Structure-Based Design of Inhibitors Selective for Human Proteasome β2c or β2i Subunits.
- Xin BT Gorlaeus Laboratories , Leiden Institute of Chemistry and Netherlands Proteomics Centre , Einsteinweg 55 , 2333 CC Leiden , Netherlands.
- Huber EM Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie , Technische Universität München , 85748 Garching , Germany.
- de Bruin G Gorlaeus Laboratories , Leiden Institute of Chemistry and Netherlands Proteomics Centre , Einsteinweg 55 , 2333 CC Leiden , Netherlands.
- Heinemeyer W Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie , Technische Universität München , 85748 Garching , Germany.
- Maurits E Gorlaeus Laboratories , Leiden Institute of Chemistry and Netherlands Proteomics Centre , Einsteinweg 55 , 2333 CC Leiden , Netherlands.
- Espinal C Gorlaeus Laboratories , Leiden Institute of Chemistry and Netherlands Proteomics Centre , Einsteinweg 55 , 2333 CC Leiden , Netherlands.
- Du Y Gorlaeus Laboratories , Leiden Institute of Chemistry and Netherlands Proteomics Centre , Einsteinweg 55 , 2333 CC Leiden , Netherlands.
- Janssens M Gorlaeus Laboratories , Leiden Institute of Chemistry and Netherlands Proteomics Centre , Einsteinweg 55 , 2333 CC Leiden , Netherlands.
- Weyburne ES Department of Molecular and Systems Biology and Norris Cotton Cancer Center , Geisel School of Medicine at Dartmouth , 1 Medical Centre Drive HB7936 , Lebanon , New Hampshire 03756 , United States.
- Kisselev AF Department of Molecular and Systems Biology and Norris Cotton Cancer Center , Geisel School of Medicine at Dartmouth , 1 Medical Centre Drive HB7936 , Lebanon , New Hampshire 03756 , United States.
- Florea BI Gorlaeus Laboratories , Leiden Institute of Chemistry and Netherlands Proteomics Centre , Einsteinweg 55 , 2333 CC Leiden , Netherlands.
- Driessen C Department of Hematology and Oncology , Kantonsspital St. Gallen , 9007 St. Gallen , Switzerland.
- van der Marel GA Gorlaeus Laboratories , Leiden Institute of Chemistry and Netherlands Proteomics Centre , Einsteinweg 55 , 2333 CC Leiden , Netherlands.
- Groll M Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie , Technische Universität München , 85748 Garching , Germany.
- Overkleeft HS Gorlaeus Laboratories , Leiden Institute of Chemistry and Netherlands Proteomics Centre , Einsteinweg 55 , 2333 CC Leiden , Netherlands.
- 2019-01-19
Published in:
- Journal of medicinal chemistry. - 2019
Animals
Catalytic Domain
Cell Line, Tumor
Crystallography, X-Ray
Drug Design
Humans
Mice
Mutation
Oligopeptides
Peptide Library
Proteasome Endopeptidase Complex
Proteasome Inhibitors
Protein Binding
Protein Engineering
Protein Subunits
Recombinant Fusion Proteins
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins
Small Molecule Libraries
Stereoisomerism
English
Subunit-selective proteasome inhibitors are valuable tools to assess the biological and medicinal relevance of individual proteasome active sites. Whereas the inhibitors for the β1c, β1i, β5c, and β5i subunits exploit the differences in the substrate-binding channels identified by X-ray crystallography, compounds selectively targeting β2c or β2i could not yet be rationally designed because of the high structural similarity of these two subunits. Here, we report the development, chemical synthesis, and biological screening of a compound library that led to the identification of the β2c- and β2i-selective compounds LU-002c (4; IC50 β2c: 8 nM, IC50 β2i/β2c: 40-fold) and LU-002i (5; IC50 β2i: 220 nM, IC50 β2c/β2i: 45-fold), respectively. Co-crystal structures with β2 humanized yeast proteasomes visualize protein-ligand interactions crucial for subunit specificity. Altogether, organic syntheses, activity-based protein profiling, yeast mutagenesis, and structural biology allowed us to decipher significant differences of β2 substrate-binding channels and to complete the set of subunit-selective proteasome inhibitors.
- Language
-
- English
- Open access status
- hybrid
- Identifiers
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- DOI 10.1021/acs.jmedchem.8b01884
- PMID 30657666
- Persistent URL
- https://sonar.ch/global/documents/93259
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