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Open data
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Basic information
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Title | Human VMAT2 complex with ketanserin | |||||||||
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![]() | transporter1 / ![]() | |||||||||
Function / homology | ![]() 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 / monoamine transport / histamine secretion by mast cell / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | ![]() ![]() | |||||||||
![]() | Jiang DH / Wu D | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Transport and inhibition mechanisms of human VMAT2. Authors: Di Wu / Qihao Chen / Zhuoya Yu / Bo Huang / Jun Zhao / Yuhang Wang / Jiawei Su / Feng Zhou / Rui Yan / Na Li / Yan Zhao / Daohua Jiang / ![]() Abstract: Vesicular monoamine transporter 2 (VMAT2) accumulates monoamines in presynaptic vesicles for storage and exocytotic release, and has a vital role in monoaminergic neurotransmission. Dysfunction of ...Vesicular monoamine transporter 2 (VMAT2) accumulates monoamines in presynaptic vesicles for storage and exocytotic release, and has a vital role in monoaminergic neurotransmission. Dysfunction of monoaminergic systems causes many neurological and psychiatric disorders, including Parkinson's disease, hyperkinetic movement disorders and depression. Suppressing VMAT2 with reserpine and tetrabenazine alleviates symptoms of hypertension and Huntington's disease, respectively. Here we describe cryo-electron microscopy structures of human VMAT2 complexed with serotonin and three clinical drugs at 3.5-2.8 Å, demonstrating the structural basis for transport and inhibition. Reserpine and ketanserin occupy the substrate-binding pocket and lock VMAT2 in cytoplasm-facing and lumen-facing states, respectively, whereas tetrabenazine binds in a VMAT2-specific pocket and traps VMAT2 in an occluded state. The structures in three distinct states also reveal the structural basis of the VMAT2 transport cycle. Our study establishes a structural foundation for the mechanistic understanding of substrate recognition, transport, drug inhibition and pharmacology of VMAT2 while shedding light on the rational design of potential therapeutic agents. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 116 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 13.8 KB 13.8 KB | Display Display | ![]() |
Images | ![]() | 44.3 KB | ||
Filedesc metadata | ![]() | 5.4 KB | ||
Others | ![]() ![]() | 116 MB 116 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8jt9MC ![]() 8jswC ![]() 8jtaC ![]() 8jtcC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 0.82 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_36637_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_36637_half_map_2.map | ||||||||||||
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Density Histograms |
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Sample components
-Entire : transporter1
Entire | Name: transporter1 |
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Components |
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-Supramolecule #1: transporter1
Supramolecule | Name: transporter1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() ![]() |
-Macromolecule #1: Synaptic vesicular amine transporter
Macromolecule | Name: Synaptic vesicular amine transporter / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 49.086848 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: SRKLILFIVF LALLLDNMLL TVVVPIIPSY LYSIKHEKNA TEIQTARPVH TASISDSFQS IFSYYDNSTM VTGNATRDLT LHQTATQHM VTNASAVPSD CPSEDKDLLN ENVQVGLLFA SKATVQLITN PFIGLLTNRI GYPIPIFAGF CIMFVSTIMF A FSSSYAFL ...String: SRKLILFIVF LALLLDNMLL TVVVPIIPSY LYSIKHEKNA TEIQTARPVH TASISDSFQS IFSYYDNSTM VTGNATRDLT LHQTATQHM VTNASAVPSD CPSEDKDLLN ENVQVGLLFA SKATVQLITN PFIGLLTNRI GYPIPIFAGF CIMFVSTIMF A FSSSYAFL LIARSLQGIG SSCSSVAGMG MLASVYTDDE ERGNVMGIAL GGLAMGVLVG PPFGSVLYEF VGKTAPFLVL AA LVLLDGA IQLFVLQPSR VQPESQKGTP LTTLLKDPYI LIAAGSICFA NMGIAMLEPA LPIWMMETMC SRKWQLGVAF LPA SISYLI GTNIFGILAH KMGRWLCALL GMIIVGVSIL CIPFAKNIYG LIAPNFGVGF AIGMVDSSMM PIMGYLVDLR HVSV YGSVY AIADVAFCMG YAIGPSAGGA IAKAIGFPWL MTIIGIIDIL FAPLCFFLRS PP UniProtKB: Synaptic vesicular amine transporter |
-Macromolecule #2: 3-[2-[4-(4-fluorophenyl)carbonylpiperidin-1-yl]ethyl]-1~{H}-quina...
Macromolecule | Name: 3-[2-[4-(4-fluorophenyl)carbonylpiperidin-1-yl]ethyl]-1~{H}-quinazoline-2,4-dione type: ligand / ID: 2 / Number of copies: 1 / Formula: UYX |
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Molecular weight | Theoretical: 395.427 Da |
Chemical component information | ![]() ChemComp-UYX: |
-Experimental details
-Structure determination
Method | ![]() |
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Aggregation state | particle |
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Sample preparation
Buffer | pH: 8 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD![]() |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2 |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Startup model | Type of model: OTHER |
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Initial angle assignment | Type: RANDOM ASSIGNMENT |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.97 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 504617 |