Serine proteases and their natural inhibitors have long been served as excellent models for
studying (primary, secondary and tertiary) structure - activity relationships of biologically interacting
proteins. As protein flexibility has been accepted as a “fourth dimension” of the protein structure, its
contribution to the binding process has gained much interest. In this article we review extreme cases of
serine protease interactions with canonical serine protease inhibitors that provide unique insights into the dynamics of protein-
protein interactions. The major conclusions of our review article are: a) taxon-specific inhibitory effects of two highly
homologous protease inhibitors from Schistocerca gregaria (SGCI and SGTI), as investigated by H/D exchange experiments
and NMR spectroscopy, are due to their differential flexibilities, b) stabilities of some protease and inhibitor complexes,
the wide-spread and increased flexibility of some segments in the protein-protein complexes, as studied by X-ray
crystallography and NMR-spectroscopy, appear to be proportional to the physical stability of the complex.
Keywords: Canonical inhibitors, flexibility, protein-protein interactions, serine proteases, serpins, stability.
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