Serine and Cysteine Proteases and their Natural Inhibitors: Structures and Implications for Function and Drug Design
Serine and cysteine proteases play a central role in digestion, protein degradation and in bioregulation. Their activity may be controlled by activation from inactive proenzyme forms and by inhibition by natural inhibitors. Detailed structural studies have provided a basis for understanding the principles of activation, activity and inhibition of proteases. In serine proteases the functional significance of molecular flexibility was first documented (Huber & Bode, 1978; Walter et al, 1982). The basic pancreatic trypsin inhibitor BPTI served as model to develop biophysical and biochemical techniques (like protein NMR spectroscopy (Wiithrich, 1989), hydrogen-deuterium exchange (Wagner & Wiithrich, 1982), experimental folding studies (Creighton & Goldenberg, 1984) and theoretical methods (like molecular dynamics (Karplus & McCammon, 1981; Van Gunsteren et al, 1983) and normal mode analysis (Levitt et al., 1985)). Its polypeptide chain fold is shown in Figure 1.
KeywordsNatural Inhibitor Bovine Pancreatic Trypsin Inhibitor Pancreatic Secretory Trypsin Inhibitor Crystallographic Refinement Squash Seed
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