Structural Basis of GABAB Receptor Activation during Evolution

Abstract 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.