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TitleDrug inhibition and substrate transport mechanisms of human VMAT2.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 323, Year 2025
Publish dateJan 2, 2025
AuthorsFeiwen Wei / Huihui Liu / Wei Zhang / Jufang Wang / Yanqing Zhang /
PubMed AbstractVesicular monoamine transporter 2 (VMAT2) is crucial for packaging monoamine neurotransmitters into synaptic vesicles, with their dysregulation linked to schizophrenia, mood disorders, and ...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.
External linksNat Commun / PubMed:39747030 / PubMed Central
MethodsEM (single particle)
Resolution2.98 - 3.38 Å
Structure data

38038

8x3k

EMDB-38038, PDB-8x3k:
Cryo-EM structure of human VMAT2 in complex with serotonin.
Method: EM (single particle) / Resolution: 2.98 Å

62497

9kq8

EMDB-62497, PDB-9kq8:
Cryo-EM structure of human VMAT2 in complex with valbenazine
Method: EM (single particle) / Resolution: 3.38 Å

62498

9kqa

EMDB-62498, PDB-9kqa:
Cryo-EM structure of human VMAT2 in complex with Tetrabenazine
Method: EM (single particle) / Resolution: 3.28 Å

62501

9kqe

EMDB-62501, PDB-9kqe:
Cryo-EM structure of human VMAT2 in complex with dopamine.
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-SRO:
SEROTONIN / neurotransmitter*YM


ChemComp, No image

ChemComp-XW7:
Unknown entry

ChemComp-EBZ:
(3S,5R,11bS)-9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one

ChemComp-LDP:
L-DOPAMINE / medication*YM

Source
  • homo sapiens (human)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / transporter / VMAT2

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