ArticleNature communications2025
Drug inhibition and substrate transport mechanisms of human VMAT2.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- The genetic overlap between schizophrenia and major depression with cognitive function.Molecular psychiatry · 2026Article
- Dopamine-Derived Oxidative Stress in Attention-Deficit/Hyperactivity Disorder: A Narrative Review of Molecular Mechanisms, Neural Circuitry, and Therapeutic Implications.Antioxidants (Basel, Switzerland) · 2026Review
- Monoaminylation in Human Health and Disease: State of the Field, Challenges, and Emerging Directions.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- The contribution of phenolic endocrine-disrupting chemicals to breast cancer risk: A comprehensive bioinformatics analysis.Scientific reports · 2026Article
- Evaluation of the Relationship between Vesicular Monoamine Transporter 2 (VMAT2) Inhibition and Neurologic Adverse Events in Approved Drugs.ACS pharmacology & translational science · 2026Article
- Deutetrabenazine in Hyperkinetic Movement Disorders: VMAT2 Modulation From Choreiform Disorders to Hyperkinetic Dystonic Syndromes.Journal of central nervous system disease · 2026Review
- Design and Optimization of BRIL Fusion Constructs for Membrane Protein Cryo-EM Studies.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Pathogenic mechanism underlying parkinsonism induced by neurotoxicants (MPTP and 6-hydroxydopamine) and α-synuclein: a unifying hypothesis.Journal of molecular cell biology · 2025Review
- Article
- Predictive Value of Perivascular Space Network and Choroid Plexus for Levodopa Responsiveness in Parkinson's Disease.European journal of neurology · 2025Article
Corrections and comments
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Authors and funding
5 authors.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.