Fig. 3.

Quaternary structure of the A2AR-CB1R heterotetramer. a Schematic representation of the A2AR-CB1R heterotetramer (left) viewed from the extracellular side (colored arrows indicate the C-terminal segments of the internal protomers able to reach the external G protein-bound protomers) and the previously reported A2AR-A1R (middle) and A2AR-D2R (right) heterotetramers. Inactive/internal and active/external protomers of A2AR are shown in light and dark green, respectively, and inactive/internal and active/external protomers of CB1R, A1R, or D2R are shown in orange and red, respectively. The α-subunit of the G protein is shown in light gray, the β-subunit in dark gray, and the γ-subunit in purple. The α-helical domain (αAH) of the α-subunit, which performs a large-scale opening from the Ras domain, is shown in yellow. b A representative molecular representation of the A2AR-CB1R heterotetramer obtained from the MD simulation viewed from the membrane (left) or from the extracellular side (right). Color codes are as in panel a. c Proposed interaction between phosphorylated residues at the C-terminus of the CB1R (Gi-bound external protomer) with arginine residues at the end of TM 5 of the A2AR (internal protomer). d Proposed interaction between phosphorylated residues at the C-terminus of the A2AR (Gs-bound external protomer) with arginine residues at the end of TM 5 of the CB1R (internal protomer)