Nature—神经科学大分子结构解析重磅突破：科学家揭示神经元操控技术DREADD的分子结构基础

中文摘要

仅由设计药物激活的设计受体（DREADD，一种化学遗传技术）是一种用于远程控制神经元活动和细胞信号的强大的化学遗传学技术。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。Gq偶联的DREADD（hM3Dq）用于增强神经元活性，而Gi/o偶联的DRADD（hM4Di）用于抑制神经元活性。在此，科学家报道了四种与DREADD相关的冷冻电镜高分辨率结构：与去氯氯氮平结合的hM3Dq-miniGq复合物和hM4Di-miniGo复合物；与氯氮平-N-氧化物结合的hM3Dq-miniGq复合物；以及与伊哌罗唑结合的hM3R miniGq复合物。通过突变、功能和计算模拟数据的补充，他们的结构揭示了DREADD化学遗传致动器识别的关键细节和激活的分子基础。这些发现将加速下一代化学遗传学工具的发现。

英文摘要

Designer receptors exclusively activated by designer drugs (DREADDs) represent a powerful chemogenetic technology for the remote control of neuronal activity and cellular signalling. The muscarinic receptor-based DREADDs are the most widely used chemogenetic tools in neuroscience research. The Gq-coupled DREADD (hM3Dq) is used to enhance neuronal activity, whereas the Gi/o-coupled DREADD (hM4Di) is utilized to inhibit neuronal activity. Here we report four DREADD-related cryogenic electron microscopy high-resolution structures: a hM3Dq-miniGq complex and a hM4Di-miniGo complex bound to deschloroclozapine; a hM3Dq-miniGq complex bound to clozapine-N-oxide; and a hM3R-miniGq 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.

参考文献：Molecular basis for selective activation of DREADD-based chemogenetics. Nature. 2022 Dec;612(7939):354-362. doi: 10.1038/s41586-022-05489-0. Epub 2022 Nov 30.

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