Transport and inhibition mechanisms of human VMAT2

• 成果类型: Article
• 署名作者: Wu, Di; Chen, Qihao; Yu, Zhuoya; Huang, Bo; Zhao, Jun; Wang, Yuhang; Su, Jiawei; Zhou, Feng; Yan, Rui; Li, Na; Zhao, Yan; Jiang, Daohua
• 署名单位: Chinese Academy of Sciences; Institute of Physics, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences; Institute of Biophysics, CAS; Peking University; Capital Medical University; Capital Medical University; Songshan Lake Materials Laboratory
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4546
• DOI: 10.1038/s41586-023-06926-4
• 发表日期: 2024-02-08
• 关键词: vesicular monoamine transporter; chromaffin granule; acetylcholine transporter; functional identification; catecholamine transporter; reserpine binding; active-transport; endocrine-cells; expression; tetrabenazine

摘要

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 angstrom, 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. Structures of human vesicular monoamine transporter 2 in complexes with serotonin and three clinical drugs provide insights into the structural basis for serotonin transport and inhibition of transporter activity by the drugs.