The crystal structure of human dipeptidyl peptidase I (cathepsin C) in complex with the inhibitor Gly-Phe-CHN2

Publication: Research - peer-reviewJournal article – Annual report year: 2007

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The crystal structure of human dipeptidyl peptidase I (cathepsin C) in complex with the inhibitor Gly-Phe-CHN2. / Mølgaard, Anne; Arnau, Jose; Lauritzen, C.; Larsen, Sine; Petersen, Gitte; Pedersen, John.

In: Biochemical Journal, Vol. 401, 2007, p. 645-650.

Publication: Research - peer-reviewJournal article – Annual report year: 2007

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Mølgaard, Anne; Arnau, Jose; Lauritzen, C.; Larsen, Sine; Petersen, Gitte; Pedersen, John / The crystal structure of human dipeptidyl peptidase I (cathepsin C) in complex with the inhibitor Gly-Phe-CHN2.

In: Biochemical Journal, Vol. 401, 2007, p. 645-650.

Publication: Research - peer-reviewJournal article – Annual report year: 2007

Bibtex

@article{26f702bb931f43d9a5fd7dc620e6d02b,
title = "The crystal structure of human dipeptidyl peptidase I (cathepsin C) in complex with the inhibitor Gly-Phe-CHN2",
keywords = "Gly-Phe-diazomethane (Gly-Phe-CHN2), cathepsin C, cysteine protease, dipeptidyl peptidase I (DPPI)",
publisher = "Portland Press Ltd.",
author = "Anne Mølgaard and Jose Arnau and C. Lauritzen and Sine Larsen and Gitte Petersen and John Pedersen",
year = "2007",
doi = "10.1042/BJ20061389",
volume = "401",
pages = "645--650",
journal = "Biochemical Journal",
issn = "0264-6021",

}

RIS

TY - JOUR

T1 - The crystal structure of human dipeptidyl peptidase I (cathepsin C) in complex with the inhibitor Gly-Phe-CHN2

A1 - Mølgaard,Anne

A1 - Arnau,Jose

A1 - Lauritzen,C.

A1 - Larsen,Sine

A1 - Petersen,Gitte

A1 - Pedersen,John

AU - Mølgaard,Anne

AU - Arnau,Jose

AU - Lauritzen,C.

AU - Larsen,Sine

AU - Petersen,Gitte

AU - Pedersen,John

PB - Portland Press Ltd.

PY - 2007

Y1 - 2007

N2 - 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.

AB - 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.

KW - Gly-Phe-diazomethane (Gly-Phe-CHN2)

KW - cathepsin C

KW - cysteine protease

KW - dipeptidyl peptidase I (DPPI)

U2 - 10.1042/BJ20061389

DO - 10.1042/BJ20061389

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

VL - 401

SP - 645

EP - 650

ER -