Bensinger, Dennis ; Neumann, Theresa ; Scholz, Christoph ; Voss, Constantin ; Knorr, Sabine ; Kuckelkorn, Ulrike ; Hamacher, Kay ; Kloetzel, Peter-Michael ; Schmidt, Boris (2016)
Elastase-like Activity Is Dominant to Chymotrypsin-like Activity in 20S Proteasome's β5 Catalytic Subunit.
In: ACS chemical biology, 11 (7)
Artikel, Bibliographie
Kurzbeschreibung (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.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2016 |
| Autor(en): | Bensinger, Dennis ; Neumann, Theresa ; Scholz, Christoph ; Voss, Constantin ; Knorr, Sabine ; Kuckelkorn, Ulrike ; Hamacher, Kay ; Kloetzel, Peter-Michael ; Schmidt, Boris |
| Art des Eintrags: | Bibliographie |
| Titel: | Elastase-like Activity Is Dominant to Chymotrypsin-like Activity in 20S Proteasome's β5 Catalytic Subunit. |
| Sprache: | Englisch |
| Publikationsjahr: | 2016 |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | ACS chemical biology |
| Jahrgang/Volume einer Zeitschrift: | 11 |
| (Heft-)Nummer: | 7 |
| Kurzbeschreibung (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. |
| Fachbereich(e)/-gebiet(e): | 10 Fachbereich Biologie 10 Fachbereich Biologie > Computational Biology and Simulation |
| Hinterlegungsdatum: | 03 Mai 2016 09:33 |
| Letzte Änderung: | 24 Apr 2018 08:10 |
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