G protein-coupled receptors (GPCRs) exhibit a wide range of pharmacological efficacies, yet the molecular mechanisms responsible for the differential efficacies in response to various ligands remain poorly understood. This lack of understanding has hindered the development of a solid foundation for establishing a mathematical model for signaling efficacy. However, recent progress has been made in delineating and quantifying receptor conformational states and associating function with these conformations. This progress has allowed us to construct a mathematical model for GPCR signaling efficacy that goes beyond the traditional ON/OFF binary switch model. In this study, we present a quantitative conformation-based mathematical model for GPCR signaling efficacy using the adenosine A_2A receptor (A_2AR) as a model system, under the guide of ¹⁹F quantitative nuclear magnetic resonance experiments. This model encompasses two signaling states, a fully activated state and a partially activated state, defined as being able to regulate the cognate Gα_s nucleotide exchange with respective G protein recognition capacity. By quantifying the population distribution of each state, we can now in turn examine GPCR signaling efficacy. This advance provides a foundation for assessing GPCR signaling efficacy using a conformation-based mathematical model in response to ligand binding.

中文翻译：

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A19F-qNMR 引导的 G 蛋白偶联受体信号转导数学模型


G 蛋白偶联受体 (GPCR) 表现出广泛的药理功效，但对不同配体反应不同功效的分子机制仍知之甚少。这种缺乏理解阻碍了建立信号功效数学模型的坚实基础。然而，最近在描绘和量化受体构象状态以及将功能与这些构象相关联方面取得了进展。这一进展使我们能够构建一个超越传统 ON/OFF 二元开关模型的 GPCR 信号功效数学模型。在本研究中，我们使用腺苷 A _2A 受体 (A _2A R) 作为模型系统，在 < b2>F定量核磁共振实验。该模型包含两种信号传导状态，即完全激活状态和部分激活状态，定义为能够通过各自的 G 蛋白识别能力调节同源 Gα _s 核苷酸交换。通过量化每个州的人口分布，我们现在可以依次检查 GPCR 信号传导功效。这一进展为使用基于构象的数学模型响应配体结合来评估 GPCR 信号传导功效奠定了基础。