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Yorodumi- PDB-7a2g: Full-length structure of the substrate-free tyrosine hydroxylase ... -
+Open data
-Basic information
Entry | Database: PDB / ID: 7a2g | |||||||||
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Title | Full-length structure of the substrate-free tyrosine hydroxylase (apo-TH). | |||||||||
Components | Tyrosine 3-monooxygenase | |||||||||
Keywords | OXIDOREDUCTASE / Tetramer / catecholamine / brain / Parkinson | |||||||||
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 | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.1 Å | |||||||||
Authors | Bueno-Carrasco, M.T. / Cuellar, J. / Santiago, C. / Flydal, M.I. / Martinez, A. / Valpuesta, J.M. | |||||||||
Funding support | Norway, Spain, 2items
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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 | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7a2g.cif.gz | 304.3 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7a2g.ent.gz | 243.2 KB | Display | PDB format |
PDBx/mmJSON format | 7a2g.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7a2g_validation.pdf.gz | 1.1 MB | Display | wwPDB validaton report |
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Full document | 7a2g_full_validation.pdf.gz | 1.2 MB | Display | |
Data in XML | 7a2g_validation.xml.gz | 66.1 KB | Display | |
Data in CIF | 7a2g_validation.cif.gz | 95.9 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/a2/7a2g ftp://data.pdbj.org/pub/pdb/validation_reports/a2/7a2g | HTTPS FTP |
-Related structure data
Related structure data | 11624MC 6zn2C 6zvpC 6zzuC 7pimC C: citing same article (ref.) M: map data used to model this data |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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-Components
#1: Protein | Mass: 47475.598 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: TH, TYH / Production host: Escherichia coli (E. coli) / References: UniProt: P07101, tyrosine 3-monooxygenase #2: Chemical | ChemComp-FE / #3: Water | ChemComp-HOH / | Has ligand of interest | N | |
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-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: Tyrosine hydroxylase / 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: Escherichia coli (E. coli) | |||||||||||||||
Buffer solution | pH: 7 | |||||||||||||||
Buffer component |
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Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | |||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277 K |
-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 magnification: 130000 X / Nominal defocus max: 3000 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 39.6 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 3867 |
EM imaging optics | Energyfilter name: GIF Quantum LS |
Image scans | Width: 3838 / Height: 3710 |
-Processing
Software |
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EM software |
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CTF correction | Type: NONE | ||||||||||||||||||||||||
Particle selection | Num. of particles selected: 411680 | ||||||||||||||||||||||||
3D reconstruction | Resolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 29418 / Symmetry type: POINT | ||||||||||||||||||||||||
Refinement | Cross valid method: NONE Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
Displacement parameters | Biso mean: 325.28 Å2 | ||||||||||||||||||||||||
Refine LS restraints |
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