本期文章：《自然》：Online/在线发表

中国科学院物理研究所Daohua Jiang和中国科学院生物物理所Yan Zhao共同合作，近期取得重要工作进展。他们研究提出了人类VMAT2的转运和抑制机制。相关研究成果2023年12月11日在线发表于《自然》杂志上。

据介绍，囊泡单胺转运蛋白2（VMAT2）在突触前囊泡中积累单胺用于储存和胞外释放，在单胺能神经传递中起着至关重要的作用。单胺能系统的功能障碍会导致许多神经和精神疾病，包括帕金森病、运动障碍和抑郁症。利血平和四苯喹嗪抑制VMAT2可分别减轻高血压和亨廷顿舞蹈症的症状。

研究人员描述了人类VMAT2与血清素和三种临床药物在3.5-2.8 Å下络合的冷冻电镜结构，展示了VMAT2运输和抑制的结构基础。利血平和酮色林分别占据底物结合口袋并将VMAT2锁定在面向细胞质和面向管腔的状态，而四苯喹嗪结合在VMAT2特异性口袋中并以闭塞状态捕获VMAT2。

此外，三种不同状态下的结构揭示了VMAT2运输循环的结构基础。

总之，这一研究为了解VMAT2底物的识别、转运、药物抑制和药理学的机制奠定了结构基础，同时为合理设计潜在的治疗方法提供了线索。

附：英文原文

Title: Transport and inhibition mechanisms of human VMAT2

Author: Wu, Di, Chen, Qihao, Yu, Zhuoya, Huang, Bo, Zhao, Jun, Wang, Yuhang, Su, Jiawei, Zhou, Feng, Yan, Rui, Li, Na, Zhao, Yan, Jiang, Daohua

Issue&Volume: 2023-12-11

Abstract: Vesicular monoamine transporter 2 (VMAT2) accumulates monoamines in presynaptic vesicles for storage and exocytotic release, playing a vital role in monoaminergic neurotransmission1-3. Dysfunction of monoaminergic systems causes many neurological and psychiatric disorders, including Parkinson’s disease, hyperkinetic movement disorders, and depression4-6. Suppressing VMAT2 by reserpine and tetrabenazine alleviates symptoms of hypertension and Huntington’s disease7,8, respectively. Here, we describe the cryo-electron microscopy structures of human VMAT2 complexed with serotonin and three clinical drugs at 3.5-2.8 , demonstrating the structural basis for VMAT2 transport and inhibition. Reserpine and ketanserin occupy the substrate-binding pocket and lock VMAT2 in cytoplasm-facing and lumen-facing states, respectively, whereas tetrabenazine binds in a VMAT2-specific pocket and traps VMAT2 in an occluded state. Moreover, the structures in three distinct states reveal the structural basis of the VMAT2 transport cycle. Our study establishes a structural foundation for the mechanistic understanding of substrate recognition, transport, drug inhibition, and pharmacology of VMAT2 while shedding light on the rational design of potential therapeutics.

DOI: 10.1038/s41586-023-06926-4