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- PDB-6zvp: Atomic model of the EM-based structure of the full-length tyrosin... -

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Basic information

Entry
Database: PDB / ID: 6zvp
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
ComponentsTyrosine 3-monooxygenaseTyrosine hydroxylase
KeywordsOXIDOREDUCTASE / Tetramer / Dopamine / Catecholamine / Brain / Parkinson
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
: / L-DOPAMINE / Tyrosine 3-monooxygenase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å
AuthorsBueno-Carrasco, M.T. / Cuellar, J. / Santiago, C. / Valpuesta, J.M. / Martinez, A. / Flydal, M.I.
Funding support Spain, 2items
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, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 17, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 2, 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

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Structure visualization

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)206,43612
Polymers205,5994
Non-polymers8368
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "C"
d_2ens_1chain "B"
d_3ens_1chain "A"
d_4ens_1chain "D"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1SERGLYJ1 - 458
d_12ens_1FEFEK
d_13ens_1LDPLDPL
d_21ens_1SERGLYG1 - 458
d_22ens_1FEFEH
d_23ens_1LDPLDPI
d_31ens_1SERGLYD1 - 458
d_32ens_1FEFEE
d_33ens_1LDPLDPF
d_41ens_1SERGLYA1 - 458
d_42ens_1FEFEB
d_43ens_1LDPLDPC

NCS oper:
IDCodeMatrixVector
1given(-0.999999999892, 5.13308851639E-7, 1.46828729885E-5), (-5.1345855715E-7, -0.999999999948, -1.01959257224E-5), (1.46828677541E-5, -1.01959332603E-5, 0.99999999984)188.998800783, 189.000828051, -0.000232906271862
2given(1), (-1), (-1)4.3E-14, 189, 189
3given(-0.999999999892, 5.13308851694E-7, 1.46828729887E-5), (5.13458557205E-7, 0.999999999948, 1.01959257229E-5), (-1.46828677543E-5, 1.01959332608E-5, -0.99999999984)188.998800783, -0.000828051176924, 189.000232906

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Components

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


Mass: 51399.859 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 / Iron


Mass: 55.845 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Fe
#3: Chemical
ChemComp-LDP / L-DOPAMINE / DOPAMINE / Dopamine (medication)


Mass: 153.178 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H11NO2 / Comment: medication*YM
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 in complex with dopamine / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: UltrAuFoil R1.2/1.3
VitrificationCryogen name: ETHANE

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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 FIELDBright-field microscopy
Image recordingElectron dose: 1 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.19_4092refinement
PHENIX1.19_4092refinement
CTF correctionType: NONE
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 36368 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 201.87 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.002114904
ELECTRON MICROSCOPYf_angle_d0.514420204
ELECTRON MICROSCOPYf_chiral_restr0.03672172
ELECTRON MICROSCOPYf_plane_restr0.00452676
ELECTRON MICROSCOPYf_dihedral_angle_d12.58035540
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2BELECTRON MICROSCOPYNCS constraints5.08278702507E-11
ens_1d_3AELECTRON MICROSCOPYNCS constraints2.50277404038E-13
ens_1d_4DELECTRON MICROSCOPYNCS constraints5.08282176732E-11

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