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- EMDB-13442: Partial structure of tyrosine hydroxylase lacking the first 35 re... -

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Basic information

Entry
Database: EMDB / ID: EMD-13442
TitlePartial structure of tyrosine hydroxylase lacking the first 35 residues in complex with dopamine.
Map data
Sample
  • Complex: Tyrosine hydroxylase lacking the first 35 residues in complex with its inhibitor dopamine
    • Protein or peptide: Tyrosine 3-monooxygenase
    • Protein or peptide: Regulatory domain alpha-helix
  • Ligand: L-DOPAMINE
  • Ligand: FE (III) ION
KeywordsTetramer / Dopamine / Catecholamine / Brain / Parkinson / OXIDOREDUCTASE
Function / homology
Function and homology information


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 / smooth endoplasmic reticulum / anatomical structure morphogenesis / heart morphogenesis / visual perception / animal organ morphogenesis / learning / locomotory behavior / memory / cytoplasmic side of plasma membrane / 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
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: 4.6 Å
AuthorsBueno-Carrasco MT / Cuellar J
Funding support Norway, Spain, 2 items
OrganizationGrant numberCountry
Research Council of NorwayFRIMEDBIO 261826 Norway
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
DepositionAug 20, 2021-
Header (metadata) releaseDec 22, 2021-
Map releaseDec 22, 2021-
UpdateJul 17, 2024-
Current statusJul 17, 2024Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0042
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.0042
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7pim
  • Surface level: 0.007
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_13442.png

Downloads & links

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Map

FileDownload / File: emd_13442.map.gz / Format: CCP4 / Size: 15.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 160 pix.
= 171.52 Å		1.07 Å/pix.
x 160 pix.
= 171.52 Å		1.07 Å/pix.
x 160 pix.
= 171.52 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.072 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0042 / Movie #1: 0.0042
Minimum - Maximum-0.02652063 - 0.061326943
Average (Standard dev.)0.000469473 (±0.0030115806)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions160160160
Spacing160160160
CellA=B=C: 171.52 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0721.0721.072
M x/y/z160160160
origin x/y/z0.0000.0000.000
length x/y/z171.520171.520171.520
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS160160160
D min/max/mean-0.0270.0610.000

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Supplemental data

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Half map: #2

Fileemd_13442_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_13442_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 lacking the first 35 residues in complex wit...

EntireName: Tyrosine hydroxylase lacking the first 35 residues in complex with its inhibitor dopamine
Components
  • Complex: Tyrosine hydroxylase lacking the first 35 residues in complex with its inhibitor dopamine
    • Protein or peptide: Tyrosine 3-monooxygenase
    • Protein or peptide: Regulatory domain alpha-helix
  • Ligand: L-DOPAMINE
  • Ligand: FE (III) ION

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Supramolecule #1: Tyrosine hydroxylase lacking the first 35 residues in complex wit...

SupramoleculeName: Tyrosine hydroxylase lacking the first 35 residues in complex with its inhibitor dopamine
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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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: 38.087766 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: 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

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Macromolecule #2: Regulatory domain alpha-helix

MacromoleculeName: Regulatory domain alpha-helix / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.874081 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
SLIEDARKER EAAVAAAA

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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

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Macromolecule #4: FE (III) ION

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

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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
Component:
ConcentrationFormulaName
200.0 mMNaClsodium chloride
20.0 mMHepesHEPES
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Quantum LS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 13213 / Average electron dose: 30.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.2 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1626575
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 2.0) / Number images used: 152128
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 2.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 2.0)
Final 3D classificationSoftware - Name: RELION (ver. 2.0)

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