Structural Basis of GABA(B) Receptor Activation during Evolution.

GABA(B) receptor is a Class C G protein-coupled receptor (GPCR) for γ-aminobutyric acid (GABA), the principal inhibitory neurotransmitter. It forms an obligatory heterodimer consisting of two subunits, GB1 and GB2. Whether the activation mechanism of the GABA(B) receptor is conserved during evolution remains unknown. Here, the cryogenic electron microscopy (cryo-EM) structures of the drosophila GABA(B) receptor in both antagonist-bound inactive state and GABA-bound active state in complex with G(i) protein are reported. The drosophila GABA(B) receptor exhibits an asymmetric activation, mirroring its human homolog. However, a larger inactive interface prevents drosophila GABA(B) receptor constitutive activity. Four key residues, which are not conserved in drosophila GABA(B) receptor, are responsible for the activity of the positive allosteric modulator in its human homolog. Whereas the intracellular loop 2 of drosophila GB2 (dGB2) is less involved, the ordered C terminus of dGB2 and its corresponding region in its human homolog are required for G protein coupling. These evolutionary variations provide a complete understanding of the activation mechanism of the GABA(B) receptor and new insights for future development of allosteric modulators for medication and insecticides.