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Elastase-like Activity Is Dominant to Chymotrypsin-like Activity in 20S Proteasome's β5 Catalytic Subunit.

Bensinger, Dennis and Neumann, Theresa and Scholz, Christoph and Voss, Constantin and Knorr, Sabine and Kuckelkorn, Ulrike and Hamacher, Kay and Kloetzel, Peter-Michael and Schmidt, Boris (2016):
Elastase-like Activity Is Dominant to Chymotrypsin-like Activity in 20S Proteasome's β5 Catalytic Subunit.
In: ACS chemical biology, pp. 1800-1804, 11, (7), ISSN 1554-8937,
[Article]

Abstract

The ubiquitin/proteasome system is the major protein degradation pathway in eukaryotes with several key catalytic cores. Targeting the β5 subunit with small-molecule inhibitors is an established therapeutic strategy for hematologic cancers. Herein, we report a mouse-trap-like conformational change that influences molecular recognition depending on the substitution pattern of a bound ligand. Variation of the size of P1 residues from the highly β5-selective proteasome inhibitor BSc2118 allows for discrimination between inhibitory strength and substrate conversion. We found that increasing molecular size strengthens inhibition, whereas decreasing P1 size accelerates substrate conversion. Evaluation of substrate hydrolysis after silencing of β5 activity reveals significant residual activity for large residues exclusively. Thus, classification of the β5 subunit as chymotrypsin-like and the use of the standard tyrosine-containing substrate should be reconsidered.

Item Type: Article
Erschienen: 2016
Creators: Bensinger, Dennis and Neumann, Theresa and Scholz, Christoph and Voss, Constantin and Knorr, Sabine and Kuckelkorn, Ulrike and Hamacher, Kay and Kloetzel, Peter-Michael and Schmidt, Boris
Title: Elastase-like Activity Is Dominant to Chymotrypsin-like Activity in 20S Proteasome's β5 Catalytic Subunit.
Language: English
Abstract:

The ubiquitin/proteasome system is the major protein degradation pathway in eukaryotes with several key catalytic cores. Targeting the β5 subunit with small-molecule inhibitors is an established therapeutic strategy for hematologic cancers. Herein, we report a mouse-trap-like conformational change that influences molecular recognition depending on the substitution pattern of a bound ligand. Variation of the size of P1 residues from the highly β5-selective proteasome inhibitor BSc2118 allows for discrimination between inhibitory strength and substrate conversion. We found that increasing molecular size strengthens inhibition, whereas decreasing P1 size accelerates substrate conversion. Evaluation of substrate hydrolysis after silencing of β5 activity reveals significant residual activity for large residues exclusively. Thus, classification of the β5 subunit as chymotrypsin-like and the use of the standard tyrosine-containing substrate should be reconsidered.

Journal or Publication Title: ACS chemical biology
Volume: 11
Number: 7
Divisions: 10 Department of Biology
10 Department of Biology > Computational Biology and Simulation
Date Deposited: 03 May 2016 09:33
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