High-resolution structures of inhibitor complexes of human indoleamine 2,3-dioxygenase 1 in a new crystal form

Abstract

Edited by M. J. van Raaij, Centro Nacional de Biotecnología -CSIC, Spain Keywords: indoleamine 2,3-dioxygenase 1; cancer immunotherapy; heme proteins; tryptophan metabolism; crystal engineering.PDB references: indoleamine 2,3-dioxygenase 1, complex with epacadostat, 6e40; complex with sulfur analog of epacadostat, 6e41; complex with 4-chlorophenyl imidazole, 6e42; complex with anolog of BMS-978587, 6e43; free enzyme (ferric), 6e44; free enzyme (ferrous), 6e45; complex with tryptophan (ferrous), 6e46Supporting information: this article has supporting information at journals.iucr.org/f High-resolution structures of inhibitor complexes of human indoleamine 2,3-dioxygenase 1 in a new crystal form

Inhibitory effects of flavonoids isolated from Sophora flavescens on indoleamine 2,3-dioxygenase 1 activity

“…According to previous reports, substrate L -Trp binds to Arg 231 , Ala 264 , and Thr 379 residues in IDO1; meanwhile, Ala 264 and His 346 residues are related with haeme-binding ability of IDO1 31 . As described above, the binding site of the flavonoids was considerably distant from the active site of IDO1, and, thus, the flavonoids could act as an allosteric site of IDO1 inhibition activity.…”

Influence of the presence of the heme cofactor on the JK-loop structure in indoleamine 2,3-dioxygenase 1

“…Since the publication of the first two structures of hIDO1 by Sugimoto et al (2006), many structures of hIDO1 with l-Trp or various inhibitors have been deposited in the PDB (Tojo et al, 2014;Peng et al, 2016Peng et al, , 2020Wu et al, 2017;Crosignani et al, 2017;Lewis-Ballester et al, 2017Nelp et al, 2018;Alexandre et al, 2018;Luo et al, 2018;Pham & Yeh, 2018;Pham et al, 2019;Kumar et al, 2019;Zhang et al, 2019;Rö hrig et al, 2019;White et al, 2020). In particular, recent improvements involving surface mutations have allowed the generation of high-resolution structures (from 1.7 to 2.7 Å ) soaked with l-Trp or inhibitors (Luo et al, 2018). To date, only a few articles have focused on an in-depth analysis of the structural aspects of hIDO1 (Lewis-Ballester et al, 2017Pham & Yeh, 2018;Pham et al, 2019;Sugimoto et al, 2006).…”

Discovery and Characterisation of Dual Inhibitors of Tryptophan 2,3-Dioxygenase (TDO2) and Indoleamine 2,3-Dioxygenase 1 (IDO1) Using Virtual Screening

“…The reliability of it is established for the calculated descriptors [55]. The crystal structures for human TDO2 (PDB ID: 6A4I, resolution 2.65 Å) and IDO1 (5EK3, resolution 2.21 Å [30] and 6E43, resolution 1.71 Å [31]) were downloaded from the Protein Data Bank [56,57] and prepared using Protein Preparation Wizard (2018-4: Schrödinger, LLC, New York City, NY, USA, 2018) [58]. Solvent and non-protein residues were removed, hydrogens were added, missing sidechains were filled with Prime (2018-4: Schrödinger, LLC, New York City, NY, USA, 2018), ionization and tautomeric states were generated by Epik (2018-4: Schrödinger, LLC, New York City, NY, USA, 2018), hydrogen orientations were set by Propka.…”

“…Virtual hits need to be tested in a biological assay verifying their affinity for the target of interest. Kynurenine production can be conveniently monitored in a cell-based assay [27,28] and the crystal structures of TDO2 and IDO1 are available [29,30,31]. Herein, we applied the virtual screening technique in conjunction with the cell based kynurenine assay to identify TDO2-specific and dual IDO1/TDO2 inhibitors with potential for further development into drug candidates for cancer immunotherapy.…”