advance in our understanding of how this novel family of receptors works. However, these are only two snapshots of the receptor, and it is clear that additional movements in the 3D shape are important that result in distinct forms of the receptor with special properties. This proposal aims to gain 3D structural information on three distinct "missing" conformations/states of the receptor. (i) A "relaxed-OFF" form of the receptor in the absence of ATP that may be important for understanding of how drugs work to block/stop the receptor being turned on. (ii) An "ATP-CLOSED" desensitized receptor, where after opening following ATP binding the channel closes (i.e. turns off); a feature of the P2X1R involved in blood clotting. (iii) An "ATP-EXTRA-ON" state where the channel region gets larger and allows large molecules to enter the cell; this is particularly associated with the P2X7R and its role in inflammation and cell death. Information on these additional "missing" structures is essential to understand the fundamental mechanisms associated with the activity of this distinct family of receptors. P2XRs are made up of different amino acid "building blocks" and these can be individually changed. Of particular use for this is mutating an amino acid to cysteine; this is a chemically unique amino acid that can be targeted with a wide range of cysteine-specific compounds. These bind to the cysteine residue and change the chemical properties/size. In normal P2XRs there are no cysteine residues available for modification and cysteine-specific compounds have no effect. Therefore we can introduce cysteine mutations at defined parts of the receptor and determine the effects of cysteine reactive compounds to investigate the structure. This will be carried out in the absence of ATP (relaxed-OFF), and in the presence of ATP at desensitizing P2XRs (ATP-CLOSED) and at the ATP-EXTRA-ON P2X7R. We will test whether an introduced residue is accessible (on the receptor surface or in the channel), and by varying the size of the cysteine reactive compound measure the dimensions around that residue as well as test the effects of the modification on ATP evoked responses. These results will give molecular dimensions that will then be used in computer based studies to map the molecular changes in the receptor and provide validated 3D models of the missing receptor structures. This will provide a fundamental insight into how P2XRs work at the molecular level, understanding variations between receptors, and why genetic mutations affect receptor properties that can lead to imbalances in signalling and disease.
人体内的细胞通过释放由特定细胞表面受体识别的化学物质来相互通信。这种化学物质的一个例子是与P2X受体(P2XRs)结合并激活它们的ATP。在人类中,至少有13种不同类型的P2XR(例如,P2X1R和P2X7R)具有不同的特性,例如它们能够“开启/激活”的时间长短。P2XRs在一系列正常的身体功能中发挥着重要的作用,例如控制血液凝结和味觉,以及治疗疼痛和神经退行性疾病的药物靶点,如阿尔茨海默病。P2XRs是一种膜蛋白,在细胞外(细胞外)有识别ATP分子的部分,通过细胞壁的通道区域(调节正电荷离子的移动的阀门/龙头)和细胞内的区域(细胞内)调节受体持续多长时间(取决于受体类型)。在没有三磷酸腺苷的情况下,P2XR通道关闭并“关闭”。ATP与细胞外区的结合导致受体形状的改变;一个打开通道的“ON”信号(正离子通过它的运动会刺激细胞)。最近的研究显示了P2XR在“关闭”和“ATP-打开”状态下的3D结构,这为我们理解这一新的受体家族的工作原理提供了重大进展。然而,这些只是受体的两个快照,很明显,3D形状中的额外运动是重要的,这将导致不同形式的具有特殊属性的受体。这项建议旨在获得受体三种不同的“缺失”构象/状态的3D结构信息。(I)在没有三磷酸腺苷的情况下,受体的一种“松弛”形式,这对于了解药物如何阻断/停止受体的开启可能是重要的。(Ii)一种“三磷酸腺苷关闭的”脱敏受体,在与三磷酸腺苷结合后打开后,通道关闭(即关闭);参与凝血的P2X1R的一个特征。(Iii)通道区域变大并允许大分子进入细胞的“ATP-Extra-On”状态;这与P2X7R及其在炎症和细胞死亡中的作用特别相关。关于这些额外的“缺失”结构的信息对于理解与这一独特的受体家族的活动相关的基本机制是必不可少的。P2XRs由不同的氨基酸组成,这些“构件”可以单独改变。这种方法的特别用途是将一种氨基酸突变为半胱氨酸;这是一种化学上独特的氨基酸,可以作为一系列半胱氨酸特异性化合物的靶标。它们与半胱氨酸残基结合,改变化学性质/大小。在正常的P2XRs中,没有半胱氨酸残基可供修饰,半胱氨酸专一性化合物也没有作用。因此,我们可以在受体的特定部分引入半胱氨酸突变,并确定半胱氨酸活性化合物对结构的影响。这将在没有ATP(松弛-关闭)的情况下进行,在减敏P2XRs(ATP关闭)和在P2X7R上的ATP-Extra-On存在的情况下进行。我们将测试引入的残基是否可访问(在受体表面或通道中),并通过改变半胱氨酸活性化合物的大小来测量该残基周围的尺寸,以及测试修饰对ATP诱发反应的影响。这些结果将给出分子尺寸,然后将用于基于计算机的研究,以绘制受体中的分子变化图,并提供缺失受体结构的有效3D模型。这将提供一个基本的洞察力,了解P2XRs如何在分子水平上发挥作用,了解受体之间的差异,以及为什么基因突变会影响受体的特性,从而导致信号和疾病的失衡。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Identification of a distinct desensitisation gate in the ATP-gated P2X2 receptor
- DOI:10.1016/j.bbrc.2019.12.028
- 发表时间:2020-02-26
- 期刊:
- 影响因子:3.1
- 作者:Stavrou,Anastasios;Evans,Richard J.;Schmid,Ralf
- 通讯作者:Schmid,Ralf
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Richard Evans其他文献
Reflections on benchmarking NHS primary care psychological therapies and counselling
对 NHS 初级保健心理治疗和咨询基准的思考
- DOI:
- 发表时间:
2006 - 期刊:
- 影响因子:0
- 作者:
J. Mellor;M. Barkham;Geoff Mothersole;B. Mcinnes;Richard Evans - 通讯作者:
Richard Evans
P2Y Receptor Agonists
P2Y 受体激动剂
- DOI:
- 发表时间:
2001 - 期刊:
- 影响因子:0
- 作者:
W. Pendergast;Richard Evans - 通讯作者:
Richard Evans
Why people adopt smart transportation services: an integrated model of TAM, trust and perceived risk
人们为何采用智能交通服务:TAM、信任和感知风险的集成模型
- DOI:
10.1080/03081060.2021.1943132 - 发表时间:
2021-06 - 期刊:
- 影响因子:1.6
- 作者:
Junze Wang;Sheng Zhao;Wei Zhang;Richard Evans - 通讯作者:
Richard Evans
Effect of Adding Telephone-Based Brief Coaching to an mHealth App (Stay Strong) for Promoting Physical Activity Among Veterans: Randomized Controlled Trial (Preprint)
在移动医疗应用程序(保持坚强)中添加基于电话的简短辅导对促进退伍军人身体活动的效果:随机对照试验(预印本)
- DOI:
10.2196/preprints.19216 - 发表时间:
2020 - 期刊:
- 影响因子:8.1
- 作者:
L. Damschroder;Lorraine R. Buis;Felicia A McCant;H. M. Kim;Richard Evans;E. Oddone;L. Bastian;Gwendolyn Hooks;Reema Kadri;Courtney White;C. Richardson;J. Gierisch - 通讯作者:
J. Gierisch
Inductive general game playing
感应式一般游戏
- DOI:
10.1007/s10994-019-05843-w - 发表时间:
2019 - 期刊:
- 影响因子:7.5
- 作者:
Andrew Cropper;Richard Evans;Mark Law - 通讯作者:
Mark Law
Richard Evans的其他文献
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{{ truncateString('Richard Evans', 18)}}的其他基金
COLLABORATIVE RESEARCH: We are thriving: Challenging negative discourse through voices of women in project teams
合作研究:我们正在蓬勃发展:通过项目团队中女性的声音挑战负面言论
- 批准号:
2015741 - 财政年份:2020
- 资助金额:
$ 53.96万 - 项目类别:
Standard Grant
NSCI Elements: Software - PFSTRASE - A Parallel FileSystem TRacing and Analysis SErvice to Enhance Cyberinfrastructure Performance and Reliability
NSCI Elements:软件 - PFSTRASE - 用于增强网络基础设施性能和可靠性的并行文件系统跟踪和分析服务
- 批准号:
1835135 - 财政年份:2018
- 资助金额:
$ 53.96万 - 项目类别:
Standard Grant
Size, shape and surface properties in realistic models of magnetic nanocrystals
磁性纳米晶体真实模型中的尺寸、形状和表面特性
- 批准号:
EP/P022006/1 - 财政年份:2017
- 资助金额:
$ 53.96万 - 项目类别:
Research Grant
Cross-linking and molecular modelling to determine the structure and dynamics of the intracellular regions of ATP gated P2X receptor ion channels
交联和分子建模以确定 ATP 门控 P2X 受体离子通道细胞内区域的结构和动力学
- 批准号:
BB/M000990/1 - 财政年份:2014
- 资助金额:
$ 53.96万 - 项目类别:
Research Grant
Integrated mutagenesis, bio-informatic and fluorescence approaches to characterize the molecular basis of antagonist action at P2X7 receptors for ATP
综合诱变、生物信息和荧光方法来表征 ATP P2X7 受体拮抗剂作用的分子基础
- 批准号:
MR/K027018/1 - 财政年份:2013
- 资助金额:
$ 53.96万 - 项目类别:
Research Grant
Mathematics Teacher Development in Central and Northern New Hampshire
新罕布什尔州中部和北部的数学教师发展
- 批准号:
8470632 - 财政年份:1985
- 资助金额:
$ 53.96万 - 项目类别:
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Minority Institutions Science Improvement Program-Individual Institutional Project
少数民族机构科学进步计划-个别机构项目
- 批准号:
7419640 - 财政年份:1974
- 资助金额:
$ 53.96万 - 项目类别:
Standard Grant
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