期刊
STRUCTURE
卷 23, 期 2, 页码 407-417出版社
CELL PRESS
DOI: 10.1016/j.str.2014.11.019
关键词
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资金
- European Community's Seventh Framework Programme (FP7) [283570]
- Deutsche Forschungsgemeinschaft [GR1861/10-1]
- BMBF-ProNET-T3 project [To-03]
- [SFB 1035/A2]
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 beta 5-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 alpha',beta'-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.
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