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GABA (γ-aminobutyric acid) stimulation of the metabotropic GABA B receptor results in prolonged inhibition of neurotransmission that is central to brain physiology 1 . GABA B belongs to the Family C of G protein-coupled receptors (GPCRs), which operate as dimers to relay synaptic neurotransmitter signals into a cellular response through the binding and activation of heterotrimeric G proteins 2 , 3 . GABA B , however, is unique in its function as an obligate heterodimer in which agonist binding and G protein activation take place on distinct subunits 4 , 5 . Here we show structures of heterodimeric and homodimeric full-length GABA B receptors. Complemented by cellular signaling assays and atomistic simulations, the structures reveal an essential role for the GABA B extracellular loop 2 (ECL2) in relaying structural transitions by ordering the linker connecting the extracellular ligand-binding domain to the transmembrane region. Furthermore, the ECL2 of both GABA B subunits caps and interacts with the hydrophilic head of a phospholipid occupying the extracellular half of the transmembrane domain, thereby providing a potentially crucial link between ligand binding and the receptor core that engages G protein. These results provide a starting framework to decipher mechanistic modes of signal transduction mediated by GABA B dimers and have important implications for rational drug design targeting these receptors.

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Cryogenic electron microscopy (cryo-EM) has widened the field of structure-based drug discovery by allowing for routine determination of membrane protein structures previously intractable. However, despite representing one of the largest classes of therapeutic targets, most inactive-state G protein-coupled receptors (GPCRs) have remained .