Journal
SCIENTIFIC REPORTS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep35169
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Funding
- Protein Structure Initiative of the National Institutes of Health [P50 GM62413, U54 GM074958]
- National Institutes of Health [GM086482, GM115773, GM44037, DK26506]
- NIH NIGMS of the UCSF Bio-Organic Biomedical Mass Spectrometry Resource at UCSF [8P41GM103481]
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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-2 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-2 on the C-2 atom of the L-Trp indole ring. The structure also reveals an exo binding site for L-Trp, located similar to 42 angstrom 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.
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