Our work has focused on the contribution of a key salt bridge between Asp194 and the N-terminus, Ile16. Most importantly, we have demonstrated that BPTI affinity correlates with activity. This correlation allows us to use the structures of the trypsinogen-BPTI complexes to identify the structural features which confer activity. Although Lys15 can form the crucial salt bridge with Asp194, this trypsinogen variant has the same activity as wild-type trypsinogen. We believe that this interaction can not form rapidly enough to influence substrate turnover.
Hydrophobic interactions control zymogen activation in the trypsin family of serine proteases.
Streptokinase is a plasminogen activator. In addition, we have shown that fibrin can restore the activity of some inactive strepokinase mutants. These fibrin-dependent variants should have improved therapeutic properties. This work is a collaboration with Guy Reed at Harvard School of Public Health. Both streptokinase and plasminogen are modular proteins.