Dr. Enrico Di Cera will present the Biochemistry / Redox Biology Center Seminar on Tues. April 2, 2013 at 4:00 PM in N172 Beadle Center. The title of his seminar is "Conformational selection in trypsin-like proteases".
We have been working on thrombin since 1990 and elucidated the functional and structural aspects of the interaction with Na+ and physiological substrates. We have cast this work within the larger context of enzymes activated by monovalent cations for which we have offered a classification based on structural and functional properties. We have solved the structures of several thrombin precursors (prothrombin, prethrombin-1 and prethrombin-2) and uncovered the important role that exposure of the Arg in the activation domain plays in the mechanism of activation and autoactivation of protrombin and protein C. We have discovered the E*-E equilibrium in thrombin and trypsin-like proteases using structural biology and rapid kinetics and defined new strategies of therapeutic intervention, such as the development of thrombin mutants featuring anticoagulant activity in vitro and in vivo. One of these mutants will soon enter Phase I studies. We have elucidated the kinetic signatures of conformational selection and the important role that this mechanism of ligand recognition plays in trypsin-like proteases and proteins in general. We have considerable experience in protein engineering and structure-function approaches. We produce all critical reagents that are essential to the performance of our work and characterize their functional properties in terms of rigorous principles of ligand binding thermodynamics and kinetics. The environment in our laboratory offers a unique combination of expertise in enzyme kinetics, molecular biology, thermodynamics, ligand binding theory and X-ray structural biology that is ideal for the training of students and postdoctoral fellows interested in the molecular basis of protein function.