Three-dimensional structure of thrombin based on x-ray crystallography. Thrombin is a serine protease. A deep groove surrounds the active site serine, shown in red. The entrance into the active site is partially occluded by a hydrophobic insertion loop on the top and an autolysis (self-cleavage) loop at the bottom. Thus, physiologic substrates must align with the anion-binding exosite-I (ABE-I) on the right, and sometimes with ABE-II as well, in order to gain entrance into the groove and interact with the active site. Other features include the following:
- The pink stick figure within the groove is a direct thrombin inhibitor (peptide) used during crystallization to prevent thrombin autolysis.
- The arrow points to glutamic acid at position 229, which, when substituted with lysine (E229K), converts thrombin from a procoagulant enzyme into an anticoagulant enzyme. When this mutation is present, the active site cavity is collapsed.[1] Thus, E229K thrombin no longer cleaves fibrinogen to fibrin monomer or activates platelets, but it is able to bind to thrombomodulin on the endothelial cell surface and activate protein C.[2,3]
