Direct, unassisted interactions of thrombin. Thrombin binds directly to (A) fibrinogen Aα (blue) and Bβ (green) polypeptide chains using exosite I (fibrinogen γ chain is red). This enables the scissile bond to be positioned across the active site cleft. FPA and FPB (depicted as blue and green fragments) are then cleaved. Thrombin also binds directly to factor V (FV) (B). The 3 activation cleavage sites at R709, R1545, and R1018 are recognized using many surface residues, including those of both exosites. Although 2 thrombin molecules are depicted, a single docking event may be sufficient to complete proteolysis of each protein. The schematic of fibrinogen is adapted from Cote et al35 with permission.