Elastase-like Activity Is Dominant to Chymotrypsin-like Activity in 20S Proteasome’s β5 Catalytic Subunit
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- 作者：Dennis Bensinger ; Theresa Neumann ; Christoph Scholz ; Constantin Voss ; Sabine Knorr ; Ulrike Kuckelkorn ; Kay Hamacher ; Peter-Michael Kloetzel ; Boris Schmidt
- 刊名：ACS Chemical Biology
- 出版年：2016
- 出版时间：July 15, 2016
- 年：2016
- 卷：11
- 期：7
- 页码：1800-1804
- 全文大小：282K
- 年卷期：0
- ISSN：1554-8937
文摘
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.