4QLS

yCP in complex with tripeptidic epoxyketone inhibitor 11

4QLS の概要

• エントリーDOI: 10.2210/pdb4qls/pdb
• 関連するPDBエントリー: 1G65 1RYP 4QLQ 4QLT 4QLU 4QLV
• 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: proteasome, epoxyketone, immunoproteasome inhibitor, binding analysis, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Saccharomyces cerevisiae (Baker's yeast); 詳細
• タンパク質・核酸の鎖数: 28
• 化学式量合計: 732813.15

構造登録者

De Bruin, G.,Huber, E.,Xin, B.,Van Rooden, E.,Al-Ayed, K.,Kim, K.,Kisselev, A.,Driessen, C.,Van der Marel, G.,Groll, M.,Overkleeft, H. (登録日: 2014-06-13, 公開日: 2014-07-23, 最終更新日: 2023-11-08)

主引用文献

De Bruin, G.,Huber, E.M.,Xin, B.T.,Van Rooden, E.J.,Al-Ayed, K.,Kim, K.B.,Kisselev, A.F.,Driessen, C.,Van der Stelt, M.,Van der Marel, G.A.,Groll, M.,Overkleeft, H.S.
Structure-based design of beta 1i or beta 5i specific inhibitors of human immunoproteasomes
J.Med.Chem., 57:6197-6209, 2014

PubMed Abstract: Mammalian genomes encode seven catalytic proteasome subunits, namely, β1c, β2c, β5c (assembled into constitutive 20S proteasome core particles), β1i, β2i, β5i (incorporated into immunoproteasomes), and the thymoproteasome-specific subunit β5t. Extensive research in the past decades has yielded numerous potent proteasome inhibitors including compounds currently used in the clinic to treat multiple myeloma and mantle cell lymphoma. Proteasome inhibitors that selectively target combinations of β1c/β1i, β2c/β2i, or β5c/β5i are available, yet ligands truly selective for a single proteasome activity are scarce. In this work we report the development of cell-permeable β1i and β5i selective inhibitors that outperform existing leads in terms of selectivity and/or potency. These compounds are the result of a rational design strategy using known inhibitors as starting points and introducing structural features according to the X-ray structures of the murine constitutive and immunoproteasome 20S core particles.

PubMed: 25006746
DOI: 10.1021/jm500716s

実験手法

X-RAY DIFFRACTION (2.8 Å)