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. 2023 Jun 22;14:3737. doi: 10.1038/s41467-023-39444-y

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 5 — a structural superposition between TGR in complex with 9 (in grey, PDB ID 8A1R) and TGR in complex with NADPH (in cyan, PDB ID 2 × 99). b structural superposition between TGR in complex with 9 and human GR in complex with NADP⁺ (in yellow, PDB ID 3DK4). In both panels the FAD cofactors belonging to the different enzymes are in green sticks, while the two conformers of 9 are in pink and in magenta sticks. c hypothetical mechanism of inhibition for the noncompetitive (9) and uncompetitive (3, 7, and 8) inhibitors, considering the possibility that the destabilized NADP⁺-TGR(H) reduced forms of the enzyme may specifically accommodate uncompetitive inhibitors due to the presence of conformational states more suitable for compound binding. EH₂ and EH₄ represent the reduced species with 2 and 4 electrons, respectively, populated during the enzymatic reduced half-reaction; EH₄ is the species competent for substrate reduction in the oxidative half-reaction. During catalysis, TGR oscillates between the 2-electron reduced state and the 4-electron state. The mechanism has been depicted considering the catalytic mechanism of TGR^17,30.