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.
Cell. 2023 Nov 22;186(24):5347-5362.e24. doi: 10.1016/j.cell.2023.10.014. Epub 2023 Nov 13.
Trace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment without the side effects of catalepsy. Here, we systematically profiled the signaling properties of TAAR1 activation and present nine structures of TAAR1-Gs/Gq in complex with EAMs, clinical drugs, and synthetic compounds. These structures not only revealed the primary amine recognition pocket (PARP) harboring the conserved acidic D for conserved amine recognition and "twin" toggle switch for receptor activation but also elucidated that targeting specific residues in the second binding pocket (SBP) allowed modulation of signaling preference. In addition to traditional drug-induced Gs signaling, Gq activation by EAM or synthetic compounds is beneficial to schizophrenia treatment. Our results provided a structural and signaling framework for molecular recognition by TAAR1, which afforded structural templates and signal clues for TAAR1-targeted candidate compounds design.
痕量胺相关受体 1（TAAR1）可感知一系列内源性含胺代谢物（EAMs），从而介导多种心理功能，并且在没有僵住副作用的情况下对精神分裂症的治疗有用。在这里，我们系统地分析了 TAAR1 激活的信号特性，并展示了 TAAR1-Gs/Gq 与 EAMs、临床药物和合成化合物结合的九个结构。这些结构不仅揭示了包含保守酸性 D 的主要胺识别口袋（PARP），用于保守胺识别，以及“双”Toggle 开关用于受体激活，而且还阐明了靶向第二结合口袋（SBP）中的特定残基可以调节信号偏好。除了传统的药物诱导的 Gs 信号外，EAM 或合成化合物对 Gq 的激活有益于精神分裂症的治疗。我们的结果为 TAAR1 的分子识别提供了一个结构和信号框架，为 TAAR1 靶向候选化合物设计提供了结构模板和信号线索。
