4QZZ
yCP in complex with Omuralide
Summary for 4QZZ
Entry DOI | 10.2210/pdb4qzz/pdb |
Related | 1RYP 4QTR 4QUX 4QUY 4QV0 4QV1 4QV3 4QV4 4QV5 4QV6 4QV7 4QV8 4QV9 4QVL 4QVM 4QVN 4QVP 4QVQ 4QWR 4QWS 4QWX 4QZ0 4QZ1 4QZ2 4QZ3 4QZ5 4QZ6 4QZX 4QZZ |
Descriptor | Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (18 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 | 732654.19 |
Authors | Huber, E.M.,Heinemeyer, W.,Groll, M. (deposition date: 2014-07-29, release date: 2015-02-04, Last modification date: 2024-11-06) |
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 Cited by 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: 25599643DOI: 10.1016/j.str.2014.11.019 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
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