6f0a
Crystal structure of human indoleamine 2,3-dioxygenase bound to a triazole inhibitor and alanine molecule.
Structural highlights
FunctionI23O1_HUMAN Catalyzes the cleavage of the pyrrol ring of tryptophan and incorporates both atoms of a molecule of oxygen.[1] Publication Abstract from PubMedIndoleamine-2,3 dioxygenase (IDO) has emerged as a central regulator of immune responses in both normal and disease biology. Due to its established role in promoting tumour immune escape, IDO has become an attractive target for cancer treatment. We have identified a novel series of highly cell potent IDO inhibitors based on a 4-amino-1,2,3-triazole core. Comprehensive kinetic, biochemical and structural studies demonstrate that compounds from this series have a non-competitive kinetic mechanism-of-action with respect to the tryptophan substrate. Surprisingly, they bind in the tryptophan pocket, making a direct ligand interaction with the haem iron of the porphyrin cofactor. We propose that these data can be rationalised by an ordered binding mechanism in which the inhibitor binds an apo form of the enzyme that is not competent to bind tryptophan. These inhibitors also form a very tight, long-lived complex with the enzyme, which we propose partially explains their exquisite cellular potency. This novel series represents an attractive starting point for the future development of potent IDO targeted drugs. Novel 4-amino-1,2,3-triazole inhibitors of indoleamine 2,3-dioxygenase form a long-lived complex with the enzyme and display exquisite cellular potency.,Alexandre J, Swan M, Latchem M, Boyall D, Pollard J, Hughes S, Westcott J Chembiochem. 2017 Dec 14. doi: 10.1002/cbic.201700560. PMID:29240291[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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