1BMQ

CRYSTAL STRUCTURE OF THE COMPLEX OF INTERLEUKIN-1BETA CONVERTING ENZYME (ICE) WITH A PEPTIDE BASED INHIBITOR, (3S )-N-METHANESULFONYL-3-({1-[N-(2-NAPHTOYL)-L-VALYL]-L-PROLYL }AMINO)-4-OXOBUTANAMIDE

1BMQ の概要

• エントリーDOI: 10.2210/pdb1bmq/pdb
• 分子名称: PROTEIN (INTERLEUKIN-1 BETA CONVERTASE), (3S)-N-METHANESULFONYL-3-({1-[N-(2-NAPHTOYL)-L-VALYL]-L-PROLYL}AMINO)-4-OXOBUTANAMIDE (3 entities in total)
• 機能のキーワード: caspase, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cytoplasm: P29466 P29466
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 29614.10

構造登録者

Okamoto, Y.,Anan, H.,Nakai, E.,Morihira, K.,Yonetoku, Y.,Kurihara, H.,Katayama, N.,Sakashita, H.,Terai, Y.,Takeuchi, M.,Shibanuma, T.,Isomura, Y. (登録日: 1998-07-24, 公開日: 1998-07-29, 最終更新日: 2024-10-30)

主引用文献

Okamoto, Y.,Anan, H.,Nakai, E.,Morihira, K.,Yonetoku, Y.,Kurihara, H.,Sakashita, H.,Terai, Y.,Takeuchi, M.,Shibanuma, T.,Isomura, Y.
Peptide based interleukin-1 beta converting enzyme (ICE) inhibitors: synthesis, structure activity relationships and crystallographic study of the ICE-inhibitor complex.
Chem.Pharm.Bull., 47:11-21, 1999

PubMed Abstract: Based on the X-ray structure of the complex of Ac-Tyr-Val-Ala-Asp-H (L-709049) and interleukin-1 beta converting enzyme (ICE), we synthesized compounds which were derived from 2-NapCO-Val-Pro-Asp-CH2OPh (1) to obtain a potent inhibitor in the cell assay. Among these compounds, (3S)-N-methanesulfonyl-3-[[1-[N-(2-naphthoyl)-L-valyl]-L-prolyl]amino]- 4-oxobutanamide (27c) showed high potency not only in the enzyme assay but also cell assay with IC50 values of 38 nM and 0.23 microM, respectively. Compound 27c, with a c log P value of 1.76, had a more hydrophilic character compared with 1. Compound 27c also dose dependently inhibited LPS-primed ATP-induced IL-1 beta release in mice. The crystal structure of the complex of compound 27c and ICE revealed that compound 27c had further interactions with ICE in the naphthoyl group at the P4 position and in the methyl group of the methanesulfonamidecarbonyl group at the P1 position, compared with L-709049. To our knowledge, compound 27c is the first example that shows a strong inhibitory activity without the carboxyl group at the P1 position.

PubMed: 9987822

実験手法

X-RAY DIFFRACTION (2.5 Å)