Neurotransmitter recognition by human vesicular monoamine transporter 2.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
16 Sep 2024
16 Sep 2024
Historique:
received:
15
11
2023
accepted:
20
08
2024
medline:
17
9
2024
pubmed:
17
9
2024
entrez:
16
9
2024
Statut:
epublish
Résumé
Human vesicular monoamine transporter 2 (VMAT2), a member of the SLC18 family, plays a crucial role in regulating neurotransmitters in the brain by facilitating their uptake and storage within vesicles, preparing them for exocytotic release. Because of its central role in neurotransmitter signalling and neuroprotection, VMAT2 is a target for neurodegenerative diseases and movement disorders, with its inhibitor being used as therapeutics. Despite the importance of VMAT2 in pharmacophysiology, the molecular basis of VMAT2-mediated neurotransmitter transport and its inhibition remains unclear. Here we show the cryo-electron microscopy structure of VMAT2 in the substrate-free state, in complex with the neurotransmitter dopamine, and in complex with the inhibitor tetrabenazine. In addition to these structural determinations, monoamine uptake assays, mutational studies, and pKa value predictions were performed to characterize the dynamic changes in VMAT2 structure. These results provide a structural basis for understanding VMAT2-mediated vesicular transport of neurotransmitters and a platform for modulation of current inhibitor design.
Identifiants
pubmed: 39284862
doi: 10.1038/s41467-024-51960-z
pii: 10.1038/s41467-024-51960-z
doi:
Substances chimiques
Vesicular Monoamine Transport Proteins
0
SLC18A2 protein, human
0
Tetrabenazine
Z9O08YRN8O
Dopamine
VTD58H1Z2X
Neurotransmitter Agents
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7661Subventions
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 19H00923, 22KK0099, 23K06357
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP21am0101079, JP23ama121007, JP23ama121001, 23809479
Informations de copyright
© 2024. The Author(s).
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