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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.317 
  • R-Value Work: 0.233 
  • R-Value Observed: 0.233 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

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

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

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

  • DOI: https://doi.org/10.1248/cpb.47.11
  • Primary Citation of Related Structures:  
    1BMQ

  • 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.


  • Organizational Affiliation

    Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., Ibaraki, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
PROTEIN (INTERLEUKIN-1 BETA CONVERTASE)167Homo sapiensMutation(s): 0 
EC: 3.4.22.36
UniProt & NIH Common Fund Data Resources
Find proteins for P29466 (Homo sapiens)
Explore P29466 
Go to UniProtKB:  P29466
PHAROS:  P29466
GTEx:  ENSG00000137752 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP29466
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
PROTEIN (INTERLEUKIN-1 BETA CONVERTASE)88Homo sapiensMutation(s): 0 
EC: 3.4.22.36
UniProt & NIH Common Fund Data Resources
Find proteins for P29466 (Homo sapiens)
Explore P29466 
Go to UniProtKB:  P29466
PHAROS:  P29466
GTEx:  ENSG00000137752 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP29466
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
MNO
Query on MNO

Download Ideal Coordinates CCD File 
C [auth A](3S)-N-METHANESULFONYL-3-({1-[N-(2-NAPHTOYL)-L-VALYL]-L-PROLYL}AMINO)-4-OXOBUTANAMIDE
C26 H32 N4 O7 S
IGFYXXJBAZZOHF-FUDKSRODSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
MNO PDBBind:  1BMQ IC50: 38 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.317 
  • R-Value Work: 0.233 
  • R-Value Observed: 0.233 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 64.7α = 90
b = 64.7β = 90
c = 161.4γ = 90
Software Package:
Software NamePurpose
X-PLORmodel building
X-PLORrefinement
PROCESSdata reduction
PROCESSdata scaling
X-PLORphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 1998-07-29
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-08-09
    Changes: Data collection, Database references, Derived calculations, Refinement description