Discovery and binding mode of a small molecule inhibitor of the apo form of human TDO2

Author:

Lotz-Jenne Carina,Lange Roland,Cren Sylvaine,Bourquin Geoffroy,Goglia Laksmei,Kimmerlin Thierry,Wicki MichaORCID,Müller Manon,Artico Nadia,Ackerknecht Sabine,Joesch Christoph,Mac Sweeney AengusORCID

Abstract

AbstractTryptophan-2,3-dioxygenase (TDO2) and indoleamine-2,3-dioxygenase (IDO1) catalyze the conversion of L-tryptophan to N-formyl-kynurenine and play important roles in metabolism, inflammation, and tumor immune surveillance. Their enzymatic activities depend on their heme contents, which vary dynamically according to biological conditions. Inhibitors binding to heme-containing holo-TDO2 are known, but to date no inhibitor that binds to the heme-free state (apo-TDO2) has been reported. We describe the discovery and co-crystal structure of a first apo-TDO2 targeting inhibitor, to our knowledge, which inhibits cellular TDO2 activity at micromolar concentrations.

Publisher

Cold Spring Harbor Laboratory

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