Activation of the Galpha subunit of heterotrimeric GTP-binding proteins by transmembrane receptors requires the propagation of structural signals from the receptor-binding site to the nucleotide-binding site at the opposite side of the protein. In a previous model, it was suggested that the Gbeta-Ggamma dimer is tilted away from Galpha by a lever-arm motion of the Galpha N-terminal helix. Here, we propose that the motion occurs in the opposite direction, close-packing the Galpha-Gbeta interface and creating a novel interface between the helical domain of Galpha and the N terminus of Ggamma, which determines the specificity of activation.