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. 2019 Apr 2;9:5504. doi: 10.1038/s41598-019-41930-7

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© The Author(s) 2019

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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Compounds S10G and C13 inhibit Casp6 through a noncompetitive mode of inhibition. (a) Michaelis-Menten kinetic plots of Casp6 enzymatic activity in presence of 1% DMSO or increasing doses S10G (top) and C13 (bottom). Data points represent mean ± SD of three independent experiments. (b) Lineweaver-Burk plots of Casp6 inhibition with S10G (top) and C13 (bottom). Red circle indicates the point where lines converge. (c) The relationship between the slopes of lines in Lineweaver-Burk plot analyses in panel (b) and inhibitor concentration. (d) Plots of IC₅₀ values for S10G (top) and C13 (bottom) with varying concentrations of Ac-VEID-AFC substrate. Data points represent mean ± SD from three independent experiments for each substrate concentration. (e) Binding model of C13 into CASP6 putative allosteric site, derived from molecular docking. Left: C13 (green sticks) occupies the putative allosteric site (white surface and lines; Ala-mutated residues L200 and K284 shown as purple sticks). Right: predicted interactions with Casp6 allosteric pocket residues (pink balls polar, circled blue or red for basic and acidic, respectively. Green balls = hydrophobic. Dotted-arrow: blue and green for backbone and sidechain hydrogen-bond interactions, respectively. Blue shade = solvent exposed area). Dose-response curves of C13 for Casp6-WT and Casp6-K284A (f), and copurified LS and SS of Casp6-WT-LS-SS, Casp6-L200A-LS-SS, and Casp6-K284A-LS-SS (g). Data represent mean ± SD from at least three independent experiments. (h) Global fit of kinetics data to a noncompetitive (mixed) inhibition model for Casp6-WT-LS-SS (left panel, R² = 0.9635), Casp6-L200A-LS-SS (middle panel, R² = 0.9699), and Casp6-K284A-LS-SS (right panel, R² = 0.9794) in the presence of 0–50 µM C13. Data points on the graph represent the mean ± SD, and calculated K_i values represent mean ± standard error (SE) from three independent experiments.