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- PDB-7a2g: Full-length structure of the substrate-free tyrosine hydroxylase ... -

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Basic information

Entry
Database: PDB / ID: 7a2g
TitleFull-length structure of the substrate-free tyrosine hydroxylase (apo-TH).
ComponentsTyrosine 3-monooxygenase
KeywordsOXIDOREDUCTASE / Tetramer / catecholamine / brain / Parkinson
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 / 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 / cytoplasm / cytosol
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.1 Å
AuthorsBueno-Carrasco, M.T. / Cuellar, J. / Santiago, C. / Flydal, M.I. / Martinez, A. / Valpuesta, J.M.
Funding support Norway, Spain, 2items
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 17, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 1, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 22, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jul 10, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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Assembly

Deposited unit
A: Tyrosine 3-monooxygenase
B: Tyrosine 3-monooxygenase
C: Tyrosine 3-monooxygenase
D: Tyrosine 3-monooxygenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)190,1268
Polymers189,9024
Non-polymers2234
Water724
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, cross-linking, mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area14200 Å2
ΔGint-138 kcal/mol
Surface area73910 Å2
MethodPISA

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Components

#1: Protein
Tyrosine 3-monooxygenase / Tyrosine 3-hydroxylase / TH


Mass: 47475.598 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 / FE (III) ION


Mass: 55.845 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Fe
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Tyrosine hydroxylase / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7
Buffer component
IDConc.NameFormulaBuffer-ID
1200 mMSodium chlorideNaCl1
220 mMHEPESHepes1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 3000 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 39.6 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 3867
EM imaging opticsEnergyfilter name: GIF Quantum LS
Image scansWidth: 3838 / Height: 3710

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.17.1_3660refinement
PHENIX1.17.1_3660refinement
EM software
IDNameVersionCategory
4Gctf1.06CTF correction
10RELION2initial Euler assignment
11RELION2final Euler assignment
12RELION2classification
13RELION23D reconstruction
CTF correctionType: NONE
Particle selectionNum. of particles selected: 411680
3D reconstructionResolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 29418 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 325.28 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.005413740
ELECTRON MICROSCOPYf_angle_d0.768718624
ELECTRON MICROSCOPYf_chiral_restr0.0442000
ELECTRON MICROSCOPYf_plane_restr0.00572456
ELECTRON MICROSCOPYf_dihedral_angle_d15.84011868

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