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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·2024·eLife
DOI 10.7554/elife.91973

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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-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.

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Metadata

Authors
Dalton, M. P., Cheng, M. H., Bahar, I., & Coleman, J. A.
Affiliations
  • University of Pittsburgh (US)
  • Laufer Center for Physical and Quantitative Biology, and Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University
Corresponding author
Coleman, Jonathan A
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2024-03-22
Volume
12
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.91973
OpenAlex
W4387693883
Cited by
15
References
1
Citations by year
2026: 3 · 2025: 7 · 2024: 5
FWCI
1.11
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
Funders
  • National Institute of Neurological Disorders and Stroke (1R01NS134558)
  • National Institute of General Medical Sciences (1R01GM139297)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
vesicular monoamine transporter 2, tetrabenazine, vesicular monoamine transporter, non-competitive inhibition, monoamine transport, protein structure, Huntington's disease, Parkinson's disease, cryo-EM structure
MeSH terms
Humans, Huntington Disease, Protons, Tetrabenazine, Cryoelectron Microscopy, Vesicular Monoamine Transport Proteins

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