Serine proteases of the chymotrypsin family share a similar fold and architecture, but they differ widely in specificity. The molecular origin of this difference remains for the most part elusive. A detailed understanding of the molecular origin of their specificity is of fundamental importance for structure-function and evolutionary studies. Current approaches put much emphasis on single site substitutions of ligand sequences or protein residues and neglect second- and higher-order coupling among residues leading to an incomplete and often misleading assessment of the underlying energetics. Information on how recognition sites interact is key to unveil structure- function links and to enable the development of more effective drugs for therapeutic purposes. A novel strategy has been recently developed for dissecting enzyme specificity using the principles of site-specific thermodynamics and is applied in the present work to thrombin, trypsin, tissue plasminogen activator. The results provide a much needed data base of information for computational studies of protease specificity and protein- ligand interaction. They suggest precise guidelines for the design of novel active-site inhibitors. Basic differences are also identified between thrombin, tPA, plasmin and trypsin in the energetic contribution of the specificity sites and the coupling between them.
|Number of pages||15|
|Journal||Combinatorial Chemistry and High Throughput Screening|
|State||Published - Jun 1 1999|