8r5r | pdb_00008r5r
Structure of apo TDO with a bound inhibitor
Structural highlights
FunctionT23O_HUMAN Incorporates oxygen into the indole moiety of tryptophan. Has a broad specificity towards tryptamine and derivatives including D- and L-tryptophan, 5-hydroxytryptophan and serotonin (By similarity). Publication Abstract from PubMedTryptophan-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. Discovery and binding mode of small molecule inhibitors of the apo form of human TDO2.,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 Sci Rep. 2024 Nov 14;14(1):27937. doi: 10.1038/s41598-024-78981-4. PMID:39537789[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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