EMD-62501

Single-particle
3.0 Å
EMD-62501 Deposition: 25/11/2024
Map released: 15/01/2025
Last modified: 15/01/2025
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-62501

Cryo-EM structure of human VMAT2 in complex with dopamine.

EMD-62501

Single-particle
3.0 Å
EMD-62501 Deposition: 25/11/2024
Map released: 15/01/2025
Last modified: 15/01/2025
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: VMAT2
Fitted models: 9kqe (Avg. Q-score: 0.516)

Deposition Authors: Wei F , Zhang W, Zhang Y
Drug inhibition and substrate transport mechanisms of human VMAT2.
Wei F , Liu H , Zhang W, Wang J, Zhang Y
(2025) Nat Commun , 16 , 323 - 323
PUBMED: 39747030
DOI: doi:10.1038/s41467-024-55361-0
ISSN: 2041-1723
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.