Figure 1. Structural models of receptor-catalyzed nucleotide exchange.

Multiple lines of evidence suggest that a separation of the G protein ras-homology domain (RHD) and alpha-helical domain (AHD) is necessary to exchange bound GDP for GTP. While motion of the alpha helical domain was observed in the crystal structure of β₂AR in complex with nucleotide-free G_s heterotrimer (top left) and in a model of rhodopsin in complex with GDP-bound G_i heterotrimer (bottom left), domain separation is likely not sufficient to trigger GDP release from Gα. Rather, binding to an activated receptor stabilizes conformational changes within the G protein that disrupt nucleotide interactions with the RHD. Interaction of intracellular loop 2 (ICL2) of the receptor with the αN helix and αN-β1 junction of the G protein leads to a reorganization of the P-loop that coordinates the β-phosphate of GDP (middle column). Furthermore, the C-terminal α5 helix of Gα undergoes a rotation and translation to occupy its binding site within the hydrophobic core of the receptor that is opened upon outward movement of TM6. Movement of the α5 helix in turn alters the β6-α5 loop that directly contacts GDP (right column). Similar receptor-G protein contacts, and G protein conformational changes, are seen in the structure of β₂AR-G_s complex (top panels) and the model of the rhodopsin-G_i complex (bottom panels). In both scenarios, receptor is shown in gray (PDB: 3SN6 for β₂AR-G_s; Rho*-G_i is from Alexander et al. [43]). For comparison of receptor-bound and unbound Gα_s in the top panels, the RHD of GTPγS-bound Gα_s (PDB: 1AZT, cyan) was aligned to the RHD of Gα_s in the β₂AR complex (PDB: 3SN6, orange). A similar alignment was used in the bottom panels to overlay GDP-bound Gα_i (PDB: 1GOT, cyan) with the RHD of receptor-bound Gα_i (orange).