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- PDB-7pim: Partial structure of tyrosine hydroxylase lacking the first 35 re... -

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Basic information

Entry
Database: PDB / ID: 7pim
TitlePartial structure of tyrosine hydroxylase lacking the first 35 residues in complex with dopamine.
Components
  • Regulatory domain alpha-helix
  • Tyrosine 3-monooxygenase
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 / 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 / circadian sleep/wake cycle / epinephrine biosynthetic process / Catecholamine biosynthesis / aminergic neurotransmitter loading into synaptic vesicle / dopamine binding / response to pyrethroid / eye photoreceptor cell development / response to isolation stress / melanosome membrane / sphingolipid metabolic process / 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 / pigmentation / response to corticosterone / response to zinc ion / cellular response to alkaloid / social behavior / response to immobilization stress / smooth endoplasmic reticulum / response to light stimulus / 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 / learning / response to activity / locomotory behavior / cellular response to glucose stimulus / animal organ morphogenesis / ferrous iron binding / terminal bouton / cytoplasmic side of plasma membrane / cerebral cortex development / memory / cellular response to growth factor stimulus / 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 / 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
: / L-DOPAMINE / Tyrosine 3-monooxygenase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.6 Å
AuthorsBueno-Carrasco, M.T. / Cuellar, J. / Santiago, C. / Valpuesta, J.M. / Martinez, A. / Flydal, M.I.
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 20, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 22, 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
Revision 1.2Jul 17, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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Structure visualization

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  • Deposited structure unit
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Assembly

Deposited unit
B: Tyrosine 3-monooxygenase
G: Regulatory domain alpha-helix
A: Tyrosine 3-monooxygenase
C: Regulatory domain alpha-helix
D: Tyrosine 3-monooxygenase
E: Regulatory domain alpha-helix
F: Tyrosine 3-monooxygenase
H: Regulatory domain alpha-helix
hetero molecules


Theoretical massNumber of molelcules
Total (without water)160,68316
Polymers159,8478
Non-polymers8368
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, cross-linking, gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "F"
d_2ens_1chain "A"
d_3ens_1chain "D"
d_4ens_1chain "B"
d_1ens_2chain "H"
d_2ens_2chain "G"
d_3ens_2chain "C"
d_4ens_2chain "E"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1VALGLYM1 - 335
d_12ens_1LDPLDPN
d_21ens_1VALGLYE1 - 335
d_22ens_1LDPLDPF
d_31ens_1VALGLYI1 - 335
d_32ens_1LDPLDPJ
d_41ens_1VALGLYA1 - 335
d_42ens_1LDPLDPB
d_11ens_2SERALAP1 - 18
d_21ens_2SERALAD1 - 18
d_31ens_2SERALAH1 - 18
d_41ens_2SERALAL1 - 18

NCS ensembles :
ID
ens_1
ens_2

NCS oper:
IDCodeMatrixVector
1given(0.999999947878, -0.000227735659079, 0.000228867978049), (-0.000227770254315, -0.999999962638, 0.000151143350722), (0.000228833548767, -0.000151195472161, -0.999999962388)0.00471564813897, 171.52457278, 171.508364978
2given(-0.999999817618, 0.000406259424134, -0.000446897857169), (-0.000406328683299, -0.999999905452, 0.000154897740408), (-0.000446834886249, 0.000155079299575, 0.999999888144)171.517361185, 171.547238596, 0.0371617620258
3given(-0.999999986438, 0.000123998711812, -0.000108393348202), (0.000124074646406, 0.999999746728, -0.000700820837883), (0.000108306419867, -0.000700834277245, -0.99999974855)171.517280204, 0.0383867072982, 171.555615792
4given(-0.999999986739, 0.000121267744282, -0.000108702424946), (0.000121345395544, 0.999999737293, -0.000714625370785), (0.000108615735383, -0.000714638551847, -0.999999738747)171.51759712, 0.0394992923727, 171.557106092
5given(0.999999951722, -0.000216449434792, 0.00022294563859), (-0.000216483921835, -0.999999964605, 0.000154675610658), (0.000222912151251, -0.000154723867337, -0.999999963185)0.00378193807504, 171.523087284, 171.509392783
6given(-0.999999812183, 0.000410813005695, -0.000454825235913), (-0.000410887244912, -0.999999902278, 0.000163144400072), (-0.000454758169625, 0.000163331251319, 0.999999883259)171.517399221, 171.54727638, 0.037137844895

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Components

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


Mass: 38087.766 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: Protein/peptide
Regulatory domain alpha-helix


Mass: 1874.081 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Chemical
ChemComp-LDP / L-DOPAMINE / DOPAMINE


Mass: 153.178 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H11NO2 / Comment: medication*YM
#4: Chemical
ChemComp-FE / FE (III) ION


Mass: 55.845 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Fe
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 lacking the first 35 residues in complex with its inhibitor dopamine
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
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
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
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: 81000 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: 30 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 13213
EM imaging opticsEnergyfilter name: GIF Quantum LS

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.19_4092refinement
PHENIX1.19_4092refinement
EM software
IDNameVersionCategory
4Gctf1.06CTF correction
10RELION2initial Euler assignment
11RELION2final Euler assignment
12RELION2classification
13RELION23D reconstruction
CTF correctionType: NONE
Particle selectionNum. of particles selected: 1626575
3D reconstructionResolution: 4.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 152128 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 274.56 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.001111592
ELECTRON MICROSCOPYf_angle_d0.319715712
ELECTRON MICROSCOPYf_chiral_restr0.03221684
ELECTRON MICROSCOPYf_plane_restr0.00222068
ELECTRON MICROSCOPYf_dihedral_angle_d8.3384252
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2DELECTRON MICROSCOPYNCS constraints0.000707779601733
ens_1d_3DELECTRON MICROSCOPYNCS constraints0.000701244583421
ens_1d_4DELECTRON MICROSCOPYNCS constraints0.000707763666106
ens_2d_2FELECTRON MICROSCOPYNCS constraints0.000697556400164
ens_2d_3FELECTRON MICROSCOPYNCS constraints0.000724372223256
ens_2d_4FELECTRON MICROSCOPYNCS constraints0.000703445935164

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