Atomic, structural and molecular insights into GPCR ligand binding and signalling

G-protein-coupled receptors (GPCRs) are the largest group of human membrane proteins, comprising over 800 members, and represent the most common target of therapeutics. GPCRs orchestrate context-dependent functions and have diverse physiological roles. Recent advances have enabled the exploration of GPCR structure, function and regulation, leading to a deeper understanding of their signalling complexity. In this Review, we synthesize these advances at different scales of increasing complexity and discuss atomic-level, structural-level and molecular-level insights into GPCR signalling. Specifically, we highlight the context-dependent mechanisms by which GPCRs translate extracellular cues into intracellular signals through ligand recognition, ligand-induced conformational changes, engagement with different adaptors and interactions with various molecular pathways, as well as how these processes are modulated during disease, and the new therapeutic opportunities they present. Through inter-disciplinary efforts aimed at elucidating GPCR multiscale signalling, we are approaching a holistic understanding that will inform the rational development of specific, effective and safer medicines.