Energetic dissection of specificity in serine proteases.
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.
Vindigni
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Department of Biochemistry & Molecular Biophysics, Washington University Medical School, St. Louis, MO 63110, USA. vindigni@icgeb.trieste.it
D012697:Serine Endopeptidases / Q000378:metabolism*; D013379:Substrate Specificity; D013816:Thermodynamics
D012697:Serine Endopeptidases