【世界时快讯】基于DREADD的化学遗传学工具选择性激活的分子基础

美国北卡罗来纳大学教堂山分校Bryan L. Roth和美国马里兰大学医学院Jonathan F. Fay共同合作，近期取得重要工作进展。他们研究发现了基于DREADD的化学遗传学工具选择性激活的分子基础。相关研究论文2022年11月30日在线发表于《自然》杂志上。

据介绍，仅由设计药物（DREADD）激活的设计受体代表了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。

(相关资料图)

研究人员报道了四种与DREADD相关的冷冻电镜高分辨率结构：与去氯氯氮平（deschloroclozapine）结合的hM3Dq-miniGq复合物和hM4Di-miniGo复合物；与氯氮平-N-氧化物（clozapine-N-oxide）结合的hM3Dq–miniGq复合物；以及与伊佩罗索（iperoxo）结合的hM3R–miniGq复合物。通过突变、功能和计算模拟数据的补充，这些结构揭示了DREADD化学遗传执行器的关键细节和激活的分子基础。这些发现将加速结构指导下的下一代化学遗传学工具的开发。

附：英文原文

Title: Molecular basis for selective activation of DREADD-based chemogenetics

Author: Zhang, Shicheng, Gumpper, Ryan H., Huang, Xi-Ping, Liu, Yongfeng, Krumm, Brian E., Cao, Can, Fay, Jonathan F., Roth, Bryan L.

Issue&Volume: 2022-11-30

Abstract: Designer receptors exclusively activated by designer drugs (DREADDs) represent a powerful chemogenetic technology for the remote control of neuronal activity and cellular signalling1,2,3,4. 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 activity5. 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.

DOI: 10.1038/s41586-022-05489-0

Source: https://www.nature.com/articles/s41586-022-05489-0

来源：科学网小柯机器人