PDBsum entry: 1bmq

Hydrolase

PDB id: 1bmq

Contents

Protein chains

167 a.a. *

88 a.a. *

Ligands

MNO

* Residue conservation analysis

PDB id:

1bmq

Name:

Hydrolase

Title:

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

Structure:

Protein (interleukin-1 beta convertase). Chain: a. Synonym: ice, il-1beta converting enzyme, caspase-1. Engineered: yes. Other_details: the inhibitor is covalently attached to the sulphur atom of cysteine 285. Protein (interleukin-1 beta convertase). Chain: b. Synonym: ice.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Biol. unit:

Tetramer (from PQS)

Resolution:

2.50Å R-factor: 0.233 R-free: 0.317

Authors:

Y.Okamoto,H.Anan,E.Nakai,K.Morihira,Y.Yonetoku,H.Kurihara, N.Katayama,H.Sakashita,Y.Terai,M.Takeuchi,T.Shibanuma, Y.Isomura

Key ref:

Y.Okamoto et al. (1999). Peptide based interleukin-1 beta converting enzyme (ICE) inhibitors: synthesis, structure activity relationships and crystallographic study of the ICE-inhibitor complex. Chem Pharm Bull (tokyo), 47, 11-21. PubMed id: 9987822

Date:

24-Jul-98 Release date: 29-Jul-98

Protein chain

P29466  (CASP1_HUMAN) -  Caspase-1

Seq: 404 a.a.

Struc: 167 a.a.

Protein chain

P29466  (CASP1_HUMAN) -  Caspase-1

Seq: 404 a.a.

Struc: 88 a.a.

Enzyme reactions

• Enzyme class: Chains A, B: E.C.3.4.22.36 - Caspase-1.
• Reaction: Release of interleukin 1-beta by specific cleavage at 116-Asp-|-Ala-117 and 27-Asp-|-Gly-28 bonds in precursor. Also hydrolyzes the small- molecule substrate, Ac-Tyr-Val-Ala-Asp-|-NHMec.

 Gene Ontology (GO) functional annotation 

• Biological process: apoptosis (2 terms)
• Biochemical function: cysteine-type peptidase activity (2 terms)

Chem Pharm Bull (tokyo) 47:11-21 (1999)

PubMed id: 9987822

Peptide based interleukin-1 beta converting enzyme (ICE) inhibitors: synthesis, structure activity relationships and crystallographic study of the ICE-inhibitor complex.

Y.Okamoto, H.Anan, E.Nakai, K.Morihira, Y.Yonetoku, H.Kurihara, H.Sakashita, Y.Terai, M.Takeuchi, T.Shibanuma, Y.Isomura.

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.