Protein inhibitors of serine proteinases

Serine proteinases and their natural protein inhibitors belong to the most intensively studied models of protein-protein recognition. Protein inhibito rs do not form a single group but can be divided into about 20 different fa milies. Global structures of proteins representing different inhibitor fami lies are completely different and comprise alpha-helical proteins, beta-she et proteins, alpha/beta-proteins and different folds of small disulfide-ric h proteins. Three different types of inhibitors can be distinguished: canon ical (standard mechanism) inhibitors, non-canonical inhibitors, and serpins . The canonical inhibitor binds to the enzyme through the exposed and conve x binding loop, which is complementary to the active site of the enzyme. Th e mechanism of inhibition in this group is consistently very similar and re sembles that of an ideal substrate. Non-canonical inhibitors, originating f rom blood sucking organisms, specifically block enzymes of the blood clotti ng cascade. The interaction is mediated through inhibitor N-terminus which binds to the proteinase forming a parallel beta-sheet. There are also exten sive secondary interactions which provide an additional buried area and con tribute significantly to the strength and specificity of recognition. Serpi ns are major proteinase inhibitors occurring in plasma. Similarly to canoni cal inhibitors, serpins interact with their target proteinases in a substra te-like manner. However, in the case of serpins, cleavage of a single pepti de bond in a flexible and exposed binding loop leads to dramatic structural changes.