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- EMDB-32540: Cryo-EM structure of human TPH2 tetramer -

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Basic information

Entry
Database: EMDB / ID: EMD-32540
TitleCryo-EM structure of human TPH2 tetramer
Map datahalf map 2
Sample
  • Complex: Complex of human TPH2 with bound Fe2+ and imidazole
    • Protein or peptide: Tryptophan 5-hydroxylase 2
  • Ligand: FE (III) ION
  • Ligand: IMIDAZOLE
KeywordsHuman / Tryptophan 5-hydroxylase 2 / tetramer / BIOSYNTHETIC PROTEIN
Function / homology
Function and homology information


tryptophan 5-monooxygenase / tryptophan 5-monooxygenase activity / Serotonin and melatonin biosynthesis / aromatic amino acid metabolic process / serotonin biosynthetic process / neuron projection / iron ion binding / cytosol
Similarity search - Function
Tryptophan 5-monooxygenase / Tryptophan 5-hydroxylase, catalytic 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 ...Tryptophan 5-monooxygenase / Tryptophan 5-hydroxylase, catalytic 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 domain profile. / ACT domain / ACT-like domain
Similarity search - Domain/homology
Tryptophan 5-hydroxylase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.09 Å
AuthorsZhu KF / Liu C / Zhang HW / Wang DP
Funding support China, 3 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31900046 China
National Natural Science Foundation of China (NSFC)81972085 China
National Natural Science Foundation of China (NSFC)82172465 China
CitationJournal: Front Pharmacol / Year: 2022
Title: Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2.
Authors: Kongfu Zhu / Chao Liu / Yuanzhu Gao / Jianping Lu / Daping Wang / Huawei Zhang /
Abstract: Human tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in the synthesis of serotonin. Its dysfunction has been implicated in various psychiatric disorders such as depression, autism, and ...Human tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in the synthesis of serotonin. Its dysfunction has been implicated in various psychiatric disorders such as depression, autism, and bipolar disorder. TPH2 is typically decreased in stability and catalytic activity in patients; thus, screening of molecules capable of binding and stabilizing the structure of TPH2 in activated conformation is desired for drug development in mental disorder treatment. Here, we solved the 3.0 Å cryo-EM structure of the TPH2 tetramer. Then, based on the structure, we conducted allosteric site prediction and small-molecule activator screening to the obtained cavity. ZINC000068568685 was successfully selected as the best candidate with highest binding affinity. To better understand the driving forces and binding stability of the complex, we performed molecular dynamics simulation, which indicates that ZINC000068568685 has great potential to stabilize the folding of the TPH2 tetramer to facilitate its activity. The research might shed light on the development of novel drugs targeting TPH2 for the treatment of psychological disorders.
History
DepositionJan 5, 2022-
Header (metadata) releaseOct 5, 2022-
Map releaseOct 5, 2022-
UpdateJun 26, 2024-
Current statusJun 26, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_32540.png

Downloads & links

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Map

FileDownload / File: emd_32540.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationhalf map 2
Voxel sizeX=Y=Z: 0.842 Å
Density
Contour LevelBy AUTHOR: 0.4
Minimum - Maximum-2.9167008 - 4.7845745
Average (Standard dev.)0.0014280446 (±0.13637945)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 215.552 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map 1

Fileemd_32540_half_map_1.map
Annotationhalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 1

Fileemd_32540_half_map_2.map
Annotationhalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of human TPH2 with bound Fe2+ and imidazole

EntireName: Complex of human TPH2 with bound Fe2+ and imidazole
Components
  • Complex: Complex of human TPH2 with bound Fe2+ and imidazole
    • Protein or peptide: Tryptophan 5-hydroxylase 2
  • Ligand: FE (III) ION
  • Ligand: IMIDAZOLE

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Supramolecule #1: Complex of human TPH2 with bound Fe2+ and imidazole

SupramoleculeName: Complex of human TPH2 with bound Fe2+ and imidazole / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Tryptophan 5-hydroxylase 2

MacromoleculeName: Tryptophan 5-hydroxylase 2 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: tryptophan 5-monooxygenase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 56.129609 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MQPAMMMFSS KYWARRGFSL DSAVPEEHQL LGSSTLNKPN SGKNDDKGNK GSSKREAATE SGKTAVVFSL KNEVGGLVKA LRLFQEKRV NMVHIESRKS RRRSSEVEIF VDCECGKTEF NELIQLLKFQ TTIVTLNPPE NIWTEEEELE DVPWFPRKIS E LDKCSHRV ...String:
MQPAMMMFSS KYWARRGFSL DSAVPEEHQL LGSSTLNKPN SGKNDDKGNK GSSKREAATE SGKTAVVFSL KNEVGGLVKA LRLFQEKRV NMVHIESRKS RRRSSEVEIF VDCECGKTEF NELIQLLKFQ TTIVTLNPPE NIWTEEEELE DVPWFPRKIS E LDKCSHRV LMYGSELDAD HPGFKDNVYR QRRKYFVDVA MGYKYGQPIP RVEYTEEETK TWGVVFRELS KLYPTHACRE YL KNFPLLT KYCGYREDNV PQLEDVSMFL KERSGFTVRP VAGYLSPRDF LAGLAYRVFH CTQYIRHGSD PLYTPEPDTC HEL LGHVPL LADPKFAQFS QEIGLASLGA SDEDVQKLAT CYFFTIEFGL CKQEGQLRAY GAGLLSSIGE LKHALSDKAC VKAF DPKTT CLQECLITTF QEAYFVSESF EEAKEKMRDF AKSITRPFSV YFNPYTQSIE ILKDTRSIEN VVQDLRSDLN TVCDA LNKM NQYLGI

UniProtKB: Tryptophan 5-hydroxylase 2

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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: IMIDAZOLE

MacromoleculeName: IMIDAZOLE / type: ligand / ID: 3 / Number of copies: 4 / Formula: IMD
Molecular weightTheoretical: 69.085 Da
Chemical component information

ChemComp-IMD:
IMIDAZOLE

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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

Concentration2.5 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5den

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.09 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 318441
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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