PROTEASE SPECIFICITY AND INHIBITION

University Of California San Francisco, San Francisco CA

Investigators

Linked publications & trials

Abstract

Protease activity is essential in nearly all cellular processes. Metabolism of proteins, development of organisms, cell death, the immune response and blood clotting all rest on the regulation of specialized proteases. Of these, the family of serine proteases is especially important. Serine proteases of the trypsin family regulate digestion, granzyme B regulates cytotoxic lymphocyte mediated cell death and thrombin regulates blood clot formation. Each of these proteases has unique specificity, hydrolyzing selected targets with remarkable discrimination, and sparing others. Through structure and function analysis, the factors controlling the recognition and inhibition of these proteases are becoming defined. Little is known about the protein interactions of regulatory serine proteases, such as thrombin or granzyme B, which have more extensive interactions with their biological targets. Here, the investigators propose that the loops of the serine protease determine the specificity and interactions of serine proteases and that understanding how these loops determine binding and hydrolysis is important for understanding the natural functions in human biology and for the eventual design of therapeutics. The investigators propose to map the interactions of granzyme B, to determine the three- dimensional structures of complexes of granzyme B and thrombin and to discover the basis of specificity for the extended interactions for these proteases.