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Tracking Hidden Binding Pockets Along the Molecular Recognition Path of l-Trp to Indoleamine 2,3-Dioxygenase 1 |
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| Authors: | Dr Francesco A Greco Dr Elisa Albini Dr Alice Coletti Dr Daniela Dolciami Prof Andrea Carotti Dr Ciriana Orabona Prof Ursula Grohmann Prof Antonio Macchiarulo |
| Affiliation: | 1. Department of Pharmaceutical Sciences, University of Perugia, via del liceo n.1, 06123 Perugia, Italy
These authors contributed equally to this work.;2. Department of Experimental Medicine, University of Perugia, P.le Gambuli, 06132 Perugia, Italy These authors contributed equally to this work.;3. Department of Pharmaceutical Sciences, University of Perugia, via del liceo n.1, 06123 Perugia, Italy;4. Department of Experimental Medicine, University of Perugia, P.le Gambuli, 06132 Perugia, Italy These authors share senior authorship.;5. Department of Experimental Medicine, University of Perugia, P.le Gambuli, 06132 Perugia, Italy |
| Abstract: | Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the oxidative cleavage of l -Tryptophan (l -Trp) to yield N-formyl-kynurenine in the first and rate limiting step of the kynurenine pathway. Bioactive metabolites, involved in the regulation of important immunological responses and neurological processes, are then produced by downstream enzymes along the pathway. Inhibitors of IDO1 are being designed and developed as therapeutic agents for immuno-oncology. In this work, we investigated the molecular recognition path of l -Trp to IDO1, integrating biophysical methods with supervised molecular dynamics (suMD) and mutagenesis experiments. Results allowed disclosing for the first time high and low dissociation constants of l -Trp to IDO1, and the presence of a metastable interaction site located at the upper part of a channel whose borders are defined by the EF-loop and the C-terminal part of the JK-loop. Collectively, our results provide new clues for the design of next-generation IDO1 ligands. |
| Keywords: | Tryptophan Kynurenine IDO1 Molecular Dynamics Binding |