Abstract
Granzyme B is a serine protease of the chymotrypsin fold that mediates cell death by cytotoxic lymphocytes. It is a processing enzyme, requiring extended peptide substrates containing an Asp residue. The determinants that allow for this substrate specificity are revealed in the three-dimensional structure of granzyme B in complex with a macromolecular inhibitor. The primary 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 contact with the substrate and define the granzyme B extended substrate specificity profile. The substrate determinants found in this structure are shared by other members of this protein class and help to reveal the properties that define substrate specificity.
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Acknowledgements
This work was supported by grants to C.S.C from the National Science Foundation and National Institutes of Health, to R.J.F. from National Institutes of Health, and to J.L.H from the National Institutes of Health Biotechnology Training Grant Fellowship.
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Waugh, S., Harris, J., Fletterick, R. et al. The structure of the pro-apoptotic protease granzyme B reveals the molecular determinants of its specificity. Nat Struct Mol Biol 7, 762–765 (2000). https://doi.org/10.1038/78992
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DOI: https://doi.org/10.1038/78992
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