New Insights from Crystallographic Data: Diversity of Structural Motifs and Molecular Recognition Properties between Groups of IDO1 Structures

Abstract

A large number of crystallographic structures of IDO1 in different ligand-bound and -unbound states have been disclosed over the last decade. Yet, only a few of them have been exploited for structure-based drug design (SBDD) campaigns. In this study, we analyzed the structural motifs and molecularrecognition properties of three groups of IDO1 structures: 1) structures containing the heme group and inhibitors in the catalytic site; 2) heme-free structures of IDO1; 3) substratebound structures of IDO1. The results suggest that unrelated conformations of the enzyme have been solved with different ligand-induced changes of secondary motifs that localize even in regions remote from the catalytic site. Moreover, the study identified an uncharted region of molecular-recognition space covered by IDO1 binding sites that could guide the selection of diverse structures for additional SBDD studies aimed at the identification of novel lead compounds with differentiated chemical scaffolds.

Indoleamine 2,3‐dioxygenase 1 (IDO1): an up‐to‐date overview of an eclectic immunoregulatory enzyme

“…All rights reserved Several crystallographic structures of human IDO1 are available in different ligand-bound and unbound forms [13]. Overall, they show a conserved fold of the enzymic primary sequence that is composed of a large domain containing the catalytic cleft and a small domain featuring two functional immunoreceptor tyrosine-based inhibitory motifs (ITIMs) (Y111, Y249) that are associated to the non-catalytic signaling function of the enzyme (Figure 2) [8,10,14]. A further conserved post-transcriptional regulatory site is located at a YENM motif (residues 145-148), which extends from the small domain towards the large domain.…”

“…IDO1 and thus affect not only its catalytic but also the signaling function [10]. In patients with non-curable glioblastoma, the advanced age was associated with increased IDO1 expression, decreased immunotherapeutic efficacy, and was not reversed by IDO1 enzyme inhibition [146],…”

One Key and Multiple Locks: Substrate Binding in Structures of Tryptophan Dioxygenases and Hydroxylases

“…Since the determination of the first crystal structure of IDO1 (PDB codes: 2D0T, 2D0U), [51] an increasing number of crystallographic studies proved successful to disclose different ligand‐bound and unbound forms of the enzyme that show a conserved architecture with specific ligand‐induced conformational changes of secondary motifs. [52] According to these studies, the heme‐containing catalytic site is located into a large domain of IDO1, whereas two functional immunoreceptor tyrosine‐based inhibition motifs (ITIM, Tyr111, Tyr249) are placed in a small domain which, upon phosphorylation by Src kinases, accounts for the non‐catalytic signaling functions of the enzyme (Figure 2 A). [53] A further conserved phosphorylation site is located at YENM motif (residues 145–148) which protrudes from the small domain toward α‐helix B of the large domain (Figure 2 B).…”

2020 Italian Special Anniversary Collection: Celebrating NMMC 2019 and 40 Years of the DCF‐SCI

“…Antonio Macchiarulo and co-workers performed a detailed study of several groups of crystal structures of IDO1 (Indoleamine 2,3-dioxygenase 1), a relatively novel immune checkpoint protein, with multiple effects on effector and regulatory pathways of the immune response. [1] The investigated structures have been disclosed in the last decade in the apo/holo form and/or in complex with small-molecule inhibitors. The analysis suggested that unrelated conformations of the enzyme have been solved with different ligand-induced changes of secondary motifs that localize even in regions remote from the catalytic site.…”