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. (Figure presented.)
Ligand-induced conformations and dynamic allosteric motions of IDO1 affecting the recruitment of a protein signaling partner
Mazzoletti D.;Miggiano R.;
2025-01-01
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. (Figure presented.)I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
