Molecular basis for selective activation of DREADD-based chemogenetics

Designer receptors exclusively activated by designer drugs (DREADDs) represent a powerful chemogenetic technology for the remote control of neuronal activity and cellular signalling^1-4. The muscarinic receptor-based DREADDs are the most widely used chemogenetic tools in neuroscience research. The G_q-coupled DREADD (hM3Dq) is used to enhance neuronal activity, whereas the G_i/o-coupled DREADD (hM4Di) is utilized to inhibit neuronal activity⁵. Here we report four DREADD-related cryogenic electron microscopy high-resolution structures: a hM3Dq-miniG_q complex and a hM4Di-miniG_o complex bound to deschloroclozapine; a hM3Dq-miniG_q complex bound to clozapine-N-oxide; and a hM3R-miniG_q complex bound to iperoxo. Complemented with mutagenesis, functional and computational simulation data, our structures reveal key details of the recognition of DREADD chemogenetic actuators and the molecular basis for activation. These findings should accelerate the structure-guided discovery of next-generation chemogenetic tools.