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Yorodumi- EMDB-38852: Cryo-EM structure of human dopamine transporter in complex with b... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-38852 | |||||||||
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Title | Cryo-EM structure of human dopamine transporter in complex with benztropine | |||||||||
Map data | ||||||||||
Sample |
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Keywords | human dopamine transporter in complex with benztropine / MEMBRANE PROTEIN | |||||||||
Function / homology | Function and homology information Defective SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS) / Defective SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS) / Dopamine clearance from the synaptic cleft / amine binding / adenohypophysis development / dopamine uptake / hyaloid vascular plexus regression / dopamine binding / norepinephrine:sodium symporter activity / dopamine:sodium symporter activity ...Defective SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS) / Defective SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS) / Dopamine clearance from the synaptic cleft / amine binding / adenohypophysis development / dopamine uptake / hyaloid vascular plexus regression / dopamine binding / norepinephrine:sodium symporter activity / dopamine:sodium symporter activity / norepinephrine transport / regulation of dopamine metabolic process / neurotransmitter transmembrane transporter activity / dopaminergic synapse / dopamine transport / flotillin complex / dopamine catabolic process / monoamine transmembrane transporter activity / monoamine transport / Na+/Cl- dependent neurotransmitter transporters / positive regulation of multicellular organism growth / response to iron ion / neurotransmitter transport / dopamine biosynthetic process / heterocyclic compound binding / amino acid transport / dopamine uptake involved in synaptic transmission / neuronal cell body membrane / sodium ion transmembrane transport / prepulse inhibition / axon terminus / response to cAMP / lactation / protein phosphatase 2A binding / response to cocaine / cognition / locomotory behavior / response to nicotine / sensory perception of smell / presynaptic membrane / protease binding / postsynaptic membrane / response to ethanol / neuron projection / response to xenobiotic stimulus / membrane raft / axon / signaling receptor binding / neuronal cell body / protein-containing complex binding / cell surface / membrane / metal ion binding / plasma membrane / cytoplasm Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.03 Å | |||||||||
Authors | Zhao Y / Li Y | |||||||||
Funding support | China, 1 items
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Citation | Journal: Nature / Year: 2024 Title: Dopamine reuptake and inhibitory mechanisms in human dopamine transporter. Authors: Yue Li / Xianping Wang / Yufei Meng / Tuo Hu / Jun Zhao / Renjie Li / Qinru Bai / Pu Yuan / Jun Han / Kun Hao / Yiqing Wei / Yunlong Qiu / Na Li / Yan Zhao / Abstract: The dopamine transporter has a crucial role in regulation of dopaminergic neurotransmission by uptake of dopamine into neurons and contributes to the abuse potential of psychomotor stimulants. ...The dopamine transporter has a crucial role in regulation of dopaminergic neurotransmission by uptake of dopamine into neurons and contributes to the abuse potential of psychomotor stimulants. Despite decades of study, the structure, substrate binding, conformational transitions and drug-binding poses of human dopamine transporter remain unknown. Here we report structures of the human dopamine transporter in its apo state, and in complex with the substrate dopamine, the attention deficit hyperactivity disorder drug methylphenidate, and the dopamine-uptake inhibitors GBR12909 and benztropine. The dopamine-bound structure in the occluded state precisely illustrates the binding position of dopamine and associated ions. The structures bound to drugs are captured in outward-facing or inward-facing states, illuminating distinct binding modes and conformational transitions during substrate transport. Unlike the outward-facing state, which is stabilized by cocaine, GBR12909 and benztropine stabilize the dopamine transporter in the inward-facing state, revealing previously unseen drug-binding poses and providing insights into how they counteract the effects of cocaine. This study establishes a framework for understanding the functioning of the human dopamine transporter and developing therapeutic interventions for dopamine transporter-related disorders and cocaine addiction. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_38852.map.gz | 118 MB | EMDB map data format | |
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Header (meta data) | emd-38852-v30.xml emd-38852.xml | 14.4 KB 14.4 KB | Display Display | EMDB header |
Images | emd_38852.png | 33 KB | ||
Filedesc metadata | emd-38852.cif.gz | 5.6 KB | ||
Others | emd_38852_half_map_1.map.gz emd_38852_half_map_2.map.gz | 116.1 MB 116.1 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-38852 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-38852 | HTTPS FTP |
-Validation report
Summary document | emd_38852_validation.pdf.gz | 1.2 MB | Display | EMDB validaton report |
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Full document | emd_38852_full_validation.pdf.gz | 1.2 MB | Display | |
Data in XML | emd_38852_validation.xml.gz | 13.9 KB | Display | |
Data in CIF | emd_38852_validation.cif.gz | 16.3 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-38852 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-38852 | HTTPS FTP |
-Related structure data
Related structure data | 8y2eMC 8y2cC 8y2dC 8y2fC 8y2gC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_38852.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.85 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_38852_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_38852_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : human dopamine transporter in complex with benztropine
Entire | Name: human dopamine transporter in complex with benztropine |
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Components |
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-Supramolecule #1: human dopamine transporter in complex with benztropine
Supramolecule | Name: human dopamine transporter in complex with benztropine type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Sodium-dependent dopamine transporter
Macromolecule | Name: Sodium-dependent dopamine transporter / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 61.590508 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: KIDFLLSVIG FAVDLANVWR FPYLCYKNGG GAFLVPYLLF MVIAGMPLFY MELALGQFNR EGAAGVWKIC PILKGVGFTV ILISLYVGF FYNVIIAWAL HYLFSSFTTE LPWIHCNNSW NSPNCSDAHP GDSSGDSSGL NDTFGTTPAA EYFERGVLHL H QSHGIDDL ...String: KIDFLLSVIG FAVDLANVWR FPYLCYKNGG GAFLVPYLLF MVIAGMPLFY MELALGQFNR EGAAGVWKIC PILKGVGFTV ILISLYVGF FYNVIIAWAL HYLFSSFTTE LPWIHCNNSW NSPNCSDAHP GDSSGDSSGL NDTFGTTPAA EYFERGVLHL H QSHGIDDL GPPRWQLTAC LVLVIVLLYF SLWKGVKTSG KVVWITATMP YVVLTALLLR GVTLPGAIDG IRAYLSVDFY RL CEASVWI DAATQVCFSL GVGFGVLIAF SSYNKFTNNC YRDAIVTTSI NSLTSFSSGF VVFSFLGYMA QKHSVPIGDV AKD GPGLIF IIYPEAIATL PLSSAWAVVF FIMLLTLGID SAMGGMESVI TGLIDEFQLL HRHRELFTLF IVLATFLLSL FCVT NGGIY VFTLLDHFAA GTSILFGVLI EAIGVAWFYG VGQFSDDIQQ MTGQRPSLYW RLCWKLVSPC FLLFVVVVSI VTFRP PHYG AYIFPDWANA LGWVIATSSM AMVPIYAAYK FCSLPGSFRE KLAYAIAPEK DRELVDRGEV RQFTLRHWLK V UniProtKB: Sodium-dependent dopamine transporter |
-Macromolecule #2: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 2 / Number of copies: 2 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Macromolecule #3: benztropine
Macromolecule | Name: benztropine / type: ligand / ID: 3 / Number of copies: 1 / Formula: CXQ |
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Molecular weight | Theoretical: 307.429 Da |
Chemical component information | ChemComp-CXQ: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: INSILICO MODEL |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.03 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 63350 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |