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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 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 mass spectrometry, this review highlights the potential of mass spectrometry techniques for in-depth investigations of GPCR biology. Herein, we will describe the utility of mass spectrometry (MS) including HDX-MS, cross-linking and native-MS, in investigating GPCR pharmacology. Specifically, we will include ligand/drug interactions and Gi/s protein-coupling and illustrate and how these techniques can lead to the discovery of endogenous allosteric ligands and thereby offer a new perspective for drug discovery of GPCRs. Significance Statement GPCRs represent the largest family of druggable protein targets that interact with a diverse array of ligands, from metal ions and small molecules through to peptides and proteins. These extracellular stimuli are translated allosterically into intracellular signals mediated by transducer proteins. Typically, activation of GPCRs relies on binding of endogenous or exogenous agonists to stabilize the receptors in active conformations. Recent developments in MS enable capture of the extent of GPCR activation and discovery of allosteric modulators of downstream signaling.

Original publication




Journal article


Pharmacol Rev

Publication Date



g protein-coupled receptors (GPCRS), mass spectrometry