4QXJ

yCP beta5-M45A mutant in complex with the epoxyketone inhibitor ONX 0914

4QXJ の概要

• エントリーDOI: 10.2210/pdb4qxj/pdb
• 関連するPDBエントリー: 1RYP 4QTR 4QUX 4QUY 4QV0 4QV1 4QV3 4QV4 4QV5 4QV6 4QV7 4QV8 4QV9 4QVL 4QVM 4QVN 4QVP 4QVQ 4QWR 4QWS 4QWU 4QWX 4QZ0 4QZ1 4QZ2 4QZ3 4QZ4 4QZ5 4QZ6 4QZX 4QZZ
• 関連するBIRD辞書のPRD_ID: PRD_000991
• 分子名称: Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (19 entities in total)
• 機能のキーワード: cancer, proteasome, bortezomib, drug resistance, binding analysis, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Saccharomyces cerevisiae (Baker's yeast); 詳細
• 細胞内の位置: Cytoplasm: P23639 P22141 P30656 P23724 P30657 P38624 P23638 P40303 P32379 P40302 P21242 P21243 P25043 P25451
• タンパク質・核酸の鎖数: 28
• 化学式量合計: 735436.44

構造登録者

Huber, E.M.,Heinemeyer, W.,Groll, M. (登録日: 2014-07-21, 公開日: 2015-02-04, 最終更新日: 2023-09-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.8 Å)