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- EMDB-37622: Cryo-EM structure of human VMAT2 in presence of Tetrabenazine, de... -

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Basic information

Entry
Database: EMDB / ID: EMD-37622
TitleCryo-EM structure of human VMAT2 in presence of Tetrabenazine, determined in an outward-facing conformation
Map data
Sample
  • Complex: Complex of vesicular Monoamine Transporter 2 with Tetrabenazine
    • Protein or peptide: 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
KeywordsHuman VMAT2 / Tetrabenazine / outward-facing conformation / TRANSPORT PROTEIN
Function / homology
Function and homology information


serotonin secretion by mast cell / somato-dendritic dopamine secretion / histamine uptake / aminergic neurotransmitter loading into synaptic vesicle / neurotransmitter loading into synaptic vesicle / monoamine:proton antiporter activity / 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 / aminergic neurotransmitter loading into synaptic vesicle / neurotransmitter loading into synaptic vesicle / monoamine:proton antiporter activity / 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 / histamine secretion by mast cell / monoamine transmembrane transporter activity / dopaminergic synapse / 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 / response to toxic substance / terminal bouton / synaptic vesicle membrane / synaptic vesicle / chemical synaptic transmission / axon / intracellular membrane-bounded organelle / dendrite / centrosome / membrane / plasma membrane
Similarity search - Function
: / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Synaptic vesicular amine transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.37 Å
AuthorsQu Q / Wang Y / Zhou Z
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32171194 China
CitationJournal: Cell Res / Year: 2024
Title: Transport and inhibition mechanism for VMAT2-mediated synaptic vesicle loading of monoamines.
Authors: Yuwei Wang / Pei Zhang / Yulin Chao / Zhini Zhu / Chuanhui Yang / Zixuan Zhou / Yaohui Li / Yonghui Long / Yuehua Liu / Dianfan Li / Sheng Wang / Qianhui Qu /
Abstract: Monoamine neurotransmitters such as serotonin and dopamine are loaded by vesicular monoamine transporter 2 (VMAT2) into synaptic vesicles for storage and subsequent release in neurons. Impaired VMAT2 ...Monoamine neurotransmitters such as serotonin and dopamine are loaded by vesicular monoamine transporter 2 (VMAT2) into synaptic vesicles for storage and subsequent release in neurons. Impaired VMAT2 function underlies various neuropsychiatric diseases. VMAT2 inhibitors reserpine and tetrabenazine are used to treat hypertension, movement disorders associated with Huntington's Disease and Tardive Dyskinesia. Despite its physiological and pharmacological significance, the structural basis underlying VMAT2 substrate recognition and its inhibition by various inhibitors remains unknown. Here we present cryo-EM structures of human apo VMAT2 in addition to states bound to serotonin, tetrabenazine, and reserpine. These structures collectively capture three states, namely the lumen-facing, occluded, and cytosol-facing conformations. Notably, tetrabenazine induces a substantial rearrangement of TM2 and TM7, extending beyond the typical rocker-switch movement. These functionally dynamic snapshots, complemented by biochemical analysis, unveil the essential components responsible for ligand recognition, elucidate the proton-driven exchange cycle, and provide a framework to design improved pharmaceutics targeting VMAT2.
History
DepositionSep 30, 2023-
Header (metadata) releaseJun 12, 2024-
Map releaseJun 12, 2024-
UpdateJul 2, 2025-
Current statusJul 2, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37622.png

Downloads & links

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Map

FileDownload / File: emd_37622.map.gz / Format: CCP4 / Size: 40.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 220 pix.
= 205.04 Å		0.93 Å/pix.
x 220 pix.
= 205.04 Å		0.93 Å/pix.
x 220 pix.
= 205.04 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: 0.22
Minimum - Maximum-2.9573522 - 3.4357934
Average (Standard dev.)-0.00060639175 (±0.09404977)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions220220220
Spacing220220220
CellA=B=C: 205.04 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_37622_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_37622_half_map_2.map
Projections & Slices
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Sample components

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Entire : Complex of vesicular Monoamine Transporter 2 with Tetrabenazine

EntireName: Complex of vesicular Monoamine Transporter 2 with Tetrabenazine
Components
  • Complex: Complex of vesicular Monoamine Transporter 2 with Tetrabenazine
    • Protein or peptide: 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: Complex of vesicular Monoamine Transporter 2 with Tetrabenazine

SupramoleculeName: Complex of vesicular Monoamine Transporter 2 with Tetrabenazine
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Synaptic vesicular amine transporter

MacromoleculeName: Synaptic vesicular amine transporter / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 53.823184 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MALSELALVR WLQESRRSRK LILFIVFLAL LLDNMLLTVV VPIIPSYLYS IKHEKNATEI QTARPVHTAS ISDSFQSIFS YYDNSTMVT GNATRDLTLH QTATQHMVTN ASAVPSDCPS EDKDLLNENV QVGLLFASKA TVQLITNPFI GLLTNRIGYP I PIFAGFCI ...String:
MALSELALVR WLQESRRSRK LILFIVFLAL LLDNMLLTVV VPIIPSYLYS IKHEKNATEI QTARPVHTAS ISDSFQSIFS YYDNSTMVT GNATRDLTLH QTATQHMVTN ASAVPSDCPS EDKDLLNENV QVGLLFASKA TVQLITNPFI GLLTNRIGYP I PIFAGFCI MFVSTIMFAF SSSYAFLLIA RSLQGIGSSC SSVAGMGMLA SVYTDDEERG NVMGIALGGL AMGVLVGPPF GS VLYEFVG KTAPFLVLAA LVLLDGAIQL FVLQPSRVQP ESQKGTPLTT LLKDPYILIA AGSICFANMG IAMLEPALPI WMM ETMCSR KWQLGVAFLP ASISYLIGTN IFGILAHKMG RWLCALLGMI IVGVSILCIP FAKNIYGLIA PNFGVGFAIG MVDS SMMPI MGYLVDLRHV SVYGSVYAIA DVAFCMGYAI GPSAGGAIAK AIGFPWLMTI IGIIDILFAP LCFFLRSPPS RLEEE LRRR TEGGSSDLEV LFQ

UniProtKB: 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

BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 50 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 260.0 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.37 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 335823
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-8wlk:
Cryo-EM structure of human VMAT2 in presence of Tetrabenazine, determined in an outward-facing conformation

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