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

Nature Structural Biology volume 7, pages 762–765 (2000)Cite this article

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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Figure 1: Granzyme B is a serine protease of the chymotrypsin fold.
Figure 2: Ecotin binds to granzyme B through a substrate-like active site interaction and a secondary site interaction.
Figure 3: The extended specificity determinants of grB.
Figure 4: A comparison of structure and sequence at the active sites of three serine proteases, grB, chymase (from 1PJP), and catG (from 1AUG).

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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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Author notes

  1. Jennifer L. Harris

    Present address: Genomics Institute of the Novartis Research Foundation, 3115 Merryfield Row, San Diego, California, 92121, USA

Authors and Affiliations

  1. The Graduate Group in Biophysics, University of California, San Francisco, 94143-0446, California, USA

    Sandra M. Waugh

  2. Department of Pharmaceutical Chemistry, University of California, San Francisco, 94143-0446, California, USA

    Jennifer L. Harris, Robert Fletterick & Charles S. Craik

  3. Department of Biochemistry and Biophysics, University of California, San Francisco, 94143-0446, California, USA

    Robert Fletterick & Charles S. Craik

Authors
  1. Sandra M. Waugh
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  4. Charles S. Craik
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Correspondence to Sandra M. Waugh or Charles S. Craik.

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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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