Volume 26, Issue 4, Pages e4 (April 2018)

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Volume 26, Issue 4, Pages 572-579.e4 (April 2018) Unique Substrate Specificity of SplE Serine Protease from Staphylococcus aureus Natalia Stach, Magdalena Kalinska, Michal Zdzalik, Radoslaw Kitel, Abdulkarim Karim, Karol Serwin, Wioletta Rut, Katrine Larsen, Abeer Jabaiah, Magdalena Firlej, Benedykt Wladyka, Patrick Daugherty, Henning Stennicke, Marcin Drag, Jan Potempa, Grzegorz Dubin Structure Volume 26, Issue 4, Pages 572-579.e4 (April 2018) DOI: 10.1016/j.str.2018.02.008 Copyright © 2018 Elsevier Ltd Terms and Conditions

Structure 2018 26, 572-579.e4DOI: (10.1016/j.str.2018.02.008) Copyright © 2018 Elsevier Ltd Terms and Conditions

Figure 1 Substrate Specificity of SplE at the P1 Subsite Activity of SplE was determined toward a library of synthetic fluorogenic peptide substrates of a general structure (Ac-X4-X3-X2-P1-Acc) consisting of 18 sublibraries, each having a fixed amino acid residue at the P1 position (one letter code, horizontal axis) and an equimolar mixture of those residues at other positions. Vertical bars indicate the activity of the enzyme against each tested sublibrary normalized to the most active sublibrary. Error bars indicate standard deviation (SD). Structure 2018 26, 572-579.e4DOI: (10.1016/j.str.2018.02.008) Copyright © 2018 Elsevier Ltd Terms and Conditions

Figure 2 Overall Fold of SplE and the Details of the S1 Specificity Pocket The overall folds of SplE (blue) and SplB (gray) are compared (left). S1 subsite architecture is highlighted (right). Catalytic triad residues are shown in yellow. Residues of significance in S1 specificity determination are shown in stick model form and colored according to the compared proteases. See also Figure S1. Structure 2018 26, 572-579.e4DOI: (10.1016/j.str.2018.02.008) Copyright © 2018 Elsevier Ltd Terms and Conditions

Figure 3 Directed Modification of P1 Substrate Specificity of SplB and SplE Activity of respective Spl protease and its mutants was tested against a fluorescent substrate library of a general structure indicated at the top of the figure. In each panel, the x axis represents amino acids at the P1 position within a particular library using the standard one-letter code, and the y axis shows the relative hydrolysis rate expressed as relative fluorescence units per second determined at 1 μM of enzyme. Note the P1 specificity changes associated with mutations in SplB and a significant overall drop in activity of G173S and double SplE mutants. Error bars indicate standard deviation (SD). See also Figure S2. Structure 2018 26, 572-579.e4DOI: (10.1016/j.str.2018.02.008) Copyright © 2018 Elsevier Ltd Terms and Conditions

Figure 4 Putative Interactions Guiding Substrate Recognition by SplE Binding of a consensus substrate was modeled at the active site of SplE. The substrate is shown in green, and the key interacting residues within SplE (gray surface) are shown in yellow. Hydrogen bonds are depicted as dotted lines. See also Table S1. Structure 2018 26, 572-579.e4DOI: (10.1016/j.str.2018.02.008) Copyright © 2018 Elsevier Ltd Terms and Conditions