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Open data
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Basic information
Entry | Database: PDB / ID: 8tgn | ||||||
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Title | VMAT1 dimer with serotonin and reserpine | ||||||
![]() | Chromaffin granule amine transporter | ||||||
![]() | MEMBRANE PROTEIN / VMAT / SLC18 / vascular monoamine transporter / monoamines / neurotransmitters / serotonin | ||||||
Function / homology | ![]() monoamine:proton antiporter activity / dopamine uptake / aminergic neurotransmitter loading into synaptic vesicle / norepinephrine uptake / clathrin-sculpted monoamine transport vesicle membrane / serotonin:sodium:chloride symporter activity / serotonin uptake / monoamine transmembrane transporter activity / Na+/Cl- dependent neurotransmitter transporters / monoamine transport ...monoamine:proton antiporter activity / dopamine uptake / aminergic neurotransmitter loading into synaptic vesicle / norepinephrine uptake / clathrin-sculpted monoamine transport vesicle membrane / serotonin:sodium:chloride symporter activity / serotonin uptake / monoamine transmembrane transporter activity / Na+/Cl- dependent neurotransmitter transporters / monoamine transport / xenobiotic transmembrane transporter activity / secretory granule membrane / terminal bouton / synaptic vesicle membrane / presynapse / endoplasmic reticulum membrane Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å | ||||||
![]() | Ye, J. / Liu, B. / Li, W. | ||||||
Funding support | ![]()
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![]() | ![]() 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. | ||||||
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 154.9 KB | Display | ![]() |
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PDB format | ![]() | 119.5 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 41242MC ![]() 8tggC ![]() 8tghC ![]() 8tgiC ![]() 8tgjC ![]() 8tgkC ![]() 8tglC ![]() 8tgmC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 50565.641 Da / Num. of mol.: 2 / Mutation: residues 69-123 deleted Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() #2: Chemical | ChemComp-SRO / | #3: Chemical | ChemComp-YHR / | Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: VMAT1 dimer with serotonin and reserpine / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
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Molecular weight | Value: 0.1052 MDa / Experimental value: NO |
Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() |
Buffer solution | pH: 8 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3 |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Microscopy | Model: TFS GLACIOS |
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Electron gun | Electron source: ![]() |
Electron lens | Mode: 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 holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 77.2 K / Temperature (min): 63 K |
Image recording | Average 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 software | Name: PHENIX / Version: 1.20.1_4487: / Category: model refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 151472 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
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