4QZ6

yCP beta5-A49T-A50V double mutant in complex with the epoxyketone inhibitor ONX 0914

Summary for 4QZ6

• Entry DOI: 10.2210/pdb4qz6/pdb
• Related: 1RYP
• Related PRD ID: PRD_000991
• Descriptor: Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (19 entities in total)
• Functional Keywords: cancer, proteasome, bortezomib, drug resistance, binding analysis, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Saccharomyces cerevisiae (Baker's yeast); More
• Cellular location: Cytoplasm: P23639 P22141 P30656 P23724 P30657 P38624 P23638 P40303 P32379 P40302 P21242 P21243 P25043 P25451
• Total number of polymer chains: 28
• Total formula weight: 735330.97

Authors

Huber, E.M.,Heinemeyer, W.,Groll, M. (deposition date: 2014-07-27, release date: 2015-02-04, Last modification date: 2023-09-20)

Primary citation

Huber, E.M.,Heinemeyer, W.,Groll, M.
Bortezomib-Resistant Mutant Proteasomes: Structural and Biochemical Evaluation with Carfilzomib and ONX 0914.
Structure, 23:407-417, 2015

PubMed 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.

PubMed: 25599643
DOI: 10.1016/j.str.2014.11.019

Experimental method

X-RAY DIFFRACTION (2.9 Å)