The archetypal example of serpin is antithrombin, which circulates in plasma in a partially inserted relatively inactive state. The primary specificity determining residue (the P1 Arginine) points towards the body of the serpin and is unavailable to the protease.
Upon binding a high affinity heparin pentasaccharide sequence within long chain heparin, antithrombin undergoes a conformational change, RCL expulsion and exposure of the P1 Arginine.
The heparin pentasaccharide bound form of antithrombin is thus a more effective inhibitor of thrombin and factor Xa. Furthermore, both of these coagulation proteases contain binding sites (called exosites) for heparin.
Heparin therefore also acts as a template for binding of both protease and serpin, further dramatically accelerating the interaction between the two parties.
After the initial interaction, the final serpin complex is formed and the heparin moiety is released.
This interaction is physiologically important. For example, after injury to the blood vessel wall heparin is exposed, and antithrombin is thus activated to control the clotting response.
The understanding of the molecular basis of this interaction formed the basis of the development of Fondaparinux, a synthetic form of Heparin pentasaccharide used as an anti-clotting drug.
