The three-dimensional structure of human granzyme B compared to caspase-3,key mediators of cell death with cleavage specificity for aspartic acid inP1

Background: Granzyme B, one of the most abundant granzymes in cytotoxic T-l ymphocyte (CTL) granules, and members of the caspase (cysteine aspartyl pro teinases) family have a unique cleavage specificity for aspartic acid in P1 and play critical roles in the biochemical events that culminate in cell d eath. Results: We have determined the three-dimensional structure of the complex of the human granzyme B with a potent tetrapeptide aldehyde inhibitor. The Asp-specific S1 subsite of human granzyme B is significantly larger and les s charged than the corresponding Asp-specific site in the apoptosis-promoti ng caspases, and also larger than the corresponding subsite in rat granzyme B. Conclusions: The above differences account for the variation in substrate s pecificity among granzyme B, other serine proteases and the caspases, and e nable the design of specific inhibitors that can probe the physiological fu nctions of these proteins and the disease states with which they are associ ated. (C) 2001 Published by Elsevier Science Ltd.