4QVL

yCP in complex with bortezomib

4QVL の概要

• エントリーDOI: 10.2210/pdb4qvl/pdb
• 関連するPDBエントリー: 1RYP 4QTR 4QUX 4QUY 4QV0 4QV1 4QV3 4QV4 4QV5 4QV6 4QV7 4QV8 4QV9 4QVM 4QVN 4QVP 4QVQ 4QWR 4QWS 4QWU 4QWX
• 分子名称: Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (18 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: 733692.44

構造登録者

Huber, E.M.,Heinemeyer, W.,Groll, M. (登録日: 2014-07-15, 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)