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- PDB-6zn2: Partial structure of tyrosine hydroxylase in complex with dopamin... -
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Basic information
Entry | Database: PDB / ID: 6zn2 | |||||||||
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Title | Partial structure of tyrosine hydroxylase in complex with dopamine showing the catalytic domain and an alpha-helix from the regulatory domain involved in dopamine binding. | |||||||||
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![]() | OXIDOREDUCTASE / Tetramer / Dopamine / Catecholamine / Brain / Parkinson | |||||||||
Function / homology | ![]() tyrosine 3-monooxygenase / tyrosine 3-monooxygenase activity / dopamine biosynthetic process from tyrosine / embryonic camera-type eye morphogenesis / epinephrine biosynthetic process / Catecholamine biosynthesis / norepinephrine biosynthetic process / hyaloid vascular plexus regression / eye photoreceptor cell development / melanosome membrane ...tyrosine 3-monooxygenase / tyrosine 3-monooxygenase activity / dopamine biosynthetic process from tyrosine / embryonic camera-type eye morphogenesis / epinephrine biosynthetic process / Catecholamine biosynthesis / norepinephrine biosynthetic process / hyaloid vascular plexus regression / eye photoreceptor cell development / melanosome membrane / synaptic transmission, dopaminergic / mating behavior / eating behavior / dopamine biosynthetic process / pigmentation / regulation of heart contraction / anatomical structure morphogenesis / heart morphogenesis / smooth endoplasmic reticulum / visual perception / animal organ morphogenesis / learning / locomotory behavior / cytoplasmic side of plasma membrane / memory / synaptic vesicle / heart development / cytoplasmic vesicle / response to ethanol / perikaryon / response to hypoxia / neuron projection / iron ion binding / axon / perinuclear region of cytoplasm / enzyme binding / identical protein binding / nucleus / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.3 Å | |||||||||
![]() | Bueno-Carrasco, M.T. / Cuellar, J. / Santiago, C. / Valpuesta, J.M. / Martinez, A. / Flydal, M.I. | |||||||||
Funding support | ![]()
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![]() | ![]() 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
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Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 333.3 KB | Display | ![]() |
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PDB format | ![]() | 232.3 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 930 KB | Display | ![]() |
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Full document | ![]() | 970.6 KB | Display | |
Data in XML | ![]() | 51.7 KB | Display | |
Data in CIF | ![]() | 69.1 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 11309MC ![]() 6zvpC ![]() 6zzuC ![]() 7a2gC ![]() 7pimC M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Assembly
Deposited unit | ![]()
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Noncrystallographic symmetry (NCS) | NCS domain:
NCS domain segments:
NCS ensembles :
NCS oper:
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Components
#1: Protein | Mass: 38087.766 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() #2: Protein/peptide | Mass: 1874.081 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() #3: Chemical | ChemComp-LDP / #4: Chemical | ChemComp-FE / 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 |
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Sample preparation
Component | Name: Tyrosine Hydroxylase / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT |
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Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() ![]() |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
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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: ![]() |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 1 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
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Processing
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CTF correction | Type: NONE | ||||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 125033 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||||||||||||
Refinement | Cross valid method: NONE Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 259.35 Å2 | ||||||||||||||||||||||||||||||||||||||||||
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Refine LS restraints NCS |
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