8WLK

Cryo-EM structure of human VMAT2 in presence of Tetrabenazine, determined in an outward-facing conformation

8WLK の概要

• エントリーDOI: 10.2210/pdb8wlk/pdb
• EMDBエントリー: 37622
• 分子名称: Synaptic vesicular amine transporter, (3S,5R,11bS)-9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one (2 entities in total)
• 機能のキーワード: human vmat2, tetrabenazine, outward-facing conformation, transport protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 54140.61

構造登録者

Qu, Q.,Wang, Y.,Zhou, Z. (登録日: 2023-09-30, 公開日: 2024-06-12, 最終更新日: 2025-07-02)

主引用文献

Wang, Y.,Zhang, P.,Chao, Y.,Zhu, Z.,Yang, C.,Zhou, Z.,Li, Y.,Long, Y.,Liu, Y.,Li, D.,Wang, S.,Qu, Q.
Transport and inhibition mechanism for VMAT2-mediated synaptic vesicle loading of monoamines.
Cell Res., 34:47-57, 2024

PubMed Abstract: 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.

PubMed: 38163846
DOI: 10.1038/s41422-023-00906-z

実験手法

ELECTRON MICROSCOPY (3.37 Å)