5TI9

Crystal structure of human TDO in complex with Trp and dioxygen, Northeast Structural Genomics Consortium Target HR6161

Summary for 5TI9

• Entry DOI: 10.2210/pdb5ti9/pdb
• Related: 5TIA
• Descriptor: Tryptophan 2,3-dioxygenase, OXYGEN MOLECULE, PROTOPORPHYRIN IX CONTAINING FE, ... (7 entities in total)
• Functional Keywords: human tryptophan 2, 3-dioxygenase in complex with trp and o2, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 185147.83

Authors

Forouhar, F.,Lewis-Ballester, A.,Lew, S.,Karkashon, S.,Seetharaman, J.,Yeh, S.R.,Tong, L. (deposition date: 2016-10-01, release date: 2016-10-26, Last modification date: 2023-11-15)

Primary citation

Lewis-Ballester, A.,Forouhar, F.,Kim, S.M.,Lew, S.,Wang, Y.,Karkashon, S.,Seetharaman, J.,Batabyal, D.,Chiang, B.Y.,Hussain, M.,Correia, M.A.,Yeh, S.R.,Tong, L.
Molecular basis for catalysis and substrate-mediated cellular stabilization of human tryptophan 2,3-dioxygenase.
Sci Rep, 6:35169-35169, 2016

PubMed Abstract: Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) play a central role in tryptophan metabolism and are involved in many cellular and disease processes. Here we report the crystal structure of human TDO (hTDO) in a ternary complex with the substrates L-Trp and O and in a binary complex with the product N-formylkynurenine (NFK), defining for the first time the binding modes of both substrates and the product of this enzyme. The structure indicates that the dioxygenation reaction is initiated by a direct attack of O on the C atom of the L-Trp indole ring. The structure also reveals an exo binding site for L-Trp, located ~42 Å from the active site and formed by residues conserved among tryptophan-auxotrophic TDOs. Biochemical and cellular studies indicate that Trp binding at this exo site does not affect enzyme catalysis but instead it retards the degradation of hTDO through the ubiquitin-dependent proteasomal pathway. This exo site may therefore provide a novel L-Trp-mediated regulation mechanism for cellular degradation of hTDO, which may have important implications in human diseases.

PubMed: 27762317
DOI: 10.1038/srep35169

Experimental method

X-RAY DIFFRACTION (2.5 Å)