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- EMDB-11309: Partial structure of tyrosine hydroxylase in complex with dopamin... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-11309 | |||||||||
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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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![]() | Tetramer / Dopamine / Catecholamine / Brain / Parkinson / OXIDOREDUCTASE | |||||||||
Function / homology | ![]() 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 / response to pyrethroid / dopamine binding / eye photoreceptor cell development / response to isolation stress / sphingolipid metabolic process / melanosome membrane / 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 / response to corticosterone / pigmentation / response to zinc ion / cellular response to alkaloid / social behavior / response to immobilization stress / response to light stimulus / smooth endoplasmic reticulum / anatomical structure morphogenesis / cellular response to manganese ion / heart morphogenesis / response to electrical stimulus / 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 / memory / cellular response to growth factor stimulus / cerebral cortex development / 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 / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 4.3 Å | |||||||||
![]() | Bueno-Carrasco MT / Cuellar J | |||||||||
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
Movie |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 1.8 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 15.6 KB 15.6 KB | Display Display | ![]() |
Images | ![]() | 104.4 KB | ||
Filedesc metadata | ![]() | 5.5 KB | ||
Others | ![]() ![]() | 13.2 MB 13.3 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6zn2MC ![]() 6zvpC ![]() 6zzuC ![]() 7a2gC ![]() 7pimC M: atomic model generated by this map C: citing same article ( |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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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: #2
File | emd_11309_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_11309_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
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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-#2 |
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Source (natural) | Organism: ![]() |
-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: ![]() |
Molecular weight | Theoretical: 38.087766 KDa |
Recombinant expression | Organism: ![]() ![]() |
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: SER-LEU-ILE-GLU-ASP-ALA-ARG-LYS-GLU-ARG-GLU-ALA-ALA-VAL-ALA-ALA-A...
Macromolecule | Name: SER-LEU-ILE-GLU-ASP-ALA-ARG-LYS-GLU-ARG-GLU-ALA-ALA-VAL-ALA-ALA-ALA-ALA type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 1.874081 KDa |
Recombinant expression | Organism: ![]() ![]() |
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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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 1.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: OTHER / Imaging mode: BRIGHT FIELD |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Startup model | Type of model: INSILICO MODEL |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 125033 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |