ArticleBiochemistry2016
Structural Study of a Flexible Active Site Loop in Human Indoleamine 2,3-Dioxygenase and Its Functional Implications.
Article in Biochemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 30 citations in OpenAlex.
- Monooxygenase Activity of Indoleamine 2,3-Dioxygenase.Journal of the American Chemical Society · 2026Article
- Ligand-induced conformations and dynamic allosteric motions of IDO1 affecting the recruitment of a protein signaling partner.Communications chemistry · 2025Article
- Phosphorylation of ITIM motifs drives the structural transition of indoleamine 2,3-dioxygenase 1 between enzymatic and non-enzymatic states.Protein science : a publication of the Protein Society · 2025Article
- Action mechanism and molecular design of indolepyrrodione inhibitors targeting IDO1.Frontiers in molecular biosciences · 2025Article
- Secondary Sphere Lewis Acid Activated Heme Superoxo Adducts Mimic Crucial Non-Covalent Interactions in IDO/TDO Heme Dioxygenases.Chemistry (Weinheim an der Bergstrasse, Germany) · 2024Article
- Indoleamine 2,3-dioxygenase 1 (IDO1): an up-to-date overview of an eclectic immunoregulatory enzyme.The FEBS journal · 2022Review
- One Key and Multiple Locks: Substrate Binding in Structures of Tryptophan Dioxygenases and Hydroxylases.ChemMedChem · 2021Review
- Conformational Plasticity in Human Heme-Based Dioxygenases.Journal of the American Chemical Society · 2021Article
- Temporary Intermediates of L-Trp Along the Reaction Pathway of Human Indoleamine 2,3-Dioxygenase 1 and Identification of an Exo Site.International journal of tryptophan research : IJTR · 2021Article
- Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase 1.Nature communications · 2017Article
- Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases.Cellular and molecular life sciences : CMLS · 2017Review
- Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry.MedChemComm · 2017Review
- A short history of heme dioxygenases: rise, fall and rise again.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2017Review
- Different Mechanisms of Catalytic Complex Formation in Two L-Tryptophan Processing Dioxygenases.Frontiers in molecular biosciences · 2017Review
Corrections and comments
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Authors and funding
7 authors at 5 institutions in 2 countries.
Funding
Abstract
Human indoleamine 2,3-dioxygenase catalyzes the oxidative cleavage of tryptophan to N-formyl kynurenine, the initial and rate-limiting step in the kynurenine pathway. Additionally, this enzyme has been identified as a possible target for cancer therapy. A 20-amino acid protein segment (the JK loop), which connects the J and K helices, was not resolved in the reported hIDO crystal structure. Previous studies have shown that this loop undergoes structural rearrangement upon substrate binding. In this work, we apply a combination of replica exchange molecular dynamics simulations and site-directed mutagenesis experiments to characterize the structure and dynamics of this protein region. Our simulations show that the JK loop can be divided into two regions: the first region (JK loop(C)) displays specific and well-defined conformations and is within hydrogen bonding distance of the substrate, while the second region (JK loop(N)) is highly disordered and exposed to the solvent. The peculiar flexible nature of JK loop(N) suggests that it may function as a target for post-translational modifications and/or a mediator for protein-protein interactions. In contrast, hydrogen bonding interactions are observed between the substrate and Thr379 in the highly conserved "GTGG" motif of JK loop(C), thereby anchoring JK loop(C) in a closed conformation, which secures the appropriate substrate binding mode for catalysis. Site-directed mutagenesis experiments confirm the key role of this residue, highlighting the importance of the JK loop(C) conformation in regulating the enzymatic activity. Furthermore, the existence of the partially and totally open conformations in the substrate-free form suggests a role of JK loop(C) in controlling substrate and product dynamics.
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