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- EMDB-37775: Transporter bound with dopamine -

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ID or keywords:

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Basic information

Entry
Database: EMDB / ID: EMD-37775
TitleTransporter bound with dopamine
Map data
Sample
  • Complex: VMAT2-Fab0801 complex apo state
    • Protein or peptide: Synaptic vesicular amine transporter
    • Protein or peptide: FabL
    • Protein or peptide: FabH
  • Ligand: L-DOPAMINE
Keywordstransporter / MEMBRANE PROTEIN
Function / homology
Function and homology information


serotonin secretion by mast cell / sequestering of neurotransmitter / 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 ...serotonin secretion by mast cell / sequestering of neurotransmitter / 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 / monoamine transmembrane transporter activity / histamine secretion by mast cell / monoamine transport / Na+/Cl- dependent neurotransmitter transporters / neurotransmitter transport / negative regulation of reactive oxygen species biosynthetic process / response to amphetamine / post-embryonic development / secretory granule membrane / locomotory behavior / terminal bouton / response to toxic substance / synaptic vesicle membrane / synaptic vesicle / chemical synaptic transmission / axon / intracellular membrane-bounded organelle / centrosome / dendrite / 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) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsIm D / Iwata S
Funding support Japan, 1 items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS) Japan
CitationJournal: Nat Commun / Year: 2024
Title: Neurotransmitter recognition by human vesicular monoamine transporter 2.
Authors: Dohyun Im / Mika Jormakka / Narinobu Juge / Jun-Ichi Kishikawa / Takayuki Kato / Yukihiko Sugita / Takeshi Noda / Tomoko Uemura / Yuki Shiimura / Takaaki Miyaji / Hidetsugu Asada / So Iwata /
Abstract: Human vesicular monoamine transporter 2 (VMAT2), a member of the SLC18 family, plays a crucial role in regulating neurotransmitters in the brain by facilitating their uptake and storage within ...Human vesicular monoamine transporter 2 (VMAT2), a member of the SLC18 family, plays a crucial role in regulating neurotransmitters in the brain by facilitating their uptake and storage within vesicles, preparing them for exocytotic release. Because of its central role in neurotransmitter signalling and neuroprotection, VMAT2 is a target for neurodegenerative diseases and movement disorders, with its inhibitor being used as therapeutics. Despite the importance of VMAT2 in pharmacophysiology, the molecular basis of VMAT2-mediated neurotransmitter transport and its inhibition remains unclear. Here we show the cryo-electron microscopy structure of VMAT2 in the substrate-free state, in complex with the neurotransmitter dopamine, and in complex with the inhibitor tetrabenazine. In addition to these structural determinations, monoamine uptake assays, mutational studies, and pKa value predictions were performed to characterize the dynamic changes in VMAT2 structure. These results provide a structural basis for understanding VMAT2-mediated vesicular transport of neurotransmitters and a platform for modulation of current inhibitor design.
History
DepositionOct 13, 2023-
Header (metadata) releaseSep 25, 2024-
Map releaseSep 25, 2024-
UpdateNov 13, 2024-
Current statusNov 13, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37775.png

Downloads & links

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Map

FileDownload / File: emd_37775.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.88 Å/pix.
x 320 pix.
= 281.6 Å		0.88 Å/pix.
x 320 pix.
= 281.6 Å		0.88 Å/pix.
x 320 pix.
= 281.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.88 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 11.0
Minimum - Maximum-34.698900000000002 - 61.54166
Average (Standard dev.)-0.000000000005237 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 281.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : VMAT2-Fab0801 complex apo state

EntireName: VMAT2-Fab0801 complex apo state
Components
  • Complex: VMAT2-Fab0801 complex apo state
    • Protein or peptide: Synaptic vesicular amine transporter
    • Protein or peptide: FabL
    • Protein or peptide: FabH
  • Ligand: L-DOPAMINE

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Supramolecule #1: VMAT2-Fab0801 complex apo state

SupramoleculeName: VMAT2-Fab0801 complex apo state / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 90 KDa

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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: 55.749352 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
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 LCFFLRSPPA KEEKM AILM DHNCPIKTKM YTQNNIQSYP IGEDEESESD

UniProtKB: Synaptic vesicular amine transporter

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Macromolecule #2: FabL

MacromoleculeName: FabL / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 24.418936 KDa
SequenceString: AQAAELDIVM TQSQKFMSTS VGDRVSITCK ASQNVGTDVS WYQQKPGKSP KPLIYWASNR FTGVPDRFTG SRSGTDFTLT ISNVQSEDL ADYFCEQYSS YPLTFGAGTK LELKRADAAP TVSIFPPSSE QLTSGGASVV CFLNNFYPKD INVKWKIDGS E RQNGVLNS ...String:
AQAAELDIVM TQSQKFMSTS VGDRVSITCK ASQNVGTDVS WYQQKPGKSP KPLIYWASNR FTGVPDRFTG SRSGTDFTLT ISNVQSEDL ADYFCEQYSS YPLTFGAGTK LELKRADAAP TVSIFPPSSE QLTSGGASVV CFLNNFYPKD INVKWKIDGS E RQNGVLNS WTDQDSKDST YSMSSTLTLT KDEYERHNSY TCEATHKTST SPIVKSFNRN EC

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Macromolecule #3: FabH

MacromoleculeName: FabH / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 36.424773 KDa
SequenceString: GGSSRSSLEV KLQESGAELV KPGASVKLSC KASGYTFTSY WIDWVKQRPG QGLEWIGNIY PGNSSTNYNE KFKNKATLTV DTSSSTAYM QLSSLTSDDS AVYYCAREDY YDGTYVYYAM DFWGQGTSVT VSSAKTTAPS VYPLAPVCGD TSGSSVTLGC L VKGYFPEP ...String:
GGSSRSSLEV KLQESGAELV KPGASVKLSC KASGYTFTSY WIDWVKQRPG QGLEWIGNIY PGNSSTNYNE KFKNKATLTV DTSSSTAYM QLSSLTSDDS AVYYCAREDY YDGTYVYYAM DFWGQGTSVT VSSAKTTAPS VYPLAPVCGD TSGSSVTLGC L VKGYFPEP VTLTWNSGSL SSGVHTFPAV LQSDLYTLSS SVTVTSSTWP SQSITCNVAH PASSTKVDKK IEPRGPTIKP CP PCKCPAP NLLGGPSVFI FPPKIKDVLM ISLSPIVTCV VVDVSEDDPD VQISWFVNNV EVHTAQTQTH REDYNSTLRV VSA LPIQHQ DWMSGKEFKC

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Macromolecule #4: L-DOPAMINE

MacromoleculeName: L-DOPAMINE / type: ligand / ID: 4 / Number of copies: 1 / Formula: LDP
Molecular weightTheoretical: 153.178 Da
Chemical component information

ChemComp-LDP:
L-DOPAMINE / medication*YM

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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

Concentration5 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 281.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 65.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL / In silico model: AF2 model
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1297524
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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