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- EMDB-16223: Cryo-EM structure of the catalytic domain tetramer of N-terminall... -

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Basic information

Entry
Database: EMDB / ID: EMD-16223
TitleCryo-EM structure of the catalytic domain tetramer of N-terminally truncated human tryptophan hydroxylase 2
Map data
Sample
  • Complex: 47 N-terminally truncated human tryptophan hydroxylase 2
KeywordsSerotonin biosynthesis / Tryptophan hydroxylase / aromatic amino acid hydroxylases / OXIDOREDUCTASE
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsZhang Z / Vedel IM / Skawinska NT / Harris P / Stark H / Peters GHJ
Funding support Denmark, 1 items
OrganizationGrant numberCountry
Danish Council for Independent ResearchDFF-6108-00247 Denmark
CitationJournal: Structure / Year: 2023
Title: Structural characterization of human tryptophan hydroxylase 2 reveals that L-Phe is superior to L-Trp as the regulatory domain ligand.
Authors: Ida M Vedel / Andreas Prestel / Zhenwei Zhang / Natalia T Skawinska / Holger Stark / Pernille Harris / Birthe B Kragelund / Günther H J Peters /
Abstract: Tryptophan hydroxylase 2 (TPH2) catalyzes the rate-limiting step in serotonin biosynthesis in the brain. Consequently, regulation of TPH2 is relevant for serotonin-related diseases, yet the ...Tryptophan hydroxylase 2 (TPH2) catalyzes the rate-limiting step in serotonin biosynthesis in the brain. Consequently, regulation of TPH2 is relevant for serotonin-related diseases, yet the regulatory mechanism of TPH2 is poorly understood and structural and dynamical insights are missing. We use NMR spectroscopy to determine the structure of a 47 N-terminally truncated variant of the regulatory domain (RD) dimer of human TPH2 in complex with L-Phe, and show that L-Phe is the superior RD ligand compared with the natural substrate, L-Trp. Using cryo-EM, we obtain a low-resolution structure of a similarly truncated variant of the complete tetrameric enzyme with dimerized RDs. The cryo-EM two-dimensional (2D) class averages additionally indicate that the RDs are dynamic in the tetramer and likely exist in a monomer-dimer equilibrium. Our results provide structural information on the RD as an isolated domain and in the TPH2 tetramer, which will facilitate future elucidation of TPH2's regulatory mechanism.
History
DepositionNov 23, 2022-
Header (metadata) releaseMay 10, 2023-
Map releaseMay 10, 2023-
UpdateJun 14, 2023-
Current statusJun 14, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16223.png

Downloads & links

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Map

FileDownload / File: emd_16223.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.06 Å
Density
Contour LevelBy AUTHOR: 0.027
Minimum - Maximum-0.029824512 - 0.08477662
Average (Standard dev.)0.000013627717 (±0.0023722867)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 381.59998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_16223_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_16223_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 : 47 N-terminally truncated human tryptophan hydroxylase 2

EntireName: 47 N-terminally truncated human tryptophan hydroxylase 2
Components
  • Complex: 47 N-terminally truncated human tryptophan hydroxylase 2

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Supramolecule #1: 47 N-terminally truncated human tryptophan hydroxylase 2

SupramoleculeName: 47 N-terminally truncated human tryptophan hydroxylase 2
type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Detector mode: INTEGRATING / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 4.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 197917
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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