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- PDB-8tgn: VMAT1 dimer with serotonin and reserpine -

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Basic information

Entry
Database: PDB / ID: 8tgn
TitleVMAT1 dimer with serotonin and reserpine
ComponentsChromaffin granule amine transporter
KeywordsMEMBRANE PROTEIN / VMAT / SLC18 / vascular monoamine transporter / monoamines / neurotransmitters / serotonin
Function / homology
Function and homology information


dopamine uptake / monoamine:proton antiporter activity / norepinephrine uptake / aminergic neurotransmitter loading into synaptic vesicle / clathrin-sculpted monoamine transport vesicle membrane / serotonin:sodium:chloride symporter activity / serotonin uptake / monoamine transmembrane transporter activity / monoamine transport / Na+/Cl- dependent neurotransmitter transporters ...dopamine uptake / monoamine:proton antiporter activity / norepinephrine uptake / aminergic neurotransmitter loading into synaptic vesicle / clathrin-sculpted monoamine transport vesicle membrane / serotonin:sodium:chloride symporter activity / serotonin uptake / monoamine transmembrane transporter activity / monoamine transport / Na+/Cl- dependent neurotransmitter transporters / 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
SEROTONIN / reserpine / Chromaffin granule amine transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsYe, J. / Liu, B. / Li, W.
Funding support United States, 1items
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, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 20, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 10, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.2May 15, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Chromaffin granule amine transporter
B: Chromaffin granule amine transporter
hetero molecules


Theoretical massNumber of molelcules
Total (without water)101,9164
Polymers101,1312
Non-polymers7852
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 Chromaffin granule amine transporter / Solute carrier family 18 member 1 / Vesicular amine transporter 1 / VAT1


Mass: 50565.641 Da / Num. of mol.: 2 / Mutation: residues 69-123 deleted
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC18A1, VAT1, VMAT1 / Production host: Komagataella pastoris (fungus) / References: UniProt: P54219
#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
#3: Chemical ChemComp-YHR / reserpine / methyl (4R)-11,17beta-dimethoxy-18beta-[(3,4,5-trimethoxybenzoyl)oxy]-3beta,20alpha-yohimban-16beta-carboxylate


Mass: 608.679 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H40N2O9 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: VMAT1 dimer with serotonin and reserpine / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.1052 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Komagataella pastoris (fungus)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 150000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 77.2 K / Temperature (min): 63 K
Image recordingAverage exposure time: 9.6 sec. / Electron dose: 45.22 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4680

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 151472 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0045948
ELECTRON MICROSCOPYf_angle_d0.8538101
ELECTRON MICROSCOPYf_dihedral_angle_d5.981814
ELECTRON MICROSCOPYf_chiral_restr0.046971
ELECTRON MICROSCOPYf_plane_restr0.008987

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