2OP3

The structure of cathepsin S with a novel 2-arylphenoxyacetaldehyde inhibitor derived by the Substrate Activity Screening (SAS) method

2OP3 の概要

• エントリーDOI: 10.2210/pdb2op3/pdb
• 関連するPDBエントリー: 2H7J 2HXZ
• 分子名称: Cathepsin S, SULFATE ION, 2-[(2',3',4'-TRIFLUOROBIPHENYL-2-YL)OXY]ETHANOL, ... (5 entities in total)
• 機能のキーワード: cathepsin s, nonpeptidic, substrate activity screening, hydrolase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Lysosome: P25774
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 50636.77

構造登録者

Spraggon, G.,Inagaki, H.,Tsuruoka, H.,Hornsby, M.,Lesley, S.A.,Ellman, J.A. (登録日: 2007-01-26, 公開日: 2007-05-22, 最終更新日: 2024-12-25)

主引用文献

Inagaki, H.,Tsuruoka, H.,Hornsby, M.,Lesley, S.A.,Spraggon, G.,Ellman, J.A.
Characterization and optimization of selective, nonpeptidic inhibitors of cathepsin S with an unprecedented binding mode.
J.Med.Chem., 50:2693-2699, 2007

PubMed Abstract: The substrate activity screening (SAS) method, a substrate-based fragment identification and optimization method for the development of enzyme inhibitors, was previously applied to cathepsin S to obtain a novel (2-arylphenoxy)acetaldehyde inhibitor, 2, with a 0.49 microM Ki value (Wood, W. J. L.; Patterson, A. W.; Tsuruoka, H.; Jain, R. K.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 15521-15527). In this paper we disclose the X-ray structure of a complex between cathepsin S and inhibitor 2 which reveals an unprecedented binding mode. On the basis of this structure, additional 2-biaryloxy substrates with greatly increased cleavage efficiency were designed. Conversion of the optimized substrates to the corresponding aldehyde inhibitors yielded a low molecular weight (304 Daltons) and potent (9.6 nM) cathepsin S inhibitor that showed from 100- to >1000-fold selectivity relative to cathepsins B, L, and K.

PubMed: 17469812
DOI: 10.1021/jm070111+

実験手法

X-RAY DIFFRACTION (1.6 Å)