Metabotropic γ-aminobutyric acid receptors (GABAB) are involved in the modulation of synaptic responses in the central nervous system and are implicated in various neuropsychological conditions, ranging from addiction to psychosis1. GABAB belongs to G protein-coupled receptor class C, and its functional entity consists of an obligate heterodimer composed of GB1 and GB22. Each subunit possesses an extracellular Venus flytrap domain, connected to a canonical seven-transmembrane domain. Here, we present four cryo-EM structures of the human full-length GB1-GB2 heterodimer in its inactive apo, two intermediate agonist-bound, and active agonist/positive allosteric modulator bound forms. The structures reveal startling differences, shedding light onto the complex motions underlying the unique activation mechanism of GABAB. Our results show that agonist binding in the GB1 Venus flytrap domain triggers a series of transitions, first rearranging and bringing the two transmembrane domains into close contact along transmembrane helix 6 and ultimately inducing conformational rearrangements in the GB2 transmembrane domain via a lever-like mechanism, potentiated by a positive allosteric modulator binding at the dimerization interface, to initiate downstream signaling.