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- EMDB-56042: cryo-EM structure of human Tryptophan 2,3-dioxygenase (TDO2) -

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Basic information

Entry
Database: EMDB / ID: EMD-56042
Titlecryo-EM structure of human Tryptophan 2,3-dioxygenase (TDO2)
Map data
Sample
  • Complex: Tetrameric Tryptophan 2,3-dioxygenase
    • Protein or peptide: Tryptophan 2,3-dioxygenase
  • Ligand: alpha-methyl-L-tryptophan
  • Ligand: PROTOPORPHYRIN IX CONTAINING FE
KeywordsTryptophan metabolism / Heme cofactor / OXIDOREDUCTASE
Function / homology
Function and homology information


response to nitroglycerin / tryptophan 2,3-dioxygenase / response to cortisol / L-tryptophan 2,3-dioxygenase activity / L-tryptophan catabolic process / Tryptophan catabolism / amino acid binding / response to dexamethasone / protein homotetramerization / response to ethanol ...response to nitroglycerin / tryptophan 2,3-dioxygenase / response to cortisol / L-tryptophan 2,3-dioxygenase activity / L-tryptophan catabolic process / Tryptophan catabolism / amino acid binding / response to dexamethasone / protein homotetramerization / response to ethanol / heme binding / metal ion binding / identical protein binding / cytosol
Similarity search - Function
Tryptophan 2,3-dioxygenase / Tryptophan 2,3-dioxygenase / Tryptophan/Indoleamine 2,3-dioxygenase-like
Similarity search - Domain/homology
Tryptophan 2,3-dioxygenase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.25 Å
AuthorsThielen AS / Prabu JR / Schulman BA
Funding support Germany, 2 items
OrganizationGrant numberCountry
Max Planck Society Germany
Boehringer Ingelheim Fonds (BIF) Germany
CitationJournal: Mol Cell / Year: 2026
Title: A CK2-β-TrCP kinase-E3 ubiquitin ligase cascade is a metabolic sensor regulating tryptophan 2,3-dioxygenase stability.
Authors: Alina S Thielen / Bastian Bräuning / Karthik V Gottemukkala / Judith Müller / J Rajan Prabu / Pooja Verma / Simon Klaessens / Benoit J Van den Eynde / Gary Kleiger / Peter J Murray / Brenda A Schulman /
Abstract: Small molecules toggling the ubiquitin-proteasome system (UPS) are powerful regulators of protein degradation, yet how endogenous ligands gate UPS decisions remains poorly understood. Here, we define ...Small molecules toggling the ubiquitin-proteasome system (UPS) are powerful regulators of protein degradation, yet how endogenous ligands gate UPS decisions remains poorly understood. Here, we define control of UPS access to human tryptophan 2,3-dioxygenase (TDO2), which converts the amino acid tryptophan (Trp) to N-formylkynurenine. When Trp concentrations are limiting, TDO2 is degraded to avert hypotryptophanemia. We discovered that a CK2-β-TrCP kinase-E3 ligase cascade generates and recognizes phosphodegrons in TDO2 unless they are shielded by Trp binding at an exosite distal from the catalytic site. Effects of Trp analogs on CK2-β-TrCP-dependent ubiquitylation indicated that the indole, amino, and carboxylate groups collectively protect TDO2. Cryo-EM reveals that these moieties organize a Trp-ordered flap that covers the exosite and thereby restricts generation of adjacent phosphodegrons. In the absence of Trp, the flap is flexible, enabling phosphorylation-coupled ubiquitylation. Overall, our data uncovered an endogenous small molecule conformationally stabilizing its own metabolizing enzyme through protection from a phosphorylation-ubiquitylation cascade.
History
DepositionDec 10, 2025-
Header (metadata) releaseOct 21, 2026-
Map releaseOct 21, 2026-
UpdateOct 21, 2026-
Current statusOct 21, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_56042.png

Downloads & links

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Map

FileDownload / File: emd_56042.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 256 pix.
= 210.483 Å		0.82 Å/pix.
x 256 pix.
= 210.483 Å		0.82 Å/pix.
x 256 pix.
= 210.483 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8222 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0853
Minimum - Maximum-0.2203361 - 0.4306677
Average (Standard dev.)0.0017987613 (±0.018109879)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 210.4832 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_56042_msk_1.map
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Additional map: #1

Fileemd_56042_additional_1.map
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Half map: #1

Fileemd_56042_half_map_1.map
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Half map: #2

Fileemd_56042_half_map_2.map
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Sample components

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Entire : Tetrameric Tryptophan 2,3-dioxygenase

EntireName: Tetrameric Tryptophan 2,3-dioxygenase
Components
  • Complex: Tetrameric Tryptophan 2,3-dioxygenase
    • Protein or peptide: Tryptophan 2,3-dioxygenase
  • Ligand: alpha-methyl-L-tryptophan
  • Ligand: PROTOPORPHYRIN IX CONTAINING FE

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Supramolecule #1: Tetrameric Tryptophan 2,3-dioxygenase

SupramoleculeName: Tetrameric Tryptophan 2,3-dioxygenase / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Tryptophan 2,3-dioxygenase

MacromoleculeName: Tryptophan 2,3-dioxygenase / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: tryptophan 2,3-dioxygenase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 49.707316 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: HHHHHHENLY FQGSMSGCPF LGNNFGYTFK KLPVEGSEED KSQTGVNRAS KGGLIYGNYL HLEKVLNAQE LQSETKGNKI HDEHLFIIT HQAYELWFKQ ILWELDSVRE IFQNGHVRDE RNMLKVVSRM HRVSVILKLL VQQFSILETM TALDFNDFRE Y LSPASGFQ ...String:
HHHHHHENLY FQGSMSGCPF LGNNFGYTFK KLPVEGSEED KSQTGVNRAS KGGLIYGNYL HLEKVLNAQE LQSETKGNKI HDEHLFIIT HQAYELWFKQ ILWELDSVRE IFQNGHVRDE RNMLKVVSRM HRVSVILKLL VQQFSILETM TALDFNDFRE Y LSPASGFQ SLQFRLLENK IGVLQNMRVP YNRRHYRDNF KGEENELLLK SEQEKTLLEL VEAWLERTPG LEPHGFNFWG KL EKNITRG LEEEFIRIQA KEESEEKEEQ VAEFQKQKEV LLSLFDEKRH EHLLSKGERR LSYRALQGAL MIYFYREEPR FQV PFQLLT SLMDIDSLMT KWRYNHVCMV HRMLGSKAGT GGSSGYHYLR STVSDRYKVF VDLFNLSTYL IPRHWIPKMN PTIH KFLYT AEYCDSSYFS SDESD

UniProtKB: Tryptophan 2,3-dioxygenase

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Macromolecule #2: alpha-methyl-L-tryptophan

MacromoleculeName: alpha-methyl-L-tryptophan / type: ligand / ID: 2 / Number of copies: 4 / Formula: ZIQ
Molecular weightTheoretical: 218.252 Da
Chemical component information

ChemComp-ZIQ:
alpha-methyl-L-tryptophan

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Macromolecule #3: PROTOPORPHYRIN IX CONTAINING FE

MacromoleculeName: PROTOPORPHYRIN IX CONTAINING FE / type: ligand / ID: 3 / Number of copies: 4 / Formula: HEM
Molecular weightTheoretical: 616.487 Da
Chemical component information

ChemComp-HEM:
PROTOPORPHYRIN IX CONTAINING FE

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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: 7.5
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 59.93 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.25 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 51108
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

9tlf


Chain - Source name: PDB / Chain - Initial model type: experimental model
Output model

PDB-9tl5:
cryo-EM structure of human Tryptophan 2,3-dioxygenase (TDO2)

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