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Nature Communications

Nature Communications

IF: 14.7
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Drug inhibition and substrate transport mechanisms of human VMAT2

Published:2 January 2025 DOI: 10.1038/s41467-024-55361-0 PMID: 39747030
Feiwen Wei,?Huihui Liu,?Wei Zhang,?Jufang Wang,?Yanqing Zhang

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.

Substances (12)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Tetrabenazine 58-46-8 C19H27NO3 264 suppliers $29.00-$1990.00
Tetrabenazine 58-46-8 C19H27NO3 264 suppliers $29.00-$1990.00
Tetrabenazine 58-46-8 C19H27NO3 264 suppliers $29.00-$1990.00
Tetrabenazine 58-46-8 C19H27NO3 264 suppliers $29.00-$1990.00
5-Hydroxytryptamine 50-67-9 C10H12N2O 190 suppliers $25.00-$2570.00
5-Hydroxytryptamine 50-67-9 C10H12N2O 190 suppliers $25.00-$2570.00
5-Hydroxytryptamine 50-67-9 C10H12N2O 190 suppliers $25.00-$2570.00
5-Hydroxytryptamine 50-67-9 C10H12N2O 190 suppliers $25.00-$2570.00
FFN 206 DIHYDROCHLORIDE 1883548-88-6 C12H15ClN2O2 15 suppliers $84.00-$2385.00
FFN 206 DIHYDROCHLORIDE 1883548-88-6 C12H15ClN2O2 15 suppliers $84.00-$2385.00

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