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- EMDB-41067: Human VMAT2 in complex with reserpine -

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Basic information

Entry
Database: EMDB / ID: EMD-41067
TitleHuman VMAT2 in complex with reserpine
Map data
Sample
  • Complex: Human VMAT2 in complex with reserpine
    • Protein or peptide: Synaptic vesicular amine transporter
  • Ligand: reserpine
KeywordsMembrane protein / transporter
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: 3.17 Å
AuthorsPidathala S / Dai Y / Lee CH
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM143282 United States
CitationJournal: Nature / Year: 2023
Title: Mechanisms of neurotransmitter transport and drug inhibition in human VMAT2.
Authors: Shabareesh Pidathala / Shuyun Liao / Yaxin Dai / Xiao Li / Changkun Long / Chi-Lun Chang / Zhe Zhang / Chia-Hsueh Lee /
Abstract: Monoamine neurotransmitters such as dopamine and serotonin control important brain pathways, including movement, sleep, reward and mood. Dysfunction of monoaminergic circuits has been implicated in ...Monoamine neurotransmitters such as dopamine and serotonin control important brain pathways, including movement, sleep, reward and mood. Dysfunction of monoaminergic circuits has been implicated in various neurodegenerative and neuropsychiatric disorders. Vesicular monoamine transporters (VMATs) pack monoamines into vesicles for synaptic release and are essential to neurotransmission. VMATs are also therapeutic drug targets for a number of different conditions. Despite the importance of these transporters, the mechanisms of substrate transport and drug inhibition of VMATs have remained elusive. Here we report cryo-electron microscopy structures of the human vesicular monoamine transporter VMAT2 in complex with the antichorea drug tetrabenazine, the antihypertensive drug reserpine or the substrate serotonin. Remarkably, the two drugs use completely distinct inhibition mechanisms. Tetrabenazine binds VMAT2 in a lumen-facing conformation, locking the luminal gating lid in an occluded state to arrest the transport cycle. By contrast, reserpine binds in a cytoplasm-facing conformation, expanding the vestibule and blocking substrate access. Structural analyses of VMAT2 also reveal the conformational changes following transporter isomerization that drive substrate transport into the vesicle. These findings provide a structural framework for understanding the physiology and pharmacology of neurotransmitter packaging by synaptic vesicular transporters.
History
DepositionJun 15, 2023-
Header (metadata) releaseNov 1, 2023-
Map releaseNov 1, 2023-
UpdateDec 13, 2023-
Current statusDec 13, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41067.png

Downloads & links

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Map

FileDownload / File: emd_41067.map.gz / Format: CCP4 / Size: 216 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.)
0.65 Å/pix.
x 384 pix.
= 249.216 Å		0.65 Å/pix.
x 384 pix.
= 249.216 Å		0.65 Å/pix.
x 384 pix.
= 249.216 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.649 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.31
Minimum - Maximum-1.0401446 - 1.5238498
Average (Standard dev.)0.0007300267 (±0.025338816)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 249.216 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_41067_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: #1

Fileemd_41067_half_map_2.map
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Histogram

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Sample components

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Entire : Human VMAT2 in complex with reserpine

EntireName: Human VMAT2 in complex with reserpine
Components
  • Complex: Human VMAT2 in complex with reserpine
    • Protein or peptide: Synaptic vesicular amine transporter
  • Ligand: reserpine

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Supramolecule #1: Human VMAT2 in complex with reserpine

SupramoleculeName: Human VMAT2 in complex with reserpine / 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: 53.542777 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: RKLILFIVFL ALLLDNMLLT VVVPIIPSYL YSIKHEKNAT EIQTARPVHT ASISDSFQSI FSYYDNSTMV TGNATRDLTL HQTATQHMV TNASAVPSDC PSEDKDLLNE NVQVGLLFAS KATVQLITNP FIGLLTNRIG YPIPIFAGFC IMFVSTIMFA F SSSYAFLL ...String:
RKLILFIVFL ALLLDNMLLT VVVPIIPSYL YSIKHEKNAT EIQTARPVHT ASISDSFQSI FSYYDNSTMV TGNATRDLTL HQTATQHMV TNASAVPSDC PSEDKDLLNE NVQVGLLFAS KATVQLITNP FIGLLTNRIG YPIPIFAGFC IMFVSTIMFA F SSSYAFLL IARSLQGIGS SCSSVAGMGM LASVYTDDEE RGNVMGIALG GLAMGVLVGP PFGSVLYEFV GKTAPFLVLA AL VLLDGAI QLFVLQPSRV QPESQKGTPL TTLLKDPYIL IAAGSICFAN MGIAMLEPAL PIWMMETMCS RKWQLGVAFL PAS ISYLIG TNIFGILAHK MGRWLCALLG MIIVGVSILC IPFAKNIYGL IAPNFGVGFA IGMVDSSMMP IMGYLVDLRH VSVS GSVYA IADVAFCMGY AIGPSAGGAI AKAIGFPWLM TIIGIIDILF APLCFFLRSP PAKEEKMAIL MDHNCPIKTK MYTQN NIQS YPIGEDEESE SD

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: 7
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 65.7 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.17 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 222906
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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