Regulation of proteases by protein inhibitors of the serpin superfamily.

The serpins comprise an ancient superfamily of proteins, found abundantly in eukaryotes and even in some bacteria and archea, that have evolved to regulate proteases of both serine and cysteine mechanistic classes. Unlike the thermodynamically determined lock-and-key type inhibitors, such as those of the Kunitz and Kazal families, serpins use conformational change and consequent kinetic trapping of an enzyme intermediate to effect inhibition. By combining interactions of both an exposed reactive center loop and exosites outside this loop with the active site and complementary exosites on the target protease, serpins can achieve remarkable specificity. Together with the frequent use of regulatory cofactors, this permits a sophisticated time- and location-dependent mode of protease regulation. An understanding of the structure and function of serpins has suggested that they may provide novel scaffolds for engineering protease inhibitors of desired specificity for therapeutic use.