Understanding the molecular basis of partial agonism and G protein selectivity in GPCRs

了解 GPCR 中部分激动和 G 蛋白选择性的分子基础

• 批准号: 2890327
• 金额: --
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2890327
• 关键词: Understanding; molecular; basis; partial; agonism

BBSRC strategic theme: Understanding the rules of lifeG protein-coupled receptors (GPCRs) are membrane-embedded signaling proteins that, when activated by agonists change their conformation, enabling transducers such as heterotrimeric G proteins or arrestins to bind. Structural and biophysical data have provided extensive insight into how agonists affect the function of GPCRs. However, how conformational changes in the receptor affect coupling and activation of intracellular transducers remains poorly understood. Major questions remain such as why certain agonists produce a less than full response (known as partial agonism), and why a given receptor binds selectively to one particular subtype of the G protein family over another (signal bias). Currently, we are reliant on information from static structures of immobilised proteins but to answer these questions we need additional insight on GPCR-G protein complexes that reveals their true dynamic nature.The project will investigate these aspects using NMR, to provide a much-needed dynamic explanation of how GPCRs and G proteins interact. A range of agonists and complexes with different G proteins will be investigated to establish how conformational variability arises. The molecular observations will then be related to various biophysical properties, such as binding affinity, kinetics of exchange and nucleotide exchange rates etc. that link to signaling function. Using the solution NMR data 3D model structures of b1AR-G protein complexes will be built. Overall, this work will provide a dynamic perspective of GPCR-G protein complexes and reveal key molecular features of partial agonism and G protein selectivity.

BBSRC战略主题：了解LifeG蛋白偶联受体（GPCR）的规则是膜上包含的信号传导蛋白，当受动物激活时，它们会改变其构象，使频传感器（例如异邻三聚体G蛋白或阻止蛋白）粘合。结构和生物物理数据为激动剂如何影响GPCR的功能提供了广泛的见解。然而，受体的构象变化如何影响细胞内传感器的偶联和激活仍然很少了解。仍然存在主要问题，例如为什么某些激动剂产生的反应不足（称为部分激动剂），以及为什么给定受体与G蛋白家族的一种特定亚型选择性结合另一个特定的亚型（信号偏见）。目前，我们依靠来自固定蛋白质的静态结构的信息，但是要回答这些问题，我们需要对GPCR-G蛋白复合物的更多见解，这揭示了它们的真实动态性质。该项目将使用NMR研究这些方面，以提供对GPCR和G蛋白如何相互作用的急需的动态解释。将研究一系列具有不同G蛋白的激动剂和复合物，以确定构象变异性的产生方式。然后，分子观测将与各种生物物理特性有关，例如结合亲和力，交换和核苷酸汇率等等等。将使用溶液NMR数据3D模型结构的B1AR-G蛋白复合物建立。总体而言，这项工作将提供GPCR-G蛋白复合物的动态视角，并揭示部分激动剂和G蛋白选择性的关键分子特征。