This graphic of the Gα signaling nexus delineates functional elements within the molecule such as nucleotide binding (e.g. NKxD motif, TCAT motif, P-loop) and GPCR-driven nucleotide exchange (α-helix 5, β-strand 6), the different conformations of Gα (i.e. transition and GDP-, GTP-bound states), along with mammalian macromolecules that have been reported to directly interact with Gα. Reported interactions are classified by nucleotide dependence and by functional outcome (GDI, GEF, etc.). The single-headed arrow represents an interaction leading to signaling, the ‘X’ represents an interaction that does not lead to signaling, a blunt arrow represents interactions leading to signal termination, while the double-headed arrow represents a neutral physical interaction. While the list of reported interactions is intended to be extensive, it is not intended to be exhaustive, particularly in regard to the GPCRs. An expanded figure legend with additional references is in Text S1.