4QVQ
yCP beta5-M45I mutant in complex with bortezomib
Summary for 4QVQ
| Entry DOI | 10.2210/pdb4qvq/pdb |
| Related | 1RYP 4QTR 4QUX 4QUY 4QV0 4QV1 4QV3 4QV4 4QV5 4QV6 4QV7 4QV8 4QV9 4QVL 4QVM 4QVN 4QVP 4QVQ 4QWR 4QWS 4QWU 4QWX |
| Descriptor | Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (18 entities in total) |
| Functional Keywords | cancer, proteasome, 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 | 733680.68 |
| Authors | Huber, E.M.,Heinemeyer, W.,Groll, M. (deposition date: 2014-07-15, 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 (2.6 Å) |
Structure validation
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