Activation mechanism for the Gγ C-terminal conformational switch. (A) An initial docking model of the ground state of rhodopsin (PDB accession no. 1U19) and Gβ₁γ₂ from the Gβ₁γ₂–GRK2 complex (PDB accession no. 1OMW) was constructed as described in Fig. 7 B, emphasizing atomic distances within 4 Å between the NPF motif (black) in Gγ₂ (bluishgreen) and Gβ₁ (blue), with dashed yellow lines. The C-tail of rhodopsin was removed for clarity. (B) Same view as A, except the STNPFR peptide (black) bound to αB and αC helices of EH₂ (orange) from Eps15 was manually aligned onto TM1 and H8 of rhodopsin. (C) Same view as B except the αB and αC helices of EH₂ were removed to illustrate the STNPFR peptide as a surrogate for Gγ NPF motif binding to rhodopsin. In this conformation, the Gγ₂ C-terminus is unmasked and the NPF motif no longer interacts with Gβ. A farnesyl moiety (red) is modeled in the cytoplasmic core of rhodopsin to represent one of the initial interactions between rhodopsin and Gγ₁. (D) Same view as C, except an α helix was constructed in PyMOL based on the C-terminal h2 region of Gγ₁: KGIPEDKNPFKELKGGC, and modeled as a helical extension of the three residues of the H2 Gγ₂ helix, Pro49^H2.20, Leu50^H2.21, and Leu51^H2.22, that make extensive contacts with Gβ (dashed yellow lines). The helical h2 region of Gγ₁ is in bluishgreen, except for the NPF motif, which is black. There is not enough information to know exactly where the prenyl binding site is in the hydrophobic core of rhodopsin, thus the location of the farnesyl moiety, which would direct the extension of the Gγ h2 helix into the core of the receptor, is somewhat arbitrary.