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- EMDB-36640: Human VMAT2 complex with reserpine -

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Basic information

Entry
Database: EMDB / ID: EMD-36640
TitleHuman VMAT2 complex with reserpine
Map data
Sample
  • Complex: transporterA
    • Protein or peptide: Synaptic vesicular amine transporter
  • Ligand: reserpine
KeywordstransporterA / TRANSPORT 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.52 Å
AuthorsJiang DH / Wu D
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32271272 China
CitationJournal: Nature / Year: 2024
Title: Transport and inhibition mechanisms of human VMAT2.
Authors: Di Wu / Qihao Chen / Zhuoya Yu / Bo Huang / Jun Zhao / Yuhang Wang / Jiawei Su / Feng Zhou / Rui Yan / Na Li / Yan Zhao / Daohua Jiang /
Abstract: Vesicular monoamine transporter 2 (VMAT2) accumulates monoamines in presynaptic vesicles for storage and exocytotic release, and has a vital role in monoaminergic neurotransmission. Dysfunction of ...Vesicular monoamine transporter 2 (VMAT2) accumulates monoamines in presynaptic vesicles for storage and exocytotic release, and has a vital role in monoaminergic neurotransmission. Dysfunction of monoaminergic systems causes many neurological and psychiatric disorders, including Parkinson's disease, hyperkinetic movement disorders and depression. Suppressing VMAT2 with reserpine and tetrabenazine alleviates symptoms of hypertension and Huntington's disease, respectively. Here we describe cryo-electron microscopy structures of human VMAT2 complexed with serotonin and three clinical drugs at 3.5-2.8 Å, demonstrating the structural basis for transport and inhibition. Reserpine and ketanserin occupy the substrate-binding pocket and lock VMAT2 in cytoplasm-facing and lumen-facing states, respectively, whereas tetrabenazine binds in a VMAT2-specific pocket and traps VMAT2 in an occluded state. The structures in three distinct states also reveal the structural basis of the VMAT2 transport cycle. Our study establishes a structural foundation for the mechanistic understanding of substrate recognition, transport, drug inhibition and pharmacology of VMAT2 while shedding light on the rational design of potential therapeutic agents.
History
DepositionJun 21, 2023-
Header (metadata) releaseNov 29, 2023-
Map releaseNov 29, 2023-
UpdateFeb 21, 2024-
Current statusFeb 21, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36640.png

Downloads & links

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Map

FileDownload / File: emd_36640.map.gz / Format: CCP4 / Size: 64 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.)
1.04 Å/pix.
x 256 pix.
= 266.24 Å		1.04 Å/pix.
x 256 pix.
= 266.24 Å		1.04 Å/pix.
x 256 pix.
= 266.24 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.04 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.599
Minimum - Maximum-2.2754354 - 3.7295678
Average (Standard dev.)0.00023538046 (±0.06779394)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 266.24 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_36640_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_36640_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : transporterA

EntireName: transporterA
Components
  • Complex: transporterA
    • Protein or peptide: Synaptic vesicular amine transporter
  • Ligand: reserpine

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Supramolecule #1: transporterA

SupramoleculeName: transporterA / 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: 49.086848 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SRKLILFIVF LALLLDNMLL TVVVPIIPSY LYSIKHEKNA TEIQTARPVH TASISDSFQS IFSYYDNSTM VTGNATRDLT LHQTATQHM VTNASAVPSD CPSEDKDLLN ENVQVGLLFA SKATVQLITN PFIGLLTNRI GYPIPIFAGF CIMFVSTIMF A FSSSYAFL ...String:
SRKLILFIVF LALLLDNMLL TVVVPIIPSY LYSIKHEKNA TEIQTARPVH TASISDSFQS IFSYYDNSTM VTGNATRDLT LHQTATQHM VTNASAVPSD CPSEDKDLLN ENVQVGLLFA SKATVQLITN PFIGLLTNRI GYPIPIFAGF CIMFVSTIMF A FSSSYAFL LIARSLQGIG SSCSSVAGMG MLASVYTDDE ERGNVMGIAL GGLAMGVLVG PPFGSVLYEF VGKTAPFLVL AA LVLLDGA IQLFVLQPSR VQPESQKGTP LTTLLKDPYI LIAAGSICFA NMGIAMLEPA LPIWMMETMC SRKWQLGVAF LPA SISYLI GTNIFGILAH KMGRWLCALL GMIIVGVSIL CIPFAKNIYG LIAPNFGVGF AIGMVDSSMM PIMGYLVDLR HVSV YGSVY AIADVAFCMG YAIGPSAGGA IAKAIGFPWL MTIIGIIDIL FAPLCFFLRS PP

UniProtKB: Synaptic vesicular amine transporter

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Macromolecule #2: reserpine

MacromoleculeName: reserpine / type: ligand / ID: 2 / 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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.52 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 57349
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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