8QV7
Crystal structure of human TDO with alpha-methyl-L-tryptophan
Summary for 8QV7
| Entry DOI | 10.2210/pdb8qv7/pdb |
| Descriptor | Tryptophan 2,3-dioxygenase, alpha-methyl-L-tryptophan, GLYCEROL, ... (4 entities in total) |
| Functional Keywords | inhibitor, apo, heme, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 170911.57 |
| Authors | Wicki, M.,Mac Sweeney, A. (deposition date: 2023-10-17, release date: 2024-01-17, Last modification date: 2024-12-04) |
| Primary citation | Lotz-Jenne, C.,Lange, R.,Cren, S.,Bourquin, G.,Goglia, L.,Kimmerlin, T.,Wicki, M.,Muller, M.,Artico, N.,Ackerknecht, S.,Pfaff, P.,Joesch, C.,Mac Sweeney, A. Discovery and binding mode of small molecule inhibitors of the apo form of human TDO2. Sci Rep, 14:27937-27937, 2024 Cited by PubMed Abstract: Tryptophan-2,3-dioxygenase (TDO2) and indoleamine-2,3-dioxygenase (IDO1) are structurally distinct heme enzymes that catalyze the conversion of L-tryptophan to N-formyl-kynurenine, and play important roles in metabolism, inflammation, and tumor immune surveillance. The enzymes can adopt an inactive, heme-free (apo) state or an active, heme-containing (holo) state, with the balance between them varying dynamically according to biological conditions. Inhibitors of holo-TDO2 are known but, despite several advantages of the heme-free state as a drug target, no inhibitors of apo-TDO2 have been reported. We describe the discovery of the first apo-TDO2 binding inhibitors, to our knowledge, and their inhibition of cellular TDO2 activity at low nanomolar concentrations. The crystal structure of a potent, small molecule inhibitor bound to apo-TDO2 reveals its detailed binding interactions within the large, hydrophobic heme binding pocket of the active site. PubMed: 39537789DOI: 10.1038/s41598-024-78981-4 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.928 Å) |
Structure validation
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