Crystal Structure of the Caspase Activator Human Granzyme B, a Proteinase Highly Specific for an Asp-P1 Residue
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Eva Estébanez-Perpiñá
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.
Copyright © 2000 by Walter de Gruyter GmbH & Co. KG
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- Content Index
- Author Index
- Subject Index
Articles in the same Issue
- Circadian Rhythms of Sterol 12α-Hydroxylase, Cholesterol 7α-Hydroxylase and DBP Involved in Rat Cholesterol Catabolism
- Mannosidase Action, Independent of Glucose Trimming, Is Essential for Proteasome-Mediated Degradation of Unassembled Glycosylated Ig Light Chains
- Characterization of a Receptor for Heat Shock Protein 70 on Macrophages and Monocytes
- Yeast Translational Activator Cbs2p: Mitochondrial Targeting and Effect of Overexpression
- Mutational Scanning of a Hairpin Loop in the Tryptophan Synthase β-Subunit Implicated in Allostery and Substrate Channeling
- The Difference in the Carboxy-Terminal Sequence Is Responsible for the Difference in the Activity of Chicken and Rat Liver Fructose-2,6-Bisphosphatase
- Crystal Structure of the Caspase Activator Human Granzyme B, a Proteinase Highly Specific for an Asp-P1 Residue
- Primary Structure of Potato Kunitz-Type Serine Proteinase Inhibitor
- Activation of proPHBSP, the Zymogen of a Plasma Hyaluronan Binding Serine Protease, by an Intermolecular Autocatalytic Mechanism
- Human and Rat Dipeptidyl Peptidase III: Biochemical and Mass Spectrometric Arguments for Similarities and Differences
- Recombinant Anti-Stefin A Fab Fragment: Sequence Analysis of the Variable Region and Expression in Escherichia coli
- Green Fluorescent Protein Photobleaching: a Model for Protein Damage by Endogenous and Exogenous Singlet Oxygen
- 193 nm Photolysis of Aromatic and Aliphatic Dipeptides in Aqueous Solution: Dependence of Decomposition Quantum Yield on the Amino Acid Sequence
- NADPH:Protochlorophyllide Oxidoreductase Uses the General Import Route into Chloroplasts
- Superoxide Reactivates Nitric Oxide-Inhibited Catalase
- Erratum: The following abstract was unfortunately omitted from the GBM Fall Meeting section of the Biological Chemistry Special Supplement, Vol. 381, September 2000
- Content Index
- Author Index
- Subject Index
