Comparison of tPA and FXII structures. Shown are stick diagrams of S1 pocket structures with hydrogen bonds and electrostatic interactions shown as dotted lines (purple). In panels A and B, the position of the oxyanion hole is indicated by the juxtaposed blue spheres that represent the nitrogen atoms of Ser195 and Gly193. (A) Single-chain tPA active S1 pocket crystal structure (pdb:1BDA) is shown with Asp194 stabilized by the salt bridge formed with Lys156 (indicated by + and − symbols), and also by hydrogen bonds with the main-chain nitrogens of Gly142 and Cys191. The cyan stick figure represents the side chain of the arginine P1 residue of the tPA inhibitor dansyl-Glu-Gly-Arg-chloromethylketone. (B) Homology model (SWISS-MODEL⁴⁸ ) of the S1 pocket of FXII-T based on the tPA crystal structure where Gln156 forms a hydrogen bond to the Asp194 carboxylate group. The side chain shown in cyan represents the P1 arginine of a substrate (PK or FXI). (C) Crystal structure (pdb:XDE) showing the inactive zymogen conformation of FXIIc where the oxyanion hole is absent (all figures prepared with PyMOL Molecular Graphics System, version 1.8; Schrödinger, LLC).