G-protein-coupled receptors (GPCRs) are a family of cell surface proteins that can sense a variety of extracellular stimuli and mediate multiple signaling transduction pathways involved in human physiology. Recent advances in GPCR structural biology have revealed a relatively conserved intracellular allosteric site in multiple GPCRs, which can be utilized to modulate receptors from the inside. This novel intracellular site partially overlaps with the G-protein and β-arrestin coupling sites, providing a novel avenue for biological intervention. Here, we review evidence available for GPCR structures complexed with intracellular small-molecule allosteric modulators, elucidating drug-target interactions and allosteric mechanisms. Moreover, we highlight the potential of intracellular allosteric modulators in achieving biased signaling, which provides insights into biased allosteric mechanisms.
Keywords: G-protein-coupled receptors (GPCRs); allosteric modulators; allostery; biased signaling; intracellular allosteric site.
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