Fig. 5: Structural comparison of the S1’, S1, S2 and S3 binding sites of TMPRSS11D, TMPRSS11E, TMPRSS2 and TMPRSS13.

a Surface representation of TMPRSS11D, with Subsite 1’ (S1’; green), S1 (red), S2 (purple), and S3 (blue) subsites colored. The TMPRSS11D catalytic triad, S368-H227-D272, are shown as sticks. b Comparison of the amino acids at each protease subsite for every TTSP. TTSPs with experimental crystal structures are indicated in black text. Protease amino acids predicted to form salt bridges are indicated in red (electronegative) or blue (electropositive) whereas hydrophobic amino acids are indicated in gray text. Amino acids in green are predicted to participate in H-bonding with ligands. c S1 of TMPRSS11D shown in stick representation. The R186 ligand residue (from PDB 9DPF) is shown as green sticks. H-bonds between the ligand and the TMPRSS11D S1 are shown as dashed orange lines. TMPRSS11D residues- purple TMPRSS11E (PDB 2OQ5)-teal, TMPRSS2 (PDB 8V04)-yellow, TMPRSS13 (PDB 6KD5)-pink. d S1’ of TMPRSS11D. The carboxylate of R¹⁸⁶-CO₂^- is shown as green sticks and points towards S1’ (indicated by a green squiggle). e, f S2 and S3 of TMPRSS11D. g dasTMPRSS11D (15 nM enzyme) IC₅₀ plot for ketobenzothiazole (kbt)-containing peptidomimetics 3-5. Assays contained a final concentration of 100 µM Boc-QAR-AMC substrate and relative protease activity was determined across the first 60 s of the reaction after substrate addition. Data are shown as mean values +/−SD for experiments performed in technical duplicate across 4 independent biological replicates (total n = 8). PM-3:Ac-Glu-Glu-Arg-kbt, PM-4:Ac-Glu-D-Glu-Arg-kbt, PM-5:Ac-Glu-Orn-Arg-kbt.