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PreprintCited by 6Enzyme Structure and FunctionReceptor Mechanisms and SignalingNeuroscience and Neuropharmacology Research

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Structural mechanisms for VMAT2 inhibition by tetrabenazine

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Dalton, Michael P., Cheng, Mary Hongying, Bahar, Ivet, Coleman, Jonathan A.·2023·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2023.09.05.556211PMC PMC10508774

Preprint — published as 10.7554/elife.91973 · Paper page

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Abstract

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-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.

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Metadata

Authors
Dalton, M. P., Cheng, M. H., Bahar, I., & Coleman, J. A.
Affiliations
  • University of Pittsburgh (US)
  • Stony Brook School (US)
Corresponding author
Coleman, Jonathan A.
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2023-09-05
DOI
10.1101/2023.09.05.556211
PMC
PMC10508774
OpenAlex
W4386480750
Cited by
6
References
1
Citations by year
2026: 1 · 2025: 1 · 2024: 2 · 2023: 2
Type
posted content
Language
en
Open access
Licence
cc-by
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
Funders
  • National Institutes of Health (1s10od019995-01, 1s10od025009-01, 1r01ns134558-01)
  • National Institute of General Medical Sciences (R01GM139297, U24GM129547)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
vesicular monoamine transporter 2, tetrabenazine, vesicular monoamine transporter, non-competitive inhibition, cryo-EM structure, monoamine transport, conformational dynamics, Huntington's disease, Parkinson's disease

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