The mechanisms of G protein coupling to G protein-coupled receptors (GPCR) share general characteristics but may exhibit specific interactions unique for each GPCR/G protein partnership. The extreme C terminus (CT) of G protein α-subunits has been shown to be important for association with GPCR. Hypothesizing that the extreme CT of Gα(s) is an essential component of the molecular landscape of the GPCR, human LH receptor (LHR), and β(2)-adrenergic receptor (β(2)-AR), a model cell system was created for the expression and manipulation of Gα(s) subunits in LHR(+) s49 ck cells that lack endogenous Gα(s). On the basis of studies involving truncations, mutations, and chain extensions of Gα(s), the CT was found to be necessary for LHR and β(2)-AR signaling. Some general similarities were found for the responses of the two receptors, but significant differences were also noted. Computational modeling was performed with a combination of comparative modeling, molecular dynamics simulations, and rigid body docking. The resulting models, focused on the Gα(s) CT, are supported by the experimental observations and are characterized by the interaction of the four extreme CT amino acid residues of Gα(s) with residues in LHR and β(2)-AR helix 3, (including R of the DRY motif), helix 6, and intracellular loop 2. This portion of Gα(s) recognizes the same regions of the two GPCR, although with differences in the details of selected interactions. The predicted longer cytosolic extensions of helices 5 and 6 of β(2)-AR are expected to contribute significantly to differences in Gα(s) recognition by the two receptors.