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- EMDB-62498: Cryo-EM structure of human VMAT2 in complex with Tetrabenazine -

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Basic information

Entry
Database: EMDB / ID: EMD-62498
TitleCryo-EM structure of human VMAT2 in complex with Tetrabenazine
Map data
Sample
  • Complex: VMAT2
    • Protein or peptide: Soluble cytochrome b562,Synaptic vesicular amine transporter
  • Ligand: (3S,5R,11bS)-9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one
Keywordstransporter / VMAT2 / MEMBRANE PROTEIN
Function / homology
Function and homology information


serotonin secretion by mast cell / somato-dendritic dopamine secretion / histamine uptake / neurotransmitter loading into synaptic vesicle / monoamine:proton antiporter activity / aminergic neurotransmitter loading into synaptic vesicle / clathrin-sculpted monoamine transport vesicle membrane / Serotonin Neurotransmitter Release Cycle / serotonin:sodium:chloride symporter activity / Dopamine Neurotransmitter Release Cycle ...serotonin secretion by mast cell / somato-dendritic dopamine secretion / histamine uptake / neurotransmitter loading into synaptic vesicle / monoamine:proton antiporter activity / aminergic neurotransmitter loading into synaptic vesicle / clathrin-sculpted monoamine transport vesicle membrane / Serotonin Neurotransmitter Release Cycle / serotonin:sodium:chloride symporter activity / Dopamine Neurotransmitter Release Cycle / Norepinephrine Neurotransmitter Release Cycle / serotonin uptake / dopamine transport / dopaminergic synapse / histamine secretion by mast cell / monoamine transmembrane transporter activity / monoamine transport / Na+/Cl- dependent neurotransmitter transporters / neurotransmitter transport / negative regulation of reactive oxygen species biosynthetic process / response to amphetamine / secretory granule membrane / post-embryonic development / locomotory behavior / electron transport chain / terminal bouton / response to toxic substance / synaptic vesicle membrane / synaptic vesicle / chemical synaptic transmission / periplasmic space / electron transfer activity / iron ion binding / axon / intracellular membrane-bounded organelle / heme binding / centrosome / dendrite / membrane / plasma membrane
Similarity search - Function
: / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / Cytochrome b562 / Cytochrome b562 / MFS transporter superfamily / Cytochrome c/b562
Similarity search - Domain/homology
Soluble cytochrome b562 / Synaptic vesicular amine transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.28 Å
AuthorsWei F / Zhang W / Zhang Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2025
Title: Drug inhibition and substrate transport mechanisms of human VMAT2.
Authors: 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 ...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.
History
DepositionNov 25, 2024-
Header (metadata) releaseJan 15, 2025-
Map releaseJan 15, 2025-
UpdateJan 15, 2025-
Current statusJan 15, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_62498.png

Downloads & links

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Map

FileDownload / File: emd_62498.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 256 pix.
= 238.592 Å		0.93 Å/pix.
x 256 pix.
= 238.592 Å		0.93 Å/pix.
x 256 pix.
= 238.592 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.932 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.18
Minimum - Maximum-2.512998 - 3.6624355
Average (Standard dev.)0.00038316767 (±0.074756175)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 238.592 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_62498_half_map_1.map
Projections & Slices
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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_62498_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : VMAT2

EntireName: VMAT2
Components
  • Complex: VMAT2
    • Protein or peptide: Soluble cytochrome b562,Synaptic vesicular amine transporter
  • Ligand: (3S,5R,11bS)-9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one

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Supramolecule #1: VMAT2

SupramoleculeName: VMAT2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Soluble cytochrome b562,Synaptic vesicular amine transporter

MacromoleculeName: Soluble cytochrome b562,Synaptic vesicular amine transporter
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 69.12707 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MADLEDNWET LNDNLKVIEK ADNAAQVKDA LTKMRAAALD AQKATPPKLE DKSPDSPEMK DFRHGFDILV GQIDDALKLA NEGKVKEAQ AAAEQLKTTR NAYIQKYLLQ ESRRSRKLIL FIVFLALLLD NMLLTVVVPI IPSYLYSIKH EKNATEIQTA R PVHTASIS ...String:
MADLEDNWET LNDNLKVIEK ADNAAQVKDA LTKMRAAALD AQKATPPKLE DKSPDSPEMK DFRHGFDILV GQIDDALKLA NEGKVKEAQ AAAEQLKTTR NAYIQKYLLQ ESRRSRKLIL FIVFLALLLD NMLLTVVVPI IPSYLYSIKH EKNATEIQTA R PVHTASIS DSFQSIFSYY DNSTMVTGNA TRDLTLHQTA TQHMVTNASA VPSDCPSEDK DLLNENVQVG LLFASKATVQ LI TNPFIGL LTNRIGYPIP IFAGFCIMFV STIMFAFSSS YAFLLIARSL QGIGSSCSSV AGMGMLASVY TDDEERGNVM GIA LGGLAM GVLVGPPFGS VLYEFVGKTA PFLVLAALVL LDGAIQLFVL QPSRVQPESQ KGTPLTTLLK DPYILIAAGS ICFA NMGIA MLEPALPIWM METMCSRKWQ LGVAFLPASI SYLIGTNIFG ILAHKMGRWL CALLGMIIVG VSILCIPFAK NIYGL IAPN FGVGFAIGMV DSSMMPIMGY LVDLRHVSVY GSVYAIADVA FCMGYAIGPS AGGAIAKAIG FPWLMTIIGI IDILFA PLC FFLRSPPAKE EKMAILMDHN CPIKTKMYTQ NNIQSYPIGE DEESESDHHH HHHHHHHGSV EDYKDDDDK

UniProtKB: Soluble cytochrome b562, Synaptic vesicular amine transporter

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Macromolecule #2: (3S,5R,11bS)-9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexa...

MacromoleculeName: (3S,5R,11bS)-9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one
type: ligand / ID: 2 / Number of copies: 1 / Formula: EBZ
Molecular weightTheoretical: 317.423 Da
Chemical component information

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

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration10 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 281 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 48.23 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.9 µm / Nominal magnification: 130000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.28 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 274059
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
FSC plot (resolution estimation)

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