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- EMDB-41235: VMAT1 dimer with MPP+ and reserpine -

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Basic information

Entry
Database: EMDB / ID: EMD-41235
TitleVMAT1 dimer with MPP+ and reserpine
Map dataVMAT1 dimer with MPP and reserpine
Sample
  • Complex: Complex of VMAT1 with MPP+ and Reserpine
    • Protein or peptide: Chromaffin granule amine transporter
  • Ligand: 1-methyl-4-phenylpyridin-1-ium
  • Ligand: reserpine
KeywordsVMAT / SLC18 / vascular monoamine transporter / monoamines / neurotransmitters / MPP+ / MEMBRANE PROTEIN
Function / homology
Function and homology information


norepinephrine uptake / monoamine:proton antiporter activity / aminergic neurotransmitter loading into synaptic vesicle / dopamine uptake / clathrin-sculpted monoamine transport vesicle membrane / serotonin:sodium:chloride symporter activity / Na+/Cl- dependent neurotransmitter transporters / monoamine transmembrane transporter activity / serotonin uptake / monoamine transport ...norepinephrine uptake / monoamine:proton antiporter activity / aminergic neurotransmitter loading into synaptic vesicle / dopamine uptake / clathrin-sculpted monoamine transport vesicle membrane / serotonin:sodium:chloride symporter activity / Na+/Cl- dependent neurotransmitter transporters / monoamine transmembrane transporter activity / serotonin uptake / monoamine transport / xenobiotic transmembrane transporter activity / secretory granule membrane / terminal bouton / synaptic vesicle membrane / presynapse / endoplasmic reticulum membrane
Similarity search - Function
Multidrug resistance protein / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Chromaffin granule amine transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsYe J / Liu B / Li W
Funding support United States, 1 items
OrganizationGrant numberCountry
American Heart AssociationEstablished Investigator Award United States
CitationJournal: Nature / Year: 2024
Title: Structural insights into vesicular monoamine storage and drug interactions.
Authors: Jin Ye / Huaping Chen / Kaituo Wang / Yi Wang / Aaron Ammerman / Samjhana Awasthi / Jinbin Xu / Bin Liu / Weikai Li /
Abstract: Biogenic monoamines-vital transmitters orchestrating neurological, endocrinal and immunological functions-are stored in secretory vesicles by vesicular monoamine transporters (VMATs) for controlled ...Biogenic monoamines-vital transmitters orchestrating neurological, endocrinal and immunological functions-are stored in secretory vesicles by vesicular monoamine transporters (VMATs) for controlled quantal release. Harnessing proton antiport, VMATs enrich monoamines around 10,000-fold and sequester neurotoxicants to protect neurons. VMATs are targeted by an arsenal of therapeutic drugs and imaging agents to treat and monitor neurodegenerative disorders, hypertension and drug addiction. However, the structural mechanisms underlying these actions remain unclear. Here we report eight cryo-electron microscopy structures of human VMAT1 in unbound form and in complex with four monoamines (dopamine, noradrenaline, serotonin and histamine), the Parkinsonism-inducing MPP, the psychostimulant amphetamine and the antihypertensive drug reserpine. Reserpine binding captures a cytoplasmic-open conformation, whereas the other structures show a lumenal-open conformation stabilized by extensive gating interactions. The favoured transition to this lumenal-open state contributes to monoamine accumulation, while protonation facilitates the cytoplasmic-open transition and concurrently prevents monoamine binding to avoid unintended depletion. Monoamines and neurotoxicants share a binding pocket that possesses polar sites for specificity and a wrist-and-fist shape for versatility. Variations in this pocket explain substrate preferences across the SLC18 family. Overall, these structural insights and supporting functional studies elucidate the mechanism of vesicular monoamine transport and provide the basis to develop therapeutics for neurodegenerative diseases and substance abuse.
History
DepositionJul 12, 2023-
Header (metadata) releaseMar 20, 2024-
Map releaseMar 20, 2024-
UpdateApr 10, 2024-
Current statusApr 10, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41235.png

Downloads & links

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Map

FileDownload / File: emd_41235.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationVMAT1 dimer with MPP and reserpine
Voxel sizeX=Y=Z: 0.88533 Å
Density
Contour LevelBy AUTHOR: 0.08
Minimum - Maximum-0.001683045 - 2.0044067
Average (Standard dev.)0.0006782008 (±0.019164009)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 283.30664 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: VMAT1 dimer with MPP and reserpine

Fileemd_41235_half_map_1.map
AnnotationVMAT1 dimer with MPP and reserpine
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: VMAT1 dimer with MPP and reserpine

Fileemd_41235_half_map_2.map
AnnotationVMAT1 dimer with MPP and reserpine
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of VMAT1 with MPP+ and Reserpine

EntireName: Complex of VMAT1 with MPP+ and Reserpine
Components
  • Complex: Complex of VMAT1 with MPP+ and Reserpine
    • Protein or peptide: Chromaffin granule amine transporter
  • Ligand: 1-methyl-4-phenylpyridin-1-ium
  • Ligand: reserpine

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Supramolecule #1: Complex of VMAT1 with MPP+ and Reserpine

SupramoleculeName: Complex of VMAT1 with MPP+ and Reserpine / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 105.2 KDa

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Macromolecule #1: Chromaffin granule amine transporter

MacromoleculeName: Chromaffin granule amine transporter / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 50.565641 KDa
Recombinant expressionOrganism: Komagataella pastoris (fungus)
SequenceString: MLRTILDAPQ RLLKEGRASR QLVLVVVFVA LLLDNMLFTV VVPIVPTFLY DMEFKEVNSS LHLGHAGSNC LQGTGFLEEE ITRVGVLFA SKAVMQLLVN PFVGPLTNRI GYHIPMFAGF VIMFLSTVMF AFSGTYTLLF VARTLQGIGS SFSSVAGLGM L ASVYTDDH ...String:
MLRTILDAPQ RLLKEGRASR QLVLVVVFVA LLLDNMLFTV VVPIVPTFLY DMEFKEVNSS LHLGHAGSNC LQGTGFLEEE ITRVGVLFA SKAVMQLLVN PFVGPLTNRI GYHIPMFAGF VIMFLSTVMF AFSGTYTLLF VARTLQGIGS SFSSVAGLGM L ASVYTDDH ERGRAMGTAL GGLALGLLVG APFGSVMYEF VGKSAPFLIL AFLALLDGAL QLCILQPSKV SPESAKGTPL FM LLKDPYI LVAAGSICFA NMGVAILEPT LPIWMMQTMC SPKWQLGLAF LPASVSYLIG TNLFGVLANK MGRWLCSLIG MLV VGTSLL CVPLAHNIFG LIGPNAGLGL AIGMVDSSMM PIMGHLVDLR HTSVYGSVYA IADVAFCMGF AIGPSTGGAI VKAI GFPWL MVITGVINIV YAPLCYYLRS PPAKEEKLAI LSQDCPMETR MYATQKPTKE FPLGEDSDEE PDHEE

UniProtKB: Chromaffin granule amine transporter, Chromaffin granule amine transporter

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Macromolecule #2: 1-methyl-4-phenylpyridin-1-ium

MacromoleculeName: 1-methyl-4-phenylpyridin-1-ium / type: ligand / ID: 2 / Number of copies: 1 / Formula: WRF
Molecular weightTheoretical: 170.23 Da
Chemical component information

ChemComp-WRF:
1-methyl-4-phenylpyridin-1-ium

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Macromolecule #3: reserpine

MacromoleculeName: reserpine / type: ligand / ID: 3 / Number of copies: 1 / Formula: YHR
Molecular weightTheoretical: 608.679 Da
Chemical component information

ChemComp-YHR:
reserpine

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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: 8
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 130000
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
TemperatureMin: 63.0 K / Max: 77.2 K
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 6112 / Average exposure time: 2.0 sec. / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Algorithm: SIMULTANEOUS ITERATIVE (SIRT) / Resolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 197772
FSC plot (resolution estimation)

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