4INT

Yeast 20S proteasome in complex with the vinyl sulfone LU122

4INT の概要

• エントリーDOI: 10.2210/pdb4int/pdb
• 関連するPDBエントリー: 1RYP 4INR 4INU
• 関連するBIRD辞書のPRD_ID: PRD_000992
• 分子名称: Proteasome component Y7, Proteasome component C11, Proteasome component PRE2, ... (16 entities in total)
• 機能のキーワード: ups, drug discovery, irreversible inhibition, ntn hydrolase, non-lysosomal protein breakdown, 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: 730846.80

構造登録者

Geurink, P.P.,van der Linden, W.A.,Mirabella, A.C.,Gallastegui, N.,de Bruin, G.,Blom, A.E.M.,Voges, M.J.,Mock, E.D.,Florea, B.I.,van der Marel, G.A.,Driessen, C.,van der Stelt, M.,Groll, M.,Overkleeft, H.S.,Kisselev, A.F. (登録日: 2013-01-06, 公開日: 2013-01-30, 最終更新日: 2024-10-16)

主引用文献

Geurink, P.P.,van der Linden, W.A.,Mirabella, A.C.,Gallastegui, N.,de Bruin, G.,Blom, A.E.,Voges, M.J.,Mock, E.D.,Florea, B.I.,van der Marel, G.A.,Driessen, C.,van der Stelt, M.,Groll, M.,Overkleeft, H.S.,Kisselev, A.F.
Incorporation of Non-natural Amino Acids Improves Cell Permeability and Potency of Specific Inhibitors of Proteasome Trypsin-like Sites.
J.Med.Chem., 56:1262-1275, 2013

PubMed Abstract: Proteasomes degrade the majority of proteins in mammalian cells by a concerted action of three distinct pairs of active sites. The chymotrypsin-like sites are targets of antimyeloma agents bortezomib and carfilzomib. Inhibitors of the trypsin-like site sensitize multiple myeloma cells to these agents. Here we describe systematic effort to develop inhibitors with improved potency and cell permeability, yielding azido-Phe-Leu-Leu-4-aminomethyl-Phe-methyl vinyl sulfone (4a, LU-102), and a fluorescent activity-based probe for this site. X-ray structures of 4a and related inhibitors complexed with yeast proteasomes revealed the structural basis for specificity. Nontoxic to myeloma cells when used as a single agent, 4a sensitized them to bortezomib and carfilzomib. This sensitizing effect was much stronger than the synergistic effects of histone acetylase inhibitors or additive effects of doxorubicin and dexamethasone, raising the possibility that combinations of inhibitors of the trypsin-like site with bortezomib or carfilzomib would have stronger antineoplastic activity than combinations currently used clinically.

PubMed: 23320547
DOI: 10.1021/jm3016987

実験手法

X-RAY DIFFRACTION (2.9 Å)