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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

12 Issues per year


IMPACT FACTOR increased in 2014: 3.268
Rank 106 out of 289 in category Biochemistry & Molecular Biology in the 2014 Thomson Reuters Journal Citation Report/Science Edition

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Crystal Structure of the Caspase Activator Human Granzyme B, a Proteinase Highly Specific for an Asp-P1 Residue

Eva Estébanez-Perpiñá / Pablo Fuentes-Prior / Didier Belorgey / Marianne Braun / Reiner Kiefersauer / Klaus Maskos / Robert Huber / Harvey Rubin / Wolfram Bode

Citation Information: Biological Chemistry. Volume 381, Issue 12, Pages 1203–1214, ISSN (Print) 1431-6730, DOI: 10.1515/BC.2000.148, June 2005

Publication History

Published Online:
2005-06-01

Abstract

Granzyme B is the prototypic member of the granzymes, a family of trypsin-like serine proteinases localized in the dense cytoplasmic granules of activated natural killer cells and cytotoxic T lymphocytes. Granzyme B directly triggers apoptosis in target cells by activating the caspase pathway, and has been implicated in the etiology of rheumatoid arthritis. Human granzyme B expressed in a baculovirus system has been crystallized without inhibitor and its structure has been determined to 3.1 Å resolution, after considerably improving the diffraction power of the crystals by controlled humidity changes. The granzyme B structure reveals an overall fold similar to that found in cathepsin G and human chymase. The guanidinium group of Arg226, anchored at the back of the S1-specificity pocket, can form a salt bridge with the P1-Asp side chain of a bound peptide substrate. The architecture of the substrate binding site of granzyme B appears to be designed to accommodate and cleave hexapeptides such as the sequence Ile-Glu-Thr-Asp↓ -Ser-Gly present in the activation site of pro-caspase-3, a proven physiological substrate of granzyme B. These granzyme B crystals, with fully accessible active sites, are well suited for soaking with small synthetic inhibitors that might be used for a treatment of chronic inflammatory disorders.

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