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

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Basic information

Entry
Database: PDB / ID: 9tlf
Titlecryo-EM structure of human Tryptophan 2,3-dioxygenase (TDO2)
ComponentsTryptophan 2,3-dioxygenase
KeywordsOXIDOREDUCTASE / Tryptophan metabolism / Heme cofactor
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
PROTOPORPHYRIN IX CONTAINING FE / alpha-methyl-L-tryptophan / Tryptophan 2,3-dioxygenase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.86 Å
AuthorsThielen, A.S. / Prabu, J.R. / Schulman, B.A.
Funding support Germany, 2items
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, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 21, 2026Provider: repository / Type: Initial release
Revision 1.0Oct 21, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tryptophan 2,3-dioxygenase
B: Tryptophan 2,3-dioxygenase
C: Tryptophan 2,3-dioxygenase
D: Tryptophan 2,3-dioxygenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)202,16812
Polymers198,8294
Non-polymers3,3398
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Tryptophan 2,3-dioxygenase / TDO / Tryptamin 2 / 3-dioxygenase / Tryptophan oxygenase / TO / TRPO / Tryptophan pyrrolase / Tryptophanase


Mass: 49707.316 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TDO2, TDO / Production host: Escherichia coli (E. coli) / References: UniProt: P48775, tryptophan 2,3-dioxygenase
#2: Chemical
ChemComp-ZIQ / alpha-methyl-L-tryptophan


Type: L-peptide linking / Mass: 218.252 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C12H14N2O2
#3: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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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: Tetrameric Tryptophan 2,3-dioxygenase / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 59.93 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.21.1_5286model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.86 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 528478 / Symmetry type: POINT
Atomic model buildingAccession code: P48775 / Details: Uniprot ID P48775; used AlphaFold3 / Source name: AlphaFold / Type: in silico model
RefinementHighest resolution: 2.86 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00412188
ELECTRON MICROSCOPYf_angle_d0.70616520
ELECTRON MICROSCOPYf_dihedral_angle_d8.4311636
ELECTRON MICROSCOPYf_chiral_restr0.0381740
ELECTRON MICROSCOPYf_plane_restr0.0172100

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