Volume 34, No 1, Jan 2024

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 34 Issue 1, January 2024: 47-57   |  Open Access

ORIGINAL ARTICLES

Transport and inhibition mechanism for VMAT2-mediated synaptic vesicle loading of monoamines

Yuwei Wang^1,2,† , Pei Zhang^3,† , Yulin Chao^1,2,† , Zhini Zhu^1,2,† , Chuanhui Yang^1,2,† , Zixuan Zhou^1,2,† , Yaohui Li^1,2 , Yonghui Long^1,2 , Yuehua Liu¹ , Dianfan Li³ , Sheng Wang^3,4,* , Qianhui Qu^1,2,*

¹Shanghai Stomatological Hospital, School of Stomatology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
²Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Department of Systems Biology for Medicine, Fudan University, Shanghai, China
³State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecule Cell Science, Chinese Academy of Sciences, Shanghai, China
⁴Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China
^†These authors contributed equally: Yuwei Wang, Pei Zhang, Yulin Chao, Zhini Zhu, Chuanhui Yang, Zixuan Zhou
Correspondence: Sheng Wang(wangsheng@sibcb.ac.cn)Qianhui Qu(qqh@fudan.edu.cn)

Monoamine neurotransmitters such as serotonin and dopamine are loaded by vesicular monoamine transporter 2 (VMAT2) into synaptic vesicles for storage and subsequent release in neurons. Impaired VMAT2 function underlies various neuropsychiatric diseases. VMAT2 inhibitors reserpine and tetrabenazine are used to treat hypertension, movement disorders associated with Huntington’s Disease and Tardive Dyskinesia. Despite its physiological and pharmacological significance, the structural basis underlying VMAT2 substrate recognition and its inhibition by various inhibitors remains unknown. Here we present cryo-EM structures of human apo VMAT2 in addition to states bound to serotonin, tetrabenazine, and reserpine. These structures collectively capture three states, namely the lumen-facing, occluded, and cytosol-facing conformations. Notably, tetrabenazine induces a substantial rearrangement of TM2 and TM7, extending beyond the typical rocker-switch movement. These functionally dynamic snapshots, complemented by biochemical analysis, unveil the essential components responsible for ligand recognition, elucidate the proton-driven exchange cycle, and provide a framework to design improved pharmaceutics targeting VMAT2.

https://doi.org/10.1038/s41422-023-00906-z

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