小柯机器人

上海科技大学徐菲等研究人员合作揭示痕量胺受体TAAR1对甲基苯丙胺和其他胺类的识别。2023年11月7日，《自然》杂志在线发表了这项成果。

研究人员表示，痕量胺相关受体1（TAAR1）是由九名成员组成的痕量胺受体家族的创始成员，负责识别大脑中的一系列生物胺，包括内源性β-苯乙胺（β-PEA）和甲基苯丙胺（METH），后者是一种对人类健康和社会构成严重威胁的滥用物质。鉴于TAAR1在大脑中的独特生理作用，它也是包括精神分裂症、抑郁症和药物成瘾在内的一系列神经系统疾病的新靶点。

研究人员报告了与METH和β-PEA结合的人类TAAR1-G蛋白复合物的结构，以及与TAAR1选择性激动剂RO5256390和TAAR1与血清素受体5-HT_1AR的临床阶段双重激动剂SEP-363856结合的复合物结构。结合系统突变和功能研究，这些结构揭示了METH识别的分子基础以及TAAR1和其他单胺受体之间配体选择性和多药性的潜在机制。研究人员在配体结合口袋中发现了一个类似睑状ECL2的螺旋/环结构和一个氢键网络，这可能有助于TAAR1的配体识别。这些发现揭示了TAAR1的配体识别模式和激活机制，为开发治疗药物成瘾和各种神经系统疾病的新一代疗法提供了指导。

附：英文原文

Title: Recognition of methamphetamine and other amines by trace amine receptor TAAR1

Author: Liu, Heng, Zheng, You, Wang, Yue, Wang, Yumeng, He, Xinheng, Xu, Peiyu, Huang, Sijie, Yuan, Qingning, Zhang, Xinyue, Wang, Ling, Jiang, Kexin, Chen, Hong, Li, Zhen, Liu, Wenbin, Wang, Sheng, Xu, H. Eric, Xu, Fei

Issue&Volume: 2023-11-07

Abstract: Trace amine-associated receptor 1 (TAAR1), the founding member of a nine-member family of trace amine receptors, is responsible for recognizing a range of biogenic amines in the brain, including the endogenous β-phenylethylamine (β-PEA)1 as well as methamphetamine (METH)2, an abused substance that has posed a severe threat to human health and society3. Given its unique physiological role in the brain, TAAR1 is also an emerging target for a range of neurological disorders including schizophrenia, depression and drug addiction2,4,5. Here we report structures of human TAAR1-G protein complexes bound to METH and β-PEA as well as complexes bound to RO5256390, a TAAR1 selective agonist, and SEP-363856, a clinical-stage dual agonist for TAAR1 and serotonin receptor 5-HT1AR6,7. Together with systematic mutagenesis and functional studies, the structures reveal the molecular basis of METH recognition and underlying mechanisms of ligand selectivity and polypharmacology between TAAR1 and other monoamine receptors. We identify a lid-like ECL2 helix/loop structure and a hydrogen-bonding network in the ligand binding pockets, which may contribute to the ligand recognition in TAAR1. These findings shed light on the ligand recognition mode and activation mechanism for TAAR1 and should guide the development of next-generation therapeutics for drug addiction and various neurological disorders.

DOI: 10.1038/s41586-023-06775-1

Source: https://www.nature.com/articles/s41586-023-06775-1

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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