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Structure. 2015 Feb 3;23(2):407-17. doi: 10.1016/j.str.2014.11.019. Epub 2015 Jan 15.

Bortezomib-resistant mutant proteasomes: structural and biochemical evaluation with carfilzomib and ONX 0914.

Author information

1
Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstraße 4, 85747 Garching, Germany. Electronic address: eva.huber@mytum.de.
2
Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstraße 4, 85747 Garching, Germany.
3
Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstraße 4, 85747 Garching, Germany. Electronic address: michael.groll@tum.de.

Abstract

Inhibition of the 20S proteasome by bortezomib (Velcade) constitutes a successfully applied therapy for blood cancer. However, emerging resistance restricts its medicinal use. For example, mutations in the proteolytically active β5-subunit of the proteasome, the main target of inhibitors, were reported to impair drug binding and thus to reduce therapeutic efficacy. Using yeast as a model system, we describe here a systematic evaluation of these mutations by cell growth analysis, proteasome inhibition assays, and X-ray crystallography. The 11 mutants examined display decreased proliferation rates, impaired proteolytic activity, and marked resistance to bortezomib as well as the α',β'-epoxyketone inhibitors carfilzomib (Kyprolis) and ONX 0914, while the second-generation compound carfilzomib was the least affected. In total, 49 proteasome X-ray structures, including structural data on proteasome-carfilzomib complexes, reveal three distinct molecular mechanisms that hamper both drug binding and natural substrate turnover to an extent that is still compatible with cell survival.

PMID:
25599643
DOI:
10.1016/j.str.2014.11.019
[Indexed for MEDLINE]
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