Abstract
Human indoleamine 2,3-dioxygenase 1 (hIDO1) is an attractive cancer immunotherapeutic target owing to its role in promoting tumoral immune escape. However, drug development has been hindered by limited structural information. Here, we report the crystal structures of hIDO1 in complex with its substrate, Trp, an inhibitor, epacadostat, and/or an effector, indole ethanol (IDE). The data reveal structural features of the active site (Sa) critical for substrate activation; in addition, they disclose a new inhibitor-binding mode and a distinct small molecule binding site (Si). Structure-guided mutation of a critical residue, F270, to glycine perturbs the Si site, allowing structural determination of an inhibitory complex, where both the Sa and Si sites are occupied by Trp. The Si site offers a novel target site for allosteric inhibitors and a molecular explanation for the previously baffling substrate-inhibition behavior of the enzyme. Taken together, the data open exciting new avenues for structure-based drug design.
Highlights
Human indoleamine 2,3-dioxygenase 1 is an attractive cancer immunotherapeutic target owing to its role in promoting tumoral immune escape
We report the structures of the wild-type hIDO1 in complex with Trp, an inhibitor, and/or an effector (IDE), as well as comparable structures of an active site mutant, F270G
The JK-LoopN is only present in hIDO1, not in human tryptophan dioxygenase (hTDO), the two dioxygenases share high structure-based sequence homology, in particular in the active site (Supplementary Fig. 1)
Summary
Human indoleamine 2,3-dioxygenase 1 (hIDO1) is an attractive cancer immunotherapeutic target owing to its role in promoting tumoral immune escape. An analog of hIDO1, human tryptophan dioxygenase (hTDO)[10], and a second isoform of hIDO1, named hIDO211,12, have recently been identified as immunomodulatory proteins with potential relevance to cancer. Together, they represent a new attractive class of immunotherapeutic targets. All the reported hIDO1 inhibitors target the active site, Sa, which is spacious and flexible; in addition, most of the inhibitors are prone to heme iron coordination. Together, they pose serious limitations in computer-aided drug design[13]. The implication of the data on the dioxygenase and substrateinhibition mechanisms of hIDO1, as well as structure-based design of hIDO1-selective inhibitors, will be discussed
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