Designer receptors exclusively activated by designer drugs (DREADDs) represent a powerful chemogenetic technology for the remote control of neuronal activity and cellular signalling^1,2,3,4. 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.

仅由设计药物激活的设计受体 (DREADD) 代表了一种强大的化学遗传学技术，用于远程控制神经元活动和细胞信号传导^1,2,3,4。基于毒蕈碱受体的 DREADD 是神经科学研究中使用最广泛的化学遗传学工具。G _q耦合的 DREADD (hM3Dq) 用于增强神经元活动，而 G _i/o耦合的 DREADD (hM4Di) 用于抑制神经元活动⁵。在这里，我们报告了四种与 DREADD 相关的低温电子显微镜高分辨率结构：与去氯氯氮平结合的 hM3Dq-miniG _q复合物和 hM4Di-miniG _o复合物；与氯氮平-N-氧化物结合的hM3Dq-miniG _q复合物；和与 iperoxo 结合的hM3R-miniG _{q复合物。}辅以诱变、功能和计算模拟数据，我们的结构揭示了 DREADD 化学发生致动器识别的关键细节和激活的分子基础。这些发现应该会加速下一代化学遗传学工具的结构引导发现。