The structure of the pro-apoptotic protease granzyme B reveals the molecular determinants of its specificity

Granzyme B is a serine protease of the chymotrypsin fold that mediates cell death by cytotoxic lymphocytes. It is a processing enzyme, requiring exten ded peptide substrates containing an Asp residue. The determinants that all ow for this substrate specificity are revealed in the three-dimensional str ucture: of granzyme B in complex with a macromolecular inhibitor. The prima ry specificity for Asp occurs through a side-on interaction with Arg 226, a buried Arg side chain of granzyme B. An additional nine amino acids make c ontact with the substrate and define the granzyme B extended substrate spec ificity profile. The substrate determinants found in this structure are sha red by other members of this protein class and help to reveal the propertie s that define substrate specificity.