Abstract
G protein-coupled receptors (GPCRs) constitute a diverse and extensive array of cell surface receptors, rendering them essential targets for drugs aimed at various human diseases. Responding to a range of extracellular or intracellular cues, GPCRs regulate cellular signaling through downstream transducers such as heterotrimer G proteins, GPCR kinases (GRKs), and arrestins. The wealth of 3D structures available for GPCRs and their signaling complexes significantly enhances our understanding of GPCR biology and expedites the development of structure-based drug discovery methods aimed at GPCR signaling. While the structural exploration of GPCR-G protein complexes has advanced, recent years have seen substantial breakthroughs in unraveling the mechanism behind arrestin-mediated GPCR signaling. This review aims to explore emerging insights into arrestin activation and its interaction with GPCRs, shedding light on the various ways GPCRs engage with arrestins both conservatively and diversely. Additionally, we summarize recent endeavors focused on designing functionally selective (’biased’) ligands targeting GPCRs, with desired effects on/off arrestin signaling. Our goal with this review is to spotlight studies investigating the structural aspects of GPCR activation and arrestin-binding modes, with a specific emphasis on arrestin-mediated GPCR signaling.
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