Characterization of the THBD P401L mutation. (A) Schematic representation of thrombomodulin epidermal growth factor-like domains 4 and 5 (EGF4, EGF5). The P401 (blue), M406 (red), and C390 and C404 (yellow) residues are highlighted. Disulfide bonds are shown by yellow lines. P401 is located in the C-loop of EGF4 at the turn of a β-hairpin motif, near a critical oxidation-sensitive M406 amino acid in the linker region between EGF4 and EGF5 essential for normal thrombomodulin function. The P401L mutation is predicted to disrupt the C-loop β-turn and destabilize a disulfide bond between C390 and C404. (B) Structure of thrombomodulin EGF-like domains 4, 5, and 6 in complex with thrombin.¹¹⁰  The crystal structure was downloaded from the RCSB PDB database and visualized by PyMOL (PBD ID: 1DX5). Amino acids of interest in the EGF4 C-loop are highlighted.