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- PDB-8wlm: Cryo-EM structure of human VMAT2 in presence of 5-HT, determined ... -

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Entry
Database: PDB / ID: 8wlm
TitleCryo-EM structure of human VMAT2 in presence of 5-HT, determined in an outward-facing conformation
ComponentsSynaptic vesicular amine transporter
KeywordsTRANSPORT PROTEIN / Human VMAT2 / 5-HT / outward-facing conformation
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
SEROTONIN / Synaptic vesicular amine transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.57 Å
AuthorsQu, Q. / Wang, Y. / Zhou, Z.
Funding support China, 1items
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, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 12, 2024Provider: repository / Type: Initial release
Revision 1.1Jul 2, 2025Group: Data collection / Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_entry_details
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Synaptic vesicular amine transporter
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,9992
Polymers53,8231
Non-polymers1761
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Synaptic vesicular amine transporter / Monoamine transporter / Solute carrier family 18 member 2 / Vesicular amine transporter 2 / ...Monoamine transporter / Solute carrier family 18 member 2 / Vesicular amine transporter 2 / Vesicular Monoamine Transporter 2 / VAT2


Mass: 53823.184 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC18A2, SVMT, VMAT2 / Cell (production host): 293F / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: Q05940
#2: Chemical ChemComp-SRO / SEROTONIN / 3-(2-AMINOETHYL)-1H-INDOL-5-OL


Mass: 176.215 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H12N2O / Feature type: SUBJECT OF INVESTIGATION / Comment: neurotransmitter*YM
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Complex of vesicular Monoamine Transporter 2 with 5-HT
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1500 nm / Cs: 2.7 mm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.19.2_4158: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.57 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 124189 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0042980
ELECTRON MICROSCOPYf_angle_d0.7654056
ELECTRON MICROSCOPYf_dihedral_angle_d4.29417
ELECTRON MICROSCOPYf_chiral_restr0.046492
ELECTRON MICROSCOPYf_plane_restr0.005502

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