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Yorodumi- EMDB-11624: Full-length structure of the substrate-free tyrosine hydroxylase ... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-11624 | |||||||||
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Title | Full-length structure of the substrate-free tyrosine hydroxylase (apo-TH). | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Tetramer / 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 / terpene metabolic process / isoquinoline alkaloid metabolic process / norepinephrine biosynthetic process / embryonic camera-type eye morphogenesis ...tyrosine 3-monooxygenase / tyrosine 3-monooxygenase activity / phytoalexin metabolic process / dopamine biosynthetic process from tyrosine / phthalate metabolic process / glycoside metabolic process / terpene metabolic process / isoquinoline alkaloid metabolic process / norepinephrine biosynthetic process / embryonic camera-type eye morphogenesis / hyaloid vascular plexus regression / epinephrine biosynthetic process / circadian sleep/wake cycle / Catecholamine biosynthesis / aminergic neurotransmitter loading into synaptic vesicle / dopamine binding / response to pyrethroid / eye photoreceptor cell development / response to isolation stress / melanosome membrane / sphingolipid metabolic process / response to ether / synaptic transmission, dopaminergic / tetrahydrobiopterin binding / response to herbicide / mating behavior / dopamine biosynthetic process / amino acid binding / regulation of heart contraction / eating behavior / pigmentation / response to corticosterone / response to zinc ion / cellular response to alkaloid / social behavior / response to immobilization stress / smooth endoplasmic reticulum / response to light stimulus / anatomical structure morphogenesis / cellular response to manganese ion / response to electrical stimulus / heart morphogenesis / response to salt stress / response to amphetamine / visual perception / response to nutrient levels / ferric iron binding / fatty acid metabolic process / learning / response to activity / locomotory behavior / cellular response to glucose stimulus / animal organ morphogenesis / ferrous iron binding / terminal bouton / cytoplasmic side of plasma membrane / cerebral cortex development / memory / cellular response to growth factor stimulus / response to peptide hormone / oxygen binding / 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 / cytoplasm / cytosol Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 4.1 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_11624.map.gz | 11.1 MB | EMDB map data format | |
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Header (meta data) | emd-11624-v30.xml emd-11624.xml | 18.8 KB 18.8 KB | Display Display | EMDB header |
Images | emd_11624.png | 41.4 KB | ||
Filedesc metadata | emd-11624.cif.gz | 6 KB | ||
Others | emd_11624_half_map_1.map.gz emd_11624_half_map_2.map.gz | 19.4 MB 19.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-11624 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-11624 | HTTPS FTP |
-Validation report
Summary document | emd_11624_validation.pdf.gz | 726.2 KB | Display | EMDB validaton report |
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Full document | emd_11624_full_validation.pdf.gz | 725.7 KB | Display | |
Data in XML | emd_11624_validation.xml.gz | 10.2 KB | Display | |
Data in CIF | emd_11624_validation.cif.gz | 11.9 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-11624 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-11624 | HTTPS FTP |
-Related structure data
Related structure data | 7a2gMC 6zn2C 6zvpC 6zzuC 7pimC C: citing same article (ref.) M: atomic model generated by this map |
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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_11624.map.gz / Format: CCP4 / Size: 22.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Voxel size | X=Y=Z: 1.05 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Half map: #1
File | emd_11624_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_11624_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Tyrosine hydroxylase
Entire | Name: Tyrosine hydroxylase |
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Components |
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-Supramolecule #1: Tyrosine hydroxylase
Supramolecule | Name: Tyrosine hydroxylase / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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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: 47.475598 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: GKAMLNLLFS PRATKPSALS RAVKVFETFE AKIHHLETRP AQRPRAGGPH LEYFVRLEVR RGDLAALLSG VRQVSEDVRS PAGPKVPWF PRKVSELDKC HHLVTKFDPD LDLDHPGFSD QVYRQRRKLI AEIAFQYRHG DPIPRVEYTA EEIATWKEVY T TLKGLYAT ...String: GKAMLNLLFS PRATKPSALS RAVKVFETFE AKIHHLETRP AQRPRAGGPH LEYFVRLEVR RGDLAALLSG VRQVSEDVRS PAGPKVPWF PRKVSELDKC HHLVTKFDPD LDLDHPGFSD QVYRQRRKLI AEIAFQYRHG DPIPRVEYTA EEIATWKEVY T TLKGLYAT HACGEHLEAF ALLERFSGYR EDNIPQLEDV SRFLKERTGF QLRPVAGLLS ARDFLASLAF RVFQCTQYIR HA SSPMHSP EPDCCHELLG HVPMLADRTF AQFSQDIGLA SLGASDEEIE KLSTLYWFTV EFGLCKQNGE VKAYGAGLLS SYG ELLHCL SEEPEIRAFD PEAAAVQPYQ DQTYQSVYFV SESFSDAKDK LRSYASRIQR PFSVKFDPYT LAIDVLDSPQ AVRR SLEGV QDELDTLAHA LSAIG UniProtKB: Tyrosine 3-monooxygenase |
-Macromolecule #2: FE (III) ION
Macromolecule | Name: FE (III) ION / type: ligand / ID: 2 / Number of copies: 4 / Formula: FE |
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Molecular weight | Theoretical: 55.845 Da |
-Macromolecule #3: water
Macromolecule | Name: water / type: ligand / ID: 3 / Number of copies: 4 / Formula: HOH |
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Molecular weight | Theoretical: 18.015 Da |
Chemical component information | ChemComp-HOH: |
-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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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 K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Digitization - Dimensions - Width: 3838 pixel / Digitization - Dimensions - Height: 3710 pixel / Number grids imaged: 1 / Number real images: 3867 / Average electron dose: 39.6 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: 130000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |