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- EMDB-11467: Atomic model of the EM-based structure of the full-length tyrosin... -

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Basic information

Entry
Database: EMDB / ID: EMD-11467
TitleAtomic 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
Map data
Sample
  • Complex: Tyrosine Hydroxylase in complex with dopamine
    • Protein or peptide: Tyrosine 3-monooxygenaseTyrosine hydroxylase
  • Ligand: FE (III) ION
  • Ligand: L-DOPAMINE
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 / hyaloid vascular plexus regression ...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 / hyaloid vascular plexus regression / embryonic camera-type eye morphogenesis / aminergic neurotransmitter loading into synaptic vesicle / circadian sleep/wake cycle / epinephrine biosynthetic process / Catecholamine biosynthesis / dopamine binding / response to pyrethroid / response to isolation stress / eye photoreceptor cell development / melanosome membrane / response to ether / sphingolipid metabolic process / synaptic transmission, dopaminergic / tetrahydrobiopterin binding / response to herbicide / mating behavior / dopamine biosynthetic process / regulation of heart contraction / pigmentation / amino acid binding / eating behavior / response to corticosterone / response to zinc ion / cellular response to alkaloid / smooth endoplasmic reticulum / social behavior / response to light stimulus / response to immobilization stress / 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 / locomotory behavior / response to activity / learning / cellular response to glucose stimulus / ferrous iron binding / animal organ morphogenesis / terminal bouton / cytoplasmic side of plasma membrane / memory / cerebral cortex development / response to peptide hormone / cellular response to growth factor stimulus / oxygen binding / cellular response to nicotine / synaptic vesicle / cellular response to xenobiotic stimulus / response to estradiol / heart development / perikaryon / cytoplasmic vesicle / response to ethanol / response to lipopolysaccharide / response to hypoxia / neuron projection / axon / protein domain specific binding / dendrite / perinuclear region of cytoplasm / enzyme binding / mitochondrion / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Tyrosine 3-monooxygenase / Tyrosine hydroxylase, conserved site / Tyrosine 3-monooxygenase, catalytic domain / : / Tyrosine hydroxylase N terminal / Tyrosine 3-monooxygenase-like, ACT domain / Tyrosine 3-monooxygenase-like / Aromatic amino acid hydroxylase, iron/copper binding site / Biopterin-dependent aromatic amino acid hydroxylases signature. / Aromatic amino acid hydroxylase ...Tyrosine 3-monooxygenase / Tyrosine hydroxylase, conserved site / Tyrosine 3-monooxygenase, catalytic domain / : / Tyrosine hydroxylase N terminal / Tyrosine 3-monooxygenase-like, ACT domain / Tyrosine 3-monooxygenase-like / Aromatic amino acid hydroxylase, iron/copper binding site / Biopterin-dependent aromatic amino acid hydroxylases signature. / Aromatic amino acid hydroxylase / Aromatic amino acid hydroxylase, C-terminal / Aromatic amino acid monoxygenase, C-terminal domain superfamily / Aromatic amino acid hydroxylase superfamily / Biopterin-dependent aromatic amino acid hydroxylase / Biopterin-dependent aromatic amino acid hydroxylase family profile. / ACT-like domain
Similarity search - Domain/homology
Tyrosine 3-monooxygenase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.0 Å
AuthorsBueno-Carrasco MT / Cuellar J / Santiago C / Valpuesta JM / Martinez A / Flydal MI
Funding support Spain, 2 items
OrganizationGrant numberCountry
Research Council of NorwayFRIMEDBIO 261826 Spain
Spanish Ministry of Science, Innovation, and UniversitiesPID2019-105872GB-I00 Spain
CitationJournal: 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
DepositionJul 27, 2020-
Header (metadata) releaseNov 17, 2021-
Map releaseNov 17, 2021-
UpdateFeb 2, 2022-
Current statusFeb 2, 2022Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.01
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  • Surface view colored by radius
  • Surface level: 0.01
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  • Surface view with fitted model
  • Atomic models: PDB-6zvp
  • Surface level: 0.01
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Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_11467.png

Downloads & links

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Map

FileDownload / File: emd_11467.map.gz / Format: CCP4 / Size: 22.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.05 Å
Density
Contour LevelBy AUTHOR: 0.004 / Movie #1: 0.01
Minimum - Maximum-0.050817803 - 0.10276306
Average (Standard dev.)0.0006814199 (±0.0049492484)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions180180180
Spacing180180180
CellA=B=C: 188.99998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.051.051.05
M x/y/z180180180
origin x/y/z0.0000.0000.000
length x/y/z189.000189.000189.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS180180180
D min/max/mean-0.0510.1030.001

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Supplemental data

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Half map: #1

Fileemd_11467_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_11467_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Tyrosine Hydroxylase in complex with dopamine

EntireName: Tyrosine Hydroxylase in complex with dopamine
Components
  • Complex: Tyrosine Hydroxylase in complex with dopamine
    • Protein or peptide: Tyrosine 3-monooxygenaseTyrosine hydroxylase
  • Ligand: FE (III) ION
  • Ligand: L-DOPAMINE

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Supramolecule #1: Tyrosine Hydroxylase in complex with dopamine

SupramoleculeName: Tyrosine Hydroxylase in complex with dopamine / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli (E. coli)

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Macromolecule #1: Tyrosine 3-monooxygenase

MacromoleculeName: Tyrosine 3-monooxygenase / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: tyrosine 3-monooxygenase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 51.399859 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: SLIEDARKER EAAVAAAAAA VPSEPGDPLE AVAFEEKEGK AMLNLLFSPR ATKPSALSRA VKVFETFEAK IHHLETRPAQ RPRAGGPHL EYFVRLEVRR GDLAALLSGV RQVSEDVRSP AGPKVPWFPR KVSELDKCHH LVTKFDPDLD LDHPGFSDQV Y RQRRKLIA ...String:
SLIEDARKER EAAVAAAAAA VPSEPGDPLE AVAFEEKEGK AMLNLLFSPR ATKPSALSRA VKVFETFEAK IHHLETRPAQ RPRAGGPHL EYFVRLEVRR GDLAALLSGV RQVSEDVRSP AGPKVPWFPR KVSELDKCHH LVTKFDPDLD LDHPGFSDQV Y RQRRKLIA EIAFQYRHGD PIPRVEYTAE EIATWKEVYT TLKGLYATHA CGEHLEAFAL LERFSGYRED NIPQLEDVSR FL KERTGFQ LRPVAGLLSA RDFLASLAFR VFQCTQYIRH ASSPMHSPEP DCCHELLGHV PMLADRTFAQ FSQDIGLASL GAS DEEIEK LSTLYWFTVE FGLCKQNGEV KAYGAGLLSS YGELLHCLSE EPEIRAFDPE AAAVQPYQDQ TYQSVYFVSE SFSD AKDKL RSYASRIQRP FSVKFDPYTL AIDVLDSPQA VRRSLEGVQD ELDTLAHALS AIG

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Macromolecule #2: FE (III) ION

MacromoleculeName: FE (III) ION / type: ligand / ID: 2 / Number of copies: 4 / Formula: FE
Molecular weightTheoretical: 55.845 Da

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Macromolecule #3: L-DOPAMINE

MacromoleculeName: L-DOPAMINE / type: ligand / ID: 3 / Number of copies: 4 / Formula: LDP
Molecular weightTheoretical: 153.178 Da
Chemical component information

ChemComp-LDP:
L-DOPAMINE / medication*YM / Dopamine (medication)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 1.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 36368

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