Structure of the adenosine-bound human adenosine A1 receptor–Gi complex

The class A adenosine A 1 receptor (A 1 R) is a G-protein-coupled receptor that preferentially couples to inhibitory G i/o heterotrimeric G proteins, has been implicated in numerous diseases, yet remains poorly targeted. Here we report the 3.6 Å structure of the human A 1 R in complex with adenosine and heterotrimeric G i2 protein determined by Volta phase plate cryo-electron microscopy. Compared to inactive A 1 R, there is contraction at the extracellular surface in the orthosteric binding site mediated via movement of transmembrane domains 1 and 2. At the intracellular surface, the G protein engages the A 1 R primarily via amino acids in the C terminus of the Gα i α5-helix, concomitant with a 10.5 Å outward movement of the A 1 R transmembrane domain 6. Comparison with the agonist-bound β 2 adrenergic receptor–G s -protein complex reveals distinct orientations for each G-protein subtype upon engagement with its receptor. This active A 1 R structure provides molecular insights into receptor and G-protein selectivity. The cryo-electron microscopy structure of the human adenosine A 1 receptor in complex with adenosine and heterotrimeric G i2 protein provides molecular insights into receptor and G-protein selectivity.