9KQA

Cryo-EM structure of human VMAT2 in complex with Tetrabenazine

9KQA の概要

• エントリーDOI: 10.2210/pdb9kqa/pdb
• EMDBエントリー: 62498
• 分子名称: Soluble cytochrome b562,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: transporter, vmat2, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 69444.49

構造登録者

Wei, F.,Zhang, W.,Zhang, Y. (登録日: 2024-11-25, 公開日: 2025-01-15)

主引用文献

Wei, F.,Liu, H.,Zhang, W.,Wang, J.,Zhang, Y.
Drug inhibition and substrate transport mechanisms of human VMAT2.
Nat Commun, 16:323-323, 2025

PubMed Abstract: Vesicular monoamine transporter 2 (VMAT2) is crucial for packaging monoamine neurotransmitters into synaptic vesicles, with their dysregulation linked to schizophrenia, mood disorders, and Parkinson's disease. Tetrabenazine (TBZ) and valbenazine (VBZ), both FDA-approved VMAT2 inhibitors, are employed to treat chorea and tardive dyskinesia (TD). Our study presents the structures of VMAT2 bound to substrates serotonin (5-HT) and dopamine (DA), as well as the inhibitors TBZ and VBZ. Utilizing cryo-electron microscopy (cryo-EM), mutagenesis functional assays, and molecular dynamics (MD) simulations, we elucidate the mechanisms of substrate transport and drug inhibition. Our MD simulations indicate potential binding poses of substrate (5-HT) in both cytosol-facing and lumen-facing states, emphasizing the significance of protonation of key acidic residues for substrate release. We demonstrate that TBZ locks VMAT2 in a lumen-facing occluded state, while VBZ stabilizes it in a lumen-facing conformation. These insights enhance our understanding of VMAT2 function and provide valuable insights for the development of novel therapeutic strategies for psychiatric disorders.

PubMed: 39747030
DOI: 10.1038/s41467-024-55361-0

実験手法

ELECTRON MICROSCOPY (3.28 Å)