9TN8
cryo-EM structure of human Tryptophan 2,3-dioxygenase (TDO2)
Summary for 9TN8
| Entry DOI | 10.2210/pdb9tn8/pdb |
| Related | 9TL5 9TLF |
| EMDB information | 56042 56053 56068 56080 |
| Descriptor | Tryptophan 2,3-dioxygenase, PROTOPORPHYRIN IX CONTAINING FE (2 entities in total) |
| Functional Keywords | tryptophan metabolism, heme cofactor, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 201295.21 |
| Authors | |
| Primary citation | Thielen, A.S.,Brauning, B.,Gottemukkala, K.V.,Muller, J.,Prabu, J.R.,Verma, P.,Klaessens, S.,Van den Eynde, B.J.,Kleiger, G.,Murray, P.J.,Schulman, B.A. A CK2-beta-TrCP kinase-E3 ubiquitin ligase cascade is a metabolic sensor regulating tryptophan 2,3-dioxygenase stability. Mol.Cell, 2026 Cited by PubMed 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 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. PubMed: 42863465DOI: 10.1016/j.molcel.2026.09.023 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.95 Å) |
Structure validation
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