Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, School of Life Sciences, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, China.
State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, School of Life Sciences, Hubei University, Wuhan, Hubei 430062, China.
J Med Chem. 2024 Oct 24;67(20):18593-18605. doi: 10.1021/acs.jmedchem.4c01961. Epub 2024 Oct 2.
Trace amine-associated receptor 1 (TAAR1), a member of the trace amine receptor family, recognizes various trace amines in the brain, including endogenous β-phenylethylamine (PEA) and methamphetamine (METH). TAAR1 is a novel target for several neurological disorders, including schizophrenia, depression, and substance abuse. Herein, we report the structure of the human TAAR1-G protein complex bound to METH. Using functional studies, we reveal the molecular basis of METH recognition by TAAR1, and potential mechanisms underlying the selectivity of TAAR1 for different ligands. Molecular dynamics simulations further elucidated possible mechanisms for the binding of chiral amphetamine (AMPH)-like psychoactive drugs to TAAR1. Additionally, we discovered a hydrophobic core on the transmembrane helices (TM), TM5 and TM6, explaining the unique mechanism of TAAR1 activation. These findings reveal the ligand recognition pattern and activation mechanism of TAAR1, which has important implications for the development of next-generation treatments for substance abuse and various neurological disorders.
痕量胺相关受体 1（TAAR1）是痕量胺受体家族的成员，可识别大脑中的各种痕量胺，包括内源性β-苯乙胺（PEA）和甲基苯丙胺（METH）。TAAR1 是包括精神分裂症、抑郁症和药物滥用在内的多种神经疾病的新靶点。在此，我们报告了与人 TAAR1-G 蛋白复合物结合的 METH 的结构。通过功能研究，我们揭示了 TAAR1 识别 METH 的分子基础，以及 TAAR1 对不同配体选择性的潜在机制。分子动力学模拟进一步阐明了手性苯丙胺（AMPH）样精神活性药物与 TAAR1 结合的可能机制。此外，我们还在跨膜螺旋（TM）TM5 和 TM6 上发现了一个疏水性核心，解释了 TAAR1 激活的独特机制。这些发现揭示了 TAAR1 的配体识别模式和激活机制，这对于开发治疗物质滥用和各种神经疾病的下一代疗法具有重要意义。
