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The class A adenosine A₁ receptor (A₁R) 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 A₁R in complex with adenosine and heterotrimeric G_i2 protein determined by Volta phase plate cryo-electron microscopy. Compared to inactive A₁R, 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 A₁R primarily via amino acids in the C terminus of the Gα_i α5-helix, concomitant with a 10.5 Å outward movement of the A₁R transmembrane domain 6. Comparison with the agonist-bound β₂ adrenergic receptor–G_s-protein complex reveals distinct orientations for each G-protein subtype upon engagement with its …