2djf
Crystal Structure of human dipeptidyl peptidase I (Cathepsin C) in complex with the inhibitor Gly-Phe-CHN2
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OverviewOverview
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 A, (1 A=0.1 nm) resolution. The structure of the native enzyme was also, determined to 2.05 A 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 Cys234 at the active site. The interaction between, the totally conserved Asp1 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.
DiseaseDisease
Known diseases associated with this structure: Haim-Munk syndrome OMIM:[602365], Papillon-Lefevre syndrome OMIM:[602365], Periodontitis, juvenile OMIM:[602365]
About this StructureAbout this Structure
2DJF is a Protein complex structure of sequences from Homo sapiens with NAG, CL, GLY, PHE, CH2 and ACY as ligands. Active as Dipeptidyl-peptidase I, with EC number 3.4.14.1 Full crystallographic information is available from OCA.
ReferenceReference
The crystal structure of human dipeptidyl peptidase I (cathepsin C) in complex with the inhibitor Gly-Phe-CHN2., Molgaard A, Arnau J, Lauritzen C, Larsen S, Petersen G, Pedersen J, Biochem J. 2007 Feb 1;401(3):645-50. PMID:17020538
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