Mapping the Binding Trajectory of a Suicide Inhibitor in Human Indoleamine 2,3 Dioxygenase 1

Abstract

Human indoleamine 2,3-dioxygenase 1 (hIDO1) is a small heme-containing enzyme that is an important cancer immune therapeutic target. Several hIDO1 inhibitors have entered clinical trials, among which BMS-986205 (BMS) stands out as the only suicide inhibitor. Here, we crystalized the hIDO1-BMS complex and identified three snapshots along the inhibitor binding trajectory. BMS first binds in a surface cleft near the active site in an extended conformation. The initial binding leads to partial protein unfolding that triggers heme release and subsequent large-scale movement of the inhibitor to the vacant heme binding site, where it adopts a high-energy kinked conformation. Finally the protein reaches its energy-minimum state with the inhibitor relaxed to a bent conformation. The data offers new insights into structure-based design of hIDO1-selective inhibitors.