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Yorodumi- PDB-6zvp: Atomic model of the EM-based structure of the full-length tyrosin... -
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-Basic information
Entry | Database: PDB / ID: 6zvp | |||||||||
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Title | Atomic model of the EM-based structure of the full-length tyrosine hydroxylase in complex with dopamine (residues 40-497) in which the regulatory domain (residues 40-165) has been included only with the backbone atoms | |||||||||
Components | Tyrosine 3-monooxygenase | |||||||||
Keywords | OXIDOREDUCTASE / Tetramer / Dopamine / 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 / 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 | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å | |||||||||
Authors | Bueno-Carrasco, M.T. / Cuellar, J. / Santiago, C. / Valpuesta, J.M. / Martinez, A. / Flydal, M.I. | |||||||||
Funding support | 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 | 6zvp.cif.gz | 409.4 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6zvp.ent.gz | 294 KB | Display | PDB format |
PDBx/mmJSON format | 6zvp.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6zvp_validation.pdf.gz | 938.1 KB | Display | wwPDB validaton report |
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Full document | 6zvp_full_validation.pdf.gz | 970.5 KB | Display | |
Data in XML | 6zvp_validation.xml.gz | 57.8 KB | Display | |
Data in CIF | 6zvp_validation.cif.gz | 84.1 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/zv/6zvp ftp://data.pdbj.org/pub/pdb/validation_reports/zv/6zvp | HTTPS FTP |
-Related structure data
Related structure data | 11467MC 6zn2C 6zzuC 7a2gC 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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Noncrystallographic symmetry (NCS) | NCS domain:
NCS domain segments:
NCS oper:
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-Components
#1: Protein | Mass: 51399.859 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: Chemical | ChemComp-LDP / 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 in complex with dopamine / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Escherichia coli (E. coli) |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: GOLD / Grid type: UltrAuFoil R1.2/1.3 |
Vitrification | Cryogen name: ETHANE |
-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 |
Image recording | Electron dose: 1 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
Software |
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CTF correction | Type: NONE | ||||||||||||||||||||||||
3D reconstruction | Resolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 36368 / Symmetry type: POINT | ||||||||||||||||||||||||
Refinement | Cross valid method: NONE Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
Displacement parameters | Biso mean: 201.87 Å2 | ||||||||||||||||||||||||
Refine LS restraints |
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Refine LS restraints NCS |
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