Ligand-induced conformations and dynamic allosteric motions of IDO1 affecting the recruitment of a protein signaling partner

Indoleamine 2,3-dioxygenase 1 (IDO1) is a moonlight protein endowed with catalytic and signaling functions. It plays a pivotal role in the immune breaking mechanism leading to immunosuppression in cancer microenvironment. Intense research efforts have been devoted to designing catalytic inhibitors for developing immunotherapies, yet neglecting the enzyme's signaling function. A few IDO1 inhibitors have reached the clinical stage, including navoximod, epacadostat and linrodostat. Using second harmonic generation analysis (SHG) and molecular dynamics simulations, here we show that these clinical inhibitors can induce distinct allosteric motions in the enzyme that affect the stability of the transient signaling complex between IDO1 and Src tyrosine kinase. Next generation sequencing demonstrates that, despite sharing a similar ability to inhibit the enzyme's catalytic function, all three catalytic inhibitors modulate the IDO1's signaling function in different ways, regulating distinct transcriptomes in SKOV3 cells.

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Publication Details

Journal
Communications Chemistry
Published
2025-09-24
DOI
https://doi.org/10.1038/s42004-025-01648-2
Citations
2
Primary Topic
Tryptophan and brain disorders
Type
article
Field-Weighted Citation Impact
1.16

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article

Ligand-induced conformations and dynamic allosteric motions of IDO1 affecting the recruitment of a protein signaling partner

Sofia Rossini, Alice Coletti, Ciriana Orabona, Andrea Carotti et al.
2 citations
Communications Chemistry
Tryptophan and brain disorders
1.16
article

Ligand-induced conformations and dynamic allosteric motions of IDO1 affecting the recruitment of a protein signaling partner

Sofia Rossini, Alice Coletti, Ciriana Orabona, Andrea Carotti, Daniele Mazzoletti, Antonio Macchiarulo, Alessandra Altomare, Elisa Bianconi, Joshua Salafsky, Giancarlo Aldini, Riccardo Miggiano, Giada Mondanelli, Andrea Butticè
article en
2 citations

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is a moonlight protein endowed with catalytic and signaling functions. It plays a pivotal role in the immune breaking mechanism leading to immunosuppression in cancer microenvironment. Intense research efforts have been devoted to designing catalytic inhibitors for developing immunotherapies, yet neglecting the enzyme's signaling function. A few IDO1 inhibitors have reached the clinical stage, including navoximod, epacadostat and linrodostat. Using second harmonic generation analysis (SHG) and molecular dynamics simulations, here we show that these clinical inhibitors can induce distinct allosteric motions in the enzyme that affect the stability of the transient signaling complex between IDO1 and Src tyrosine kinase. Next generation sequencing demonstrates that, despite sharing a similar ability to inhibit the enzyme's catalytic function, all three catalytic inhibitors modulate the IDO1's signaling function in different ways, regulating distinct transcriptomes in SKOV3 cells.

Communications ChemistryVol. 8(1)
Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT), University of California, San Francisco (US), University of Milan (IT), University of Perugia (IT), Skylight (US)
Dipartimenti di Eccellenza, European Commission, Università degli Studi di Perugia, National Institutes of Health
Openalex Percentile: Top 21%
Tryptophan and brain disorders
1.16
DOIOpen Access PDFOpenAlex
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