Universal allosteric mechanism for Gα activation by GPCRs

G protein-coupled receptors (GPCRs) allosterically activate heterotrimeric G proteins and trigger GDP release. Given that there are similar to 800 human GPCRs and 16 different G alpha genes, this raises the question of whether a universal allosteric mechanism governs G alpha activation. Here we show that different GPCRs interact with and activate G alpha proteins through a highly conserved mechanism. Comparison of G alpha with the small G protein Ras reveals how the evolution of short segments that undergo disorder-to-order transitions can decouple regions important for allosteric activation from receptor binding specificity. This might explain how the GPCR-G alpha system diversified rapidly, while conserving the allosteric activation mechanism.