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Yorodumi- EMDB-13442: Partial structure of tyrosine hydroxylase lacking the first 35 re... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-13442 | |||||||||
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Title | Partial structure of tyrosine hydroxylase lacking the first 35 residues in complex with dopamine. | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Tetramer / Dopamine / Catecholamine / Brain / Parkinson / OXIDOREDUCTASE | |||||||||
Function / homology | Function and homology information tyrosine 3-monooxygenase / tyrosine 3-monooxygenase activity / phytoalexin metabolic process / dopamine biosynthetic process from tyrosine / phthalate metabolic process / glycoside metabolic process / isoquinoline alkaloid metabolic process / terpene metabolic process / embryonic camera-type eye morphogenesis / norepinephrine biosynthetic process ...tyrosine 3-monooxygenase / tyrosine 3-monooxygenase activity / phytoalexin metabolic process / dopamine biosynthetic process from tyrosine / phthalate metabolic process / glycoside metabolic process / isoquinoline alkaloid metabolic process / terpene metabolic process / embryonic camera-type eye morphogenesis / norepinephrine biosynthetic process / circadian sleep/wake cycle / epinephrine biosynthetic process / Catecholamine biosynthesis / hyaloid vascular plexus regression / response to pyrethroid / aminergic neurotransmitter loading into synaptic vesicle / dopamine binding / eye photoreceptor cell development / response to isolation stress / sphingolipid metabolic process / response to ether / melanosome membrane / synaptic transmission, dopaminergic / tetrahydrobiopterin binding / mating behavior / dopamine biosynthetic process / pigmentation / response to herbicide / eating behavior / regulation of heart contraction / response to corticosterone / amino acid binding / response to zinc ion / cellular response to alkaloid / social behavior / response to immobilization stress / response to light stimulus / anatomical structure morphogenesis / smooth endoplasmic reticulum / cellular response to manganese ion / response to electrical stimulus / heart morphogenesis / response to salt stress / visual perception / response to amphetamine / ferric iron binding / response to nutrient levels / learning / response to activity / fatty acid metabolic process / locomotory behavior / animal organ morphogenesis / cellular response to glucose stimulus / ferrous iron binding / cellular response to growth factor stimulus / terminal bouton / cerebral cortex development / memory / response to peptide hormone / oxygen binding / cytoplasmic side of plasma membrane / cellular response to nicotine / cellular response to xenobiotic stimulus / synaptic vesicle / response to estradiol / heart development / cytoplasmic vesicle / perikaryon / response to ethanol / response to lipopolysaccharide / response to hypoxia / neuron projection / protein domain specific binding / axon / dendrite / perinuclear region of cytoplasm / enzyme binding / mitochondrion / identical protein binding / nucleus / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 4.6 Å | |||||||||
Authors | Bueno-Carrasco MT / Cuellar J | |||||||||
Funding support | Norway, Spain, 2 items
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Citation | Journal: Nat Commun / Year: 2022 Title: Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation. Authors: María Teresa Bueno-Carrasco / Jorge Cuéllar / Marte I Flydal / César Santiago / Trond-André Kråkenes / Rune Kleppe / José R López-Blanco / Miguel Marcilla / Knut Teigen / Sara Alvira ...Authors: María Teresa Bueno-Carrasco / Jorge Cuéllar / Marte I Flydal / César Santiago / Trond-André Kråkenes / Rune Kleppe / José R López-Blanco / Miguel Marcilla / Knut Teigen / Sara Alvira / Pablo Chacón / Aurora Martinez / José M Valpuesta / Abstract: Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the biosynthesis of dopamine (DA) and other catecholamines, and its dysfunction leads to DA deficiency and parkinsonisms. Inhibition by ...Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the biosynthesis of dopamine (DA) and other catecholamines, and its dysfunction leads to DA deficiency and parkinsonisms. Inhibition by catecholamines and reactivation by S40 phosphorylation are key regulatory mechanisms of TH activity and conformational stability. We used Cryo-EM to determine the structures of full-length human TH without and with DA, and the structure of S40 phosphorylated TH, complemented with biophysical and biochemical characterizations and molecular dynamics simulations. TH presents a tetrameric structure with dimerized regulatory domains that are separated 15 Å from the catalytic domains. Upon DA binding, a 20-residue α-helix in the flexible N-terminal tail of the regulatory domain is fixed in the active site, blocking it, while S40-phosphorylation forces its egress. The structures reveal the molecular basis of the inhibitory and stabilizing effects of DA and its counteraction by S40-phosphorylation, key regulatory mechanisms for homeostasis of DA and TH. | |||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_13442.map.gz | 11.2 MB | EMDB map data format | |
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Header (meta data) | emd-13442-v30.xml emd-13442.xml | 19.1 KB 19.1 KB | Display Display | EMDB header |
Images | emd_13442.png | 50.3 KB | ||
Filedesc metadata | emd-13442.cif.gz | 6.1 KB | ||
Others | emd_13442_half_map_1.map.gz emd_13442_half_map_2.map.gz | 11 MB 11 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-13442 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-13442 | HTTPS FTP |
-Validation report
Summary document | emd_13442_validation.pdf.gz | 623.1 KB | Display | EMDB validaton report |
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Full document | emd_13442_full_validation.pdf.gz | 622.7 KB | Display | |
Data in XML | emd_13442_validation.xml.gz | 9.6 KB | Display | |
Data in CIF | emd_13442_validation.cif.gz | 11 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-13442 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-13442 | HTTPS FTP |
-Related structure data
Related structure data | 7pimMC 6zn2C 6zvpC 6zzuC 7a2gC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_13442.map.gz / Format: CCP4 / Size: 15.6 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: 1.072 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Half map: #2
File | emd_13442_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_13442_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Tyrosine hydroxylase lacking the first 35 residues in complex wit...
Entire | Name: Tyrosine hydroxylase lacking the first 35 residues in complex with its inhibitor dopamine |
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Components |
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-Supramolecule #1: Tyrosine hydroxylase lacking the first 35 residues in complex wit...
Supramolecule | Name: Tyrosine hydroxylase lacking the first 35 residues in complex with its inhibitor dopamine type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Tyrosine 3-monooxygenase
Macromolecule | Name: Tyrosine 3-monooxygenase / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: tyrosine 3-monooxygenase |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 38.087766 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: VPWFPRKVSE LDKCHHLVTK FDPDLDLDHP GFSDQVYRQR RKLIAEIAFQ YRHGDPIPRV EYTAEEIATW KEVYTTLKGL YATHACGEH LEAFALLERF SGYREDNIPQ LEDVSRFLKE RTGFQLRPVA GLLSARDFLA SLAFRVFQCT QYIRHASSPM H SPEPDCCH ...String: VPWFPRKVSE LDKCHHLVTK FDPDLDLDHP GFSDQVYRQR RKLIAEIAFQ YRHGDPIPRV EYTAEEIATW KEVYTTLKGL YATHACGEH LEAFALLERF SGYREDNIPQ LEDVSRFLKE RTGFQLRPVA GLLSARDFLA SLAFRVFQCT QYIRHASSPM H SPEPDCCH ELLGHVPMLA DRTFAQFSQD IGLASLGASD EEIEKLSTLY WFTVEFGLCK QNGEVKAYGA GLLSSYGELL HC LSEEPEI RAFDPEAAAV QPYQDQTYQS VYFVSESFSD AKDKLRSYAS RIQRPFSVKF DPYTLAIDVL DSPQAVRRSL EGV QDELDT LAHALSAIG UniProtKB: Tyrosine 3-monooxygenase |
-Macromolecule #2: Regulatory domain alpha-helix
Macromolecule | Name: Regulatory domain alpha-helix / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 1.874081 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: SLIEDARKER EAAVAAAA |
-Macromolecule #3: L-DOPAMINE
Macromolecule | Name: L-DOPAMINE / type: ligand / ID: 3 / Number of copies: 4 / Formula: LDP |
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Molecular weight | Theoretical: 153.178 Da |
Chemical component information | ChemComp-LDP: |
-Macromolecule #4: FE (III) ION
Macromolecule | Name: FE (III) ION / type: ligand / ID: 4 / Number of copies: 4 / Formula: FE |
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Molecular weight | Theoretical: 55.845 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7 Component:
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Grid | Model: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE | |||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Energy filter - Name: GIF Quantum LS |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 13213 / Average electron dose: 30.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: OTHER / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.2 µm / Nominal magnification: 81000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |