Wu Di, Zhao Yan, Jiang Daohua
Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
FEBS J. 2025 Jan 30. doi: 10.1111/febs.70003.
Vesicular monoamine transporter 2 (VMAT2) is a proton-monoamine antiporter that is widely expressed in central and peripheral neurons and plays a crucial role in loading monoamine neurotransmitters into secretory vesicles. Dysfunction of VMAT2 causes many neuropsychiatric disorders, such as depression and Parkinson's disease. Consequently, VMAT2 is a valid and important therapeutic target. Reserpine alleviates symptoms of hypertension via potent inhibition of VMAT2. Tetrabenazine selectively inhibits VMAT2 and has been used for the management of chorea, including Huntington's disease. Decades of extensive studies have defined the substrate specificity and transport kinetics of VMAT2. However, the structure and precise mechanisms of monoamine recognition and drug inhibition in VMAT2 remain unknown. Recently, we determined an ensemble of high-resolution cryo-EM structures of human VMAT2 in three distinct states bound to multiple substrates and inhibitors. These results lay a structural foundation for a comprehensive understanding of substrate recognition and transport, drug inhibition, and proton coupling in VMAT2 and shed light on future therapeutic development.
囊泡单胺转运体2（VMAT2）是一种质子-单胺反向转运体，在中枢和外周神经元中广泛表达，在将单胺神经递质装载到分泌囊泡中发挥关键作用。VMAT2功能障碍会导致许多神经精神疾病，如抑郁症和帕金森病。因此，VMAT2是一个有效的重要治疗靶点。利血平通过强力抑制VMAT2来缓解高血压症状。丁苯那嗪选择性抑制VMAT2，已被用于治疗包括亨廷顿舞蹈病在内的舞蹈病。数十年的广泛研究已明确了VMAT2的底物特异性和转运动力学。然而，VMAT2中胺类识别和药物抑制的结构及精确机制仍不清楚。最近，我们确定了处于三种不同状态的人VMAT2与多种底物和抑制剂结合的一系列高分辨率冷冻电镜结构。这些结果为全面理解VMAT2中的底物识别与转运、药物抑制及质子偶联奠定了结构基础，并为未来的治疗发展提供了线索。
