5DKI

Yeast 20S proteasome in complex with alkyne-PI

5DKI の概要

• エントリーDOI: 10.2210/pdb5dki/pdb
• 関連するPDBエントリー: 1RYP 2F16
• 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: hydrolase-hydrolase inhibitor complex, target delivery, proteasome, inhibitor, binding analysis, hydrolase/hydrolase inhibitor
• 由来する生物種: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (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: 733656.07

構造登録者

Beck, P.,Cui, H.,Groll, M. (登録日: 2015-09-03, 公開日: 2015-10-28, 最終更新日: 2025-10-01)

主引用文献

Beck, P.,Cui, H.,Hegemann, J.D.,Marahiel, M.A.,Kruger, A.,Groll, M.
Targeted Delivery of Proteasome Inhibitors to Somatostatin-Receptor-Expressing Cancer Cells by Octreotide Conjugation.
Chemmedchem, 10:1969-1973, 2015

PubMed Abstract: Clinical application of proteasome inhibitors (PIs) is so far limited to peripheral blood cancers due to the pronounced cytotoxicity towards all cell types. Targeted delivery of PIs could permit the treatment of other cancers along with decreasing side effects. Herein we describe the first small-molecule proteasome inhibitor conjugate for targeted delivery, created by fusing PIs to a synthetic ligand of somatostatin receptors, which are highly expressed in a variety of tumors. X-ray crystallographic studies and in vitro IC50 measurements demonstrated that addition of the cyclopeptide octreotide as a targeting vehicle does not affect the PI's binding mode. The cytotoxicity of the conjugate against somatostatin-receptor-expressing cells was up to 11-fold higher than that of a non-targeting surrogate. We have therefore established PIs as a new payload for drug conjugates and have shown that targeted delivery thereof could be a promising approach for the broader application of this FDA-approved class of compounds.

PubMed: 26471124
DOI: 10.1002/cmdc.201500449

実験手法

X-RAY DIFFRACTION (2.8 Å)