5M32

Human 26S proteasome in complex with Oprozomib

5M32 の概要

• エントリーDOI: 10.2210/pdb5m32/pdb
• EMDBエントリー: 4146
• 分子名称: Proteasome subunit alpha type-2, Proteasome subunit beta type-2, Proteasome subunit beta type-5, ... (35 entities in total)
• 機能のキーワード: proteasome, oprozomib, ups, drug-binding, hydrolase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 47
• 化学式量合計: 1535198.08

構造登録者

Haselbach, D.,Schrader, J.,Lambrecht, F.,Henneberg, F.,Chari, A.,Stark, H. (登録日: 2016-10-14, 公開日: 2017-07-05, 最終更新日: 2025-04-09)

主引用文献

Haselbach, D.,Schrader, J.,Lambrecht, F.,Henneberg, F.,Chari, A.,Stark, H.
Long-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs.
Nat Commun, 8:15578-15578, 2017

PubMed Abstract: The proteasome holoenzyme is the major non-lysosomal protease; its proteolytic activity is essential for cellular homeostasis. Thus, it is an attractive target for the development of chemotherapeutics. While the structural basis of core particle (CP) inhibitors is largely understood, their structural impact on the proteasome holoenzyme remains entirely elusive. Here, we determined the structure of the 26S proteasome with and without the inhibitor Oprozomib. Drug binding modifies the energy landscape of conformational motion in the proteasome regulatory particle (RP). Structurally, the energy barrier created by Oprozomib triggers a long-range allosteric regulation, resulting in the stabilization of a non-productive state. Thereby, the chemical drug-binding signal is converted, propagated and amplified into structural changes over a distance of more than 150 Å from the proteolytic site to the ubiquitin receptor Rpn10. The direct visualization of changes in conformational dynamics upon drug binding allows new ways to screen and develop future allosteric proteasome inhibitors.

PubMed: 28541292
DOI: 10.1038/ncomms15578

実験手法

ELECTRON MICROSCOPY (3.8 Å)