+Open data
-Basic information
Entry | Database: PDB / ID: 8t6a | ||||||
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Title | Human VMAT2 in complex with reserpine | ||||||
Components | Synaptic vesicular amine transporter | ||||||
Keywords | MEMBRANE 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 / dopaminergic synapse / dopamine transport / monoamine transmembrane transporter activity / Na+/Cl- dependent neurotransmitter transporters / histamine secretion by mast cell / monoamine transport / neurotransmitter transport / negative regulation of reactive oxygen species biosynthetic process / response to amphetamine / secretory granule membrane / post-embryonic development / 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 | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.17 Å | ||||||
Authors | Pidathala, S. / Dai, Y. / Lee, C.H. | ||||||
Funding support | United States, 1items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8t6a.cif.gz | 88.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8t6a.ent.gz | 62.6 KB | Display | PDB format |
PDBx/mmJSON format | 8t6a.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8t6a_validation.pdf.gz | 1.5 MB | Display | wwPDB validaton report |
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Full document | 8t6a_full_validation.pdf.gz | 1.5 MB | Display | |
Data in XML | 8t6a_validation.xml.gz | 26.7 KB | Display | |
Data in CIF | 8t6a_validation.cif.gz | 35.3 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/t6/8t6a ftp://data.pdbj.org/pub/pdb/validation_reports/t6/8t6a | HTTPS FTP |
-Related structure data
Related structure data | 41067MC 8t69C 8t6bC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 53542.777 Da / Num. of mol.: 1 / Mutation: Y418S Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: SLC18A2, SVMT, VMAT2 / Production host: Homo sapiens (human) / References: UniProt: Q05940 |
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#2: Chemical | ChemComp-YHR / |
Has ligand of interest | Y |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Human VMAT2 in complex with reserpine / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 65.7 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
EM software | Name: PHENIX / Version: dev_4788: / Category: model refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.17 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 222906 / Symmetry type: POINT | ||||||||||||||||||||||||
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