Selectivity determinants of GPCR–G-protein binding

The selective coupling of G-protein-coupled receptors (GPCRs) to specific G proteins is critical to trigger the appropriate physiological response. However, the determinants of selective binding have remained elusive. Here we reveal the existence of a selectivity barcode (that is, patterns of amino acids) on each of the 16 human G proteins that is recognized by distinct regions on the approximately 800 human receptors. Although universally conserved positions in the barcode allow the receptors to bind and activate G proteins in a similar manner, different receptors recognize the unique positions of the G-protein barcode through distinct residues, like multiple keys (receptors) opening the same lock (G protein) using non-identical cuts. Considering the evolutionary history of GPCRs allows the identification of these selectivity-determining residues. These findings lay the foundation for understanding the molecular basis of coupling selectivity within individual receptors and G proteins. The identification of the positions and patterns of amino acids that form the selectivity determinants for the entire human G-protein and G-protein-coupled receptor signalling system. Decoding GPCR selective interactions G-protein-coupled receptors (GPCRs) trigger the appropriate cellular response to extracellular stimuli by selective interactions with cytosolic G proteins. Elucidating the molecular basis of this selective binding has been challenging. Here, Madan Babu and colleagues perform an analysis to determine the positions and patterns of amino acids that form the selectivity determinants for the entire human GPCR–G-protein signalling system. By considering the evolutionary history of the receptors, they identify a selectivity 'barcode' on each of the 16 Gα proteins that is recognized by different regions on the roughly 800 receptors. The authors provide an online, interactive platform that allows researchers to analyse selectivity-determining residues for any receptor and G protein.