Journal article
The crystal structure of human dipeptidyl peptidase I (cathepsin C) in complex with the inhibitor Gly-Phe-CHN2
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark1
Department of Systems Biology, Technical University of Denmark2
Biotechnological Institute, Technical University of Denmark3
Office for Research and Relations, Administration, Technical University of Denmark4
Department of Environmental Engineering, Technical University of Denmark5
Department of Micro- and Nanotechnology, Technical University of Denmark6
hDDPI (human dipeptidyl peptidase I) is a lysosomal cysteine protease involved in zymogen activation of granule-associated proteases, including granzymes A and B from cytotoxic T-lymphocytes and natural killer cells, cathepsin G and neutrophil elastase, and mast cell tryptase and chymase. In the present paper, we provide the first crystal structure of an hDPPI-inhibitor complex.
The inhibitor Gly-Phe-CHN2 (Gly-Phe-diazomethane) was co-crystallized with hDPPI and the structure was determined at 2.0 angstrom (1 angstrom = 0.1 nm) resolution. The structure of the native enzyme was also determined to 2.05 angstrom resolution to resolve apparent discrepancies between the complex structure and the previously published structure of the native enzyme.
The new structure of the native enzyme is, within the experimental error, identical with the structure of the enzyme-inhibitor complex presented here. The inhibitor interacts with three subunits of hDPPI, and is covalently bound to Cys(234) at the active site. The interaction between the totally conserved Asp(1) of hDPPI and the ammonium group of the inhibitor forms an essential interaction that mimics enzyme-substrate interactions.
The structure of the inhibitor complex provides an explanation of the substrate specificity of hDPPI, and gives a background for the design of new inhibitors.
Language: | English |
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Publisher: | Portland Press Ltd. |
Year: | 2007 |
Pages: | 645-650 |
ISSN: | 14708728 and 02646021 |
Types: | Journal article |
DOI: | 10.1042/BJ20061389 |
ORCIDs: | 0000-0003-3848-1789 |