Structural mechanisms for VMAT2 inhibition by tetrabenazine.
biochemistry
chemical biology
membrane transport
neurotransmitters
none
small-molecule inhibitors
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
22 Mar 2024
22 Mar 2024
Historique:
medline:
22
3
2024
pubmed:
22
3
2024
entrez:
22
3
2024
Statut:
epublish
Résumé
The vesicular monoamine transporter 2 (VMAT2) is a proton-dependent antiporter responsible for loading monoamine neurotransmitters into synaptic vesicles. Dysregulation of VMAT2 can lead to several neuropsychiatric disorders including Parkinson's disease and schizophrenia. Furthermore, drugs such as amphetamine and MDMA are known to act on VMAT2, exemplifying its role in the mechanisms of actions for drugs of abuse. Despite VMAT2's importance, there remains a critical lack of mechanistic understanding, largely driven by a lack of structural information. Here, we report a 3.1 Å resolution cryo-electron microscopy (cryo-EM) structure of VMAT2 complexed with tetrabenazine (TBZ), a non-competitive inhibitor used in the treatment of Huntington's chorea. We find TBZ interacts with residues in a central binding site, locking VMAT2 in an occluded conformation and providing a mechanistic basis for non-competitive inhibition. We further identify residues critical for cytosolic and lumenal gating, including a cluster of hydrophobic residues which are involved in a lumenal gating strategy. Our structure also highlights three distinct polar networks that may determine VMAT2 conformational dynamics and play a role in proton transduction. The structure elucidates mechanisms of VMAT2 inhibition and transport, providing insights into VMAT2 architecture, function, and the design of small-molecule therapeutics.
Identifiants
pubmed: 38517752
doi: 10.7554/eLife.91973
pii: 91973
doi:
pii:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NINDS NIH HHS
ID : 1R01NS134558
Pays : United States
Organisme : NIGMS NIH HHS
ID : 1R01GM139297
Pays : United States
Informations de copyright
© 2023, Dalton et al.
Déclaration de conflit d'intérêts
MD, MC, IB, JC No competing interests declared
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