Transport and inhibition mechanisms of human VMAT2

Di Wu, Qihao Chen, Zhuoya Yu, Bo Huang, Jun Zhao, Yuhang Wang, Jiawei Su, Feng Zhou, Rui Yan, Na Li, Yan Zhao () and Daohua Jiang ()
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Di Wu: Chinese Academy of Sciences
Qihao Chen: University of Chinese Academy of Sciences
Zhuoya Yu: University of Chinese Academy of Sciences
Bo Huang: Beijing StoneWise Technology
Jun Zhao: Shandong Laboratory of Advanced Agricultural Sciences at Weifang
Yuhang Wang: University of Chinese Academy of Sciences
Jiawei Su: University of Chinese Academy of Sciences
Feng Zhou: Beijing StoneWise Technology
Rui Yan: Chinese Academy of Sciences
Na Li: Capital Medical University
Yan Zhao: University of Chinese Academy of Sciences
Daohua Jiang: Chinese Academy of Sciences

Nature, 2024, vol. 626, issue 7998, 427-434

Abstract: Abstract Vesicular monoamine transporter 2 (VMAT2) accumulates monoamines in presynaptic vesicles for storage and exocytotic release, and has 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 with reserpine and tetrabenazine alleviates symptoms of hypertension and Huntington’s disease7,8, respectively. Here we describe cryo-electron microscopy structures of human VMAT2 complexed with serotonin and three clinical drugs at 3.5–2.8 Å, demonstrating the structural basis for 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. The structures in three distinct states also 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 therapeutic agents.

Date: 2024
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DOI: 10.1038/s41586-023-06926-4

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