G protein-coupled receptors (GPCRs) are key drug targets due to their involvement in many physiological processes. The complexity of receptor pharmacology, however, is influenced by multiple interactions with various types of ligands and protein transducers representing significant challenges for drug discovery. The ability of mass spectrometry (MS) to observe both the binding of ligand molecules, such as lipids, ions, or drugs, and their impact on interaction with transducers provides an exciting opportunity to probe many aspects that are difficult to track directly in cell-based systems. From the early days, when hydrogen deuterium exchange (HDX) experiments were used to probe the different conformations of GPCRs, through to the most recent insights in which the intact receptor-G protein/arrestin complexes associated with small molecules can be preserved by MS, this review highlights the potential of MS techniques for in-depth investigations of GPCR biology. We describe the utility of MS, including HDX-MS and native-MS, in investigating GPCR pharmacology. Specifically, we include ligand–drug interactions and G_i/s protein coupling and illustrate how these techniques can lead to the discovery of endogenous allosteric ligands and thereby offer a new perspective for drug discovery of GPCRs.

中文翻译：

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G 蛋白偶联受体药理学——来自质谱的见解

G 蛋白偶联受体 (GPCR) 是关键的药物靶标，因为它们参与许多生理过程。然而，受体药理学的复杂性受到与各种类型的配体和​​蛋白质传感器的多重相互作用的影响，这些相互作用代表了药物发现的重大挑战。质谱法 (MS) 能够观察配体分子（如脂质、离子或药物）的结合，以及它们对与传感器相互作用的影响，这为探索细胞中难以直接追踪的许多方面提供了令人兴奋的机会基于系统。从早期开始，当氢氘交换 (HDX) 实验用于探测 GPCR 的不同构象时，通过 MS 可以保存与小分子相关的完整受体 G 蛋白/抑制蛋白复合物的最新见解，这篇综述强调了 MS 技术在深入研究 GPCR 生物学方面的潜力。我们描述了 MS（包括 HDX-MS 和 native-MS）在研究 GPCR 药理学方面的效用。具体来说，我们包括配体-药物相互作用和 G_i/s蛋白质偶联并说明这些技术如何导致内源性变构配体的发现，从而为 GPCR 的药物发现提供新的视角。