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

Summary for 1BMQ

• Entry DOI: 10.2210/pdb1bmq/pdb
• Descriptor: PROTEIN (INTERLEUKIN-1 BETA CONVERTASE), (3S)-N-METHANESULFONYL-3-({1-[N-(2-NAPHTOYL)-L-VALYL]-L-PROLYL}AMINO)-4-OXOBUTANAMIDE (3 entities in total)
• Functional Keywords: caspase, hydrolase
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P29466 P29466
• Total number of polymer chains: 2
• Total formula weight: 29614.10

Authors

Okamoto, Y.,Anan, H.,Nakai, E.,Morihira, K.,Yonetoku, Y.,Kurihara, H.,Katayama, N.,Sakashita, H.,Terai, Y.,Takeuchi, M.,Shibanuma, T.,Isomura, Y. (deposition date: 1998-07-24, release date: 1998-07-29, Last modification date: 2024-10-30)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.5 Å)