Transport and inhibition mechanisms of human VMAT2.

Autor: Wu D; Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China.; University of Chinese Academy of Sciences, Beijing, China., Chen Q; University of Chinese Academy of Sciences, Beijing, China.; Key Laboratory of Biomacromolecules, Chinese Academy of Sciences, National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China., Yu Z; University of Chinese Academy of Sciences, Beijing, China.; Key Laboratory of Biomacromolecules, Chinese Academy of Sciences, National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China., Huang B; Beijing StoneWise Technology, Beijing, China., Zhao J; Peking University Institute of Advanced Agricultural Sciences, Shandong Laboratory of Advanced Agricultural Sciences at Weifang, Weifang, China., Wang Y; University of Chinese Academy of Sciences, Beijing, China.; Key Laboratory of Biomacromolecules, Chinese Academy of Sciences, National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China., Su J; University of Chinese Academy of Sciences, Beijing, China.; Key Laboratory of Biomacromolecules, Chinese Academy of Sciences, National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China., Zhou F; Beijing StoneWise Technology, Beijing, China., Yan R; Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China., Li N; Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China., Zhao Y; University of Chinese Academy of Sciences, Beijing, China. zhaoy@ibp.ac.cn.; Key Laboratory of Biomacromolecules, Chinese Academy of Sciences, National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. zhaoy@ibp.ac.cn., Jiang D; Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China. jiangdh@iphy.ac.cn.; University of Chinese Academy of Sciences, Beijing, China. jiangdh@iphy.ac.cn.; Songshan Lake Materials Laboratory, Dongguan, China. jiangdh@iphy.ac.cn.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Feb; Vol. 626 (7998), pp. 427-434. Date of Electronic Publication: 2023 Dec 11.
DOI: 10.1038/s41586-023-06926-4
Abstrakt: Vesicular monoamine transporter 2 (VMAT2) accumulates monoamines in presynaptic vesicles for storage and exocytotic release, and has a vital role in monoaminergic neurotransmission 1-3 . Dysfunction of monoaminergic systems causes many neurological and psychiatric disorders, including Parkinson's disease, hyperkinetic movement disorders and depression 4-6 . Suppressing VMAT2 with reserpine and tetrabenazine alleviates symptoms of hypertension and Huntington's disease 7,8 , 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.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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