6GOP

Yeast 20S Proteasome in complex with Homosalinosporamide A

6GOP の概要

• エントリーDOI: 10.2210/pdb6gop/pdb
• 関連するPDBエントリー: 2FAK 5CZ4
• 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, natural product, proteasome, inhibitor, binding analysis, hydrolase
• 由来する生物種: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast); 詳細
• タンパク質・核酸の鎖数: 28
• 化学式量合計: 733341.63

構造登録者

Groll, M.,Romo, D. (登録日: 2018-06-01, 公開日: 2018-08-01, 最終更新日: 2024-11-13)

主引用文献

Groll, M.,Nguyen, H.,Vellalath, S.,Romo, D.
(-)-Homosalinosporamide A and Its Mode of Proteasome Inhibition: An X-ray Crystallographic Study.
Mar Drugs, 16:-, 2018

PubMed Abstract: Upon acylation of the proteasome by the β-lactone inhibitor salinosporamide A (SalA), tetrahydrofuran formation occurs by intramolecular alkylation of the incipient alkoxide onto the choroethyl sidechain and irreversibly blocks the active site. Our previously described synthetic approach to SalA, utilizing a bioinspired, late-stage, aldol-β-lactonization strategy to construct the bicyclic β-lactone core, enabled synthesis of (⁻)-homosalinosporamide A (homoSalA). This homolog was targeted to determine whether an intramolecular tetrahydropyran is formed in a similar manner to SalA. Herein, we report the X-ray structure of the yeast 20S proteasome:homoSalA-complex which reveals that tetrahydropyran ring formation does not occur despite comparable potency at the chymotrypsin-like active site in a luminogenic enzyme assay. Thus, the natural product derivative homoSalA blocks the proteasome by a covalent reversible mode of action, opening the door for further fine-tuning of proteasome inhibition.

PubMed: 30029468
DOI: 10.3390/md16070240

実験手法

X-RAY DIFFRACTION (2.9 Å)