A dynamic view of GPCR-G protein complexes: insight into partial agonism and G protein selectivity

GPCR-G 蛋白复合物的动态视图:深入了解部分激动和 G 蛋白选择性

基本信息

  • 批准号:
    BB/W020718/1
  • 负责人:
  • 金额:
    $ 70.49万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2022
  • 资助国家:
    英国
  • 起止时间:
    2022 至 无数据
  • 项目状态:
    未结题

项目摘要

The human body is made of many cells, which work together in large numbers to sustain life. Each cell is surrounded by a lipid membrane that is impenetrable to most chemicals. However, in order to work properly together, individual cells need to communicate with each other and respond or adjust to external needs. To help with that, a host of sensor proteins, so-called G protein-coupled receptors (GPCRs) are embedded in the lipid cell envelope. There are over 850 different kinds of GPCRs in humans and their task is to sense the presence of a wide range of ligand molecules (agonists) on the outside of the cell and to communicate that information across the lipid membrane. GPCRs excel at this, as each kind of receptor is specialised to bind a particular set of ligands. Ligand binding changes the shape of the receptor, which in turn allows other proteins, so-called transducers, to bind to that part of the receptor on the inside of the cell membrane. Coupling of the transducer to the GPCR then activates a wide range of cellular signaling processes, which instruct the cell to respond and take necessary actions. The net effect is that the presence of a particular type of ligand on the outside of a cell has been communicated to the cell interior. Owing to their central role as sensors of the cell, GPCRs regulate a wide range of physiological processes and hence are central to human function in health and disease. Not surprisingly, a large proportion of prescription drugs target GPCRs.A defining feature of GPCRs is their mobility. They can easily change conformation and the effortlessness with which agonist-binding influences this strongly relates to the intrinsic function of these receptors. Similarly, GPCRs interact with their transducer G proteins in a dynamic fashion but how these GPCR-G protein complexes interact is currently poorly understood. Most structural investigations have relied on methods that reveal the GPCRs within static complexes, where the binding partners have usually been engineered into a stabilised form. This overlooks the fact, however, that the binding partners remain inherently mobile and can adopt a range of different conformations. We propose therefore to conduct studies using a method called NMR, which allows investigation of these proteins while retaining their natural mobility. We will investigate in greater detail how GPCRs interact with their transducers, in particular the family of heterotrimeric G proteins. Obtaining structural insight into the molecular details of these interactions, while preserving the dynamic nature of these proteins, is key for improving our understanding of how these receptors work. Through our investigations with the GPCR b1AR we will learn the molecular determinants of GPCR interactions with G proteins. We will discover how the dynamic nature of the complexes relate to the properties of the binding partners and how their conformations vary with the type of agonist bound and the type of G protein that interacts. Correlating our molecular observations from NMR with biophysical properties of these complexes, such as affinity of the binding partners, how rapidly the complexes are formed and how the rate of nucleotide exchange is affected, will inform us on how these conformational differences affect signaling function. While increasing our general knowledge of these receptor-transducer complexes and how GPCRs and G proteins dynamically interact, our work also will inform us on two major unresolved questions that are key for the function of these proteins: Why do certain ligands when bound to a receptor result in a moderated, less than maximal response? Why does a particular GPCR interact with a selected member of the G protein family preferably over another one? Both questions have direct implications for cellular signaling and our investigations will provide a dynamic perspective of the key molecular determinants.
人体是由许多细胞组成的,这些细胞大量协同工作以维持生命。每个细胞都被脂质膜包围,大多数化学物质都无法穿透。然而,为了一起正常工作,单个细胞需要相互沟通,并响应或调整外部需求。为了帮助这一点,一系列传感器蛋白,所谓的G蛋白偶联受体(GPCR)嵌入脂质细胞包膜中。在人类中有超过850种不同类型的GPCR,它们的任务是感知细胞外部广泛的配体分子(激动剂)的存在,并通过脂质膜传递信息。GPCR在这方面表现出色,因为每种受体都专门结合一组特定的配体。配体结合改变了受体的形状,这反过来又允许其他蛋白质,所谓的转换器,结合到细胞膜内侧的受体部分。然后将换能器与GPCR偶联激活广泛的细胞信号传导过程,这些过程指示细胞做出反应并采取必要的行动。净效应是细胞外部存在的特定类型的配体已经传达到细胞内部。由于其作为细胞传感器的核心作用,GPCR调节广泛的生理过程,因此对人类健康和疾病的功能至关重要。毫不奇怪,很大一部分处方药靶向GPCR。GPCR的一个定义特征是它们的移动性。它们可以很容易地改变构象,而激动剂结合影响构象的不费力性与这些受体的内在功能密切相关。类似地,GPCR以动态方式与其转导G蛋白相互作用,但目前对这些GPCR-G蛋白复合物如何相互作用知之甚少。大多数结构研究依赖于揭示静态复合物内的GPCR的方法,其中结合伴侣通常被工程化为稳定形式。然而,这忽略了这样一个事实,即结合配偶体保持固有的移动的并且可以采用一系列不同的构象。因此,我们建议使用一种称为NMR的方法进行研究,该方法可以在保留其自然流动性的同时对这些蛋白质进行研究。我们将更详细地研究GPCR如何与它们的换能器相互作用,特别是异源三聚体G蛋白家族。获得对这些相互作用的分子细节的结构洞察,同时保留这些蛋白质的动态性质,是提高我们对这些受体如何工作的理解的关键。通过我们对GPCR b1 AR的研究,我们将了解GPCR与G蛋白相互作用的分子决定因素。我们将发现复合物的动态性质如何与结合伴侣的性质相关,以及它们的构象如何随激动剂结合的类型和相互作用的G蛋白的类型而变化。将我们的NMR分子观察结果与这些复合物的生物物理性质(如结合伴侣的亲和力,复合物形成的速度以及核苷酸交换速率如何受到影响)相关联,将告知我们这些构象差异如何影响信号功能。在增加我们对这些受体-转导复合物以及GPCR和G蛋白如何动态相互作用的一般知识的同时,我们的工作还将告知我们两个主要的未解决的问题,这是这些蛋白质功能的关键:为什么某些配体与受体结合时会导致适度的,低于最大反应?为什么一个特定的GPCR与G蛋白家族的一个选定成员相互作用,而不是另一个?这两个问题对细胞信号传导有直接影响,我们的研究将提供关键分子决定因素的动态视角。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Structurally similar G protein complexes with ß1-adrenergic receptor active state show differential binding kinetics, mediating selectivity
具有α1-肾上腺素能受体活性状态的结构相似的 G 蛋白复合物表现出不同的结合动力学,介导选择性
  • DOI:
    10.21203/rs.3.rs-3295734/v1
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Nietlispach D
  • 通讯作者:
    Nietlispach D
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Daniel Nietlispach其他文献

NMR studies of 56 kDa E. coli nickel binding protein NikA
56 kDa 大肠杆菌镍结合蛋白 NikA 的 NMR 研究
  • DOI:
  • 发表时间:
    2010
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Joanna Jakus;Yuusuke Tsuchie;Teppei Ikeya;Masaki Mishima;Daniel Nietlispach;Jeremy R. H. Tame;Yutaka Ito
  • 通讯作者:
    Yutaka Ito
Structural and dynamics studies of proteins in living cells by in-cell NMR spectroscopy
通过细胞内核磁共振波谱对活细胞中蛋白质的结构和动力学研究
  • DOI:
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Junpei Hamatsu;Takahiro Shirai;Daniel Nietlispach;Teppei Ikeya;Masaki Mishima;Masahiro Shirakawa and Yutaka Ito
  • 通讯作者:
    Masahiro Shirakawa and Yutaka Ito
異なるサイズの微粒子を取り込んだミドリゾウリムシの食胞の観察
含有不同尺寸微粒的鹿角草履虫食物液泡的观察
  • DOI:
  • 发表时间:
    2010
  • 期刊:
  • 影响因子:
    0
  • 作者:
    重光佳基,池谷鉄兵,土江祐介,三島正規;Daniel Nietlispach;Markus Waelchli;Peter Guentert;Brian O. Smith,伊藤隆;児玉有紀
  • 通讯作者:
    児玉有紀
Formatex Research Center Current Research, Technology and Education Topics in Applied Microbiology and Microbial Biotechnology
Formatex 研究中心应用微生物学和微生物生物技术的当前研究、技术和教育主题
  • DOI:
  • 发表时间:
    2010
  • 期刊:
  • 影响因子:
    0
  • 作者:
    重光佳基,池谷鉄兵,土江祐介,三島正規;Daniel Nietlispach;Markus Waelchli;Peter Guentert;Brian O. Smith,伊藤隆;児玉有紀;宮川直也;Kodama Y. and Fujishima M.
  • 通讯作者:
    Kodama Y. and Fujishima M.
Backbone ^1H, ^<13>C, and ^<15>N assignments of a 42 kDa RecR homodimer.
42 kDa RecR 同二聚体的主链^1H、^13C 和^15N 分配。
  • DOI:
  • 发表时间:
    2004
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Masayoshi Honda;Sundaresan Rajesh;Daniel Nietlispach;Tsutomu Mikawa;Takehiko Shibata;Yutaka Ito
  • 通讯作者:
    Yutaka Ito

Daniel Nietlispach的其他文献

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{{ truncateString('Daniel Nietlispach', 18)}}的其他基金

Understanding the functional activation of G protein-coupled receptors (GPCRs) in the context of their lipid bilayer environment
了解 G 蛋白偶联受体 (GPCR) 在脂质双层环境中的功能激活
  • 批准号:
    BB/S015892/1
  • 财政年份:
    2019
  • 资助金额:
    $ 70.49万
  • 项目类别:
    Research Grant
Solution NMR spectroscopy studies of an adrenergic receptor b1AR
肾上腺素受体 b1AR 的溶液核磁共振波谱研究
  • 批准号:
    BB/K01983X/1
  • 财政年份:
    2013
  • 资助金额:
    $ 70.49万
  • 项目类别:
    Research Grant
Structure determination of the 7-helix transmembrane protein receptor pSRII by solution NMR
通过溶液 NMR 测定 7 螺旋跨膜蛋白受体 pSRII 的结构
  • 批准号:
    BB/G011915/1
  • 财政年份:
    2009
  • 资助金额:
    $ 70.49万
  • 项目类别:
    Research Grant
High Sensitivity Cryoprobe Equipment for the NMR Facility of the Department of Biochemistry University of Cambridge
剑桥大学生物化学系核磁共振设备的高灵敏度冷冻探针设备
  • 批准号:
    BB/E013228/1
  • 财政年份:
    2007
  • 资助金额:
    $ 70.49万
  • 项目类别:
    Research Grant

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