<br>TAAR1 的结构和信号传导机制支持优先激动剂设计,Cell

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TAAR1 的结构和信号传导机制支持优先激动剂设计
Cell ( IF 45.5 ) Pub Date : 2023-11-13 , DOI: 10.1016/j.cell.2023.10.014
Pan Shang ₁ , Naikang Rong ₁ , Jing-Jing Jiang ₂ , Jie Cheng ₁ , Ming-Hui Zhang ₃ , Dongwei Kang ₄ , Lei Qi ₅ , Lulu Guo ₆ , Gong-Ming Yang ₂ , Qun Liu ₁ , Zhenzhen Zhou ₄ , Xiao-Bing Li ₇ , Kong-Kai Zhu ₆ , Qing-Biao Meng ₂ , Xiang Han ₂ , Wenqi Yan ₂ , Yalei Kong ₈ , Lejin Yang ₉ , Xiaohui Wang ₁₀ , Dapeng Lei ₂ , Xin Feng ₂ , Xinyong Liu ₄ , Xiao Yu ₂ , Yue Wang ₇ , Qian Li ₈ , Zhen-Hua Shao ₁₁ , Fan Yang ₁ , Jin-Peng Sun ₁

Affiliation

NHC Key Laboratory of Otorhinolaryngology, Qilu hospital and School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China; Advanced Medical Research Institute and Meili Lake Translational Research Park, Shandong University, Jinan, Shandong 250012, China.
NHC Key Laboratory of Otorhinolaryngology, Qilu hospital and School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China.
Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, China.
Advanced Medical Research Institute and Meili Lake Translational Research Park, Shandong University, Jinan, Shandong 250012, China; Biomedical Research Center for Structural Analysis, Shandong University, No.44 Wenhua Xi Road, Jinan, Shandong 250012, China.
Advanced Medical Research Institute and Meili Lake Translational Research Park, Shandong University, Jinan, Shandong 250012, China.
Medical Science and Technology Innovation Center, Shandong Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.
Songjiang Institute and Shanghai Songjiang District Central Hospital, Center for Brain Science in Shanghai Children's Medical Center, Department of Anatomy and Physiology, Ministry of Education, Shanghai Key Laboratory of Children's Environmental Health in Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Psychology, Qilu Hospital of Shandong University, Jinan, China.
Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.
Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.

痕量胺相关受体 1 (TAAR1) 感知一系列内源性含胺代谢物 (EAM)，以调节多种心理功能，可用于精神分裂症治疗，且不会产生僵直症的副作用。在这里，我们系统地分析了 TAAR1 激活的信号传导特性，并展示了 TAAR1-Gs/Gq 与 EAM、临床药物和合成化合物复合物的九种结构。这些结构不仅揭示了伯胺识别口袋（PARP）包含用于保守胺识别的保守酸性D和用于受体激活的“双”切换开关，而且还阐明了靶向第二结合口袋（SBP）中的特定残基允许调节信号传导偏爱。除了传统药物诱导的 Gs 信号传导外，EAM 或合成化合物激活 Gq 也有利于精神分裂症的治疗。我们的结果为 TAAR1 的分子识别提供了结构和信号传导框架，为 TAAR1 靶向候选化合物的设计提供了结构模板和信号线索。

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更新日期：2023-11-13

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