Life is a balancing act. Within all organisms protein molecules are continuously being made and destroyed. The levels of important structural proteins, enzymes, and regulatory proteins depend on the careful control of the rates of synthesis and degradation. Thus, complex and highly regulated mechanisms have evolved to carry out proteolytic degradation. It is well known that unregulated proteolysis can destroy normal cells and tissue and contribute to diseases such as heart attack, stroke, arthritis, emphysema and cancer.

The question then is how are the proteases regulated? Many proteases are controlled by a group of proteins called serpins (SERine Proteinase INhibitors). Serpins act as 'bait' by presenting part of an exposed, flexible, ∼20 amino acid long peptide loop (the reactive center loop). Once the target protease 'bites', or attempts to, it becomes irreversibly locked in a stable complex. The serpin–protease complex is then cleared from the system. Thus, serpins act as 'protease sinks', removing proteases before they damage surrounding cells or tissue.

While a number of lines of evidence suggest that a major conformational change plays an important role in the mechanism of inhibition by serpins, many different models have been proposed. Now, the structure of a serpin–protease complex shows an unexpected degree of conformational disorder induced in the protease (Huntington, J.A., Read, R.J. & Carrell, R.W. Nature 407, 923–926, 2000).

By comparing the structures of trypsin and antitrypsin alone and in complex Huntington et al. propose the following scenario. The serpin (lower molecule on the left) reacts with the protease (upper molecule on the left) via the reactive center loop (yellow). The active site serine of the protease is covalently linked to the reactive center loop of the serpin. This cleaves the reactive center loop which then inserts into the β-sheet of the serpin (blue). This movement swings the protease 71 Å to the opposite end of the serpin. The part of trypsin that becomes disordered upon complex formation is in red. Thus, inhibition occurs by a kind of 'one, two punch' — by disrupting the active site and effectively “crushing the protease against the body of the serpin”. Clearly, inhibition by serpins is not for the faint of heart.