Structures of G protein-coupled receptors reveal new opportunities for drug discovery

•X-ray structures are now available for more than 60 ligands and 20 GPCRs.•Structures reveal details of ligand biding that could not be predicted.•Structure-based drug design for GPCRs has been transformed by the new results.•Lipophilic sites and water molecules have key roles in ligand-binding properties. X-ray structures of G protein-coupled receptors (GPCRs) have now been reported for more than 60 ligands and 20 receptors, including examples from GPCR classes A, B, C and F. The new structures show previously unobtainable details of interactions between GPCRs and ligands, including the roles of lipophilic regions and water molecules as key drivers of binding. In addition, the structures have revealed several surprising ligand-binding modes, including sites outside the orthosteric pocket. This new information is dramatically changing the way we approach GPCR drug discovery.