1RHK

Crystal structure of the complex of caspase-3 with a phenyl-propyl-ketone inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.190 

wwPDB Validation   3D Report Full Report


This is version 1.7 of the entry. See complete history


Literature

Reducing the Peptidyl Features of Caspase-3 Inhibitors: A Structural Analysis.

Becker, J.W.Rotonda, J.Soisson, S.M.Aspiotis, R.Bayly, C.Francoeur, S.Gallant, M.Garcia-Calvo, M.Giroux, A.Grimm, E.Han, Y.McKay, D.Nicholson, D.W.Peterson, E.Renaud, J.Roy, S.Thornberry, N.Zamboni, R.

(2004) J Med Chem 47: 2466-2474

  • DOI: https://doi.org/10.1021/jm0305523
  • Primary Citation of Related Structures:  
    1RE1, 1RHJ, 1RHK, 1RHM, 1RHQ, 1RHR, 1RHU

  • PubMed Abstract: 

    Caspases are cysteine proteases that specifically cleave Asp-Xxx bonds. They are key agents in inflammation and apoptosis and are attractive targets for therapy against inflammation, neurodegeneration, ischemia, and cancer. Many caspase structures are known, but most involve either peptide or protein inhibitors, unattractive candidates for drug development. We present seven crystal structures of inhibited caspase-3 that illustrate several approaches to reducing the peptidyl characteristics of the inhibitors while maintaining their potency and selectivity. The inhibitors reduce the peptidyl nature of inhibitors while preserving binding potency by (1). exploiting a hydrophobic binding site C-terminal to the cleavage site, (2). replacing the negatively charged aspartyl residue at P4 with neutral groups, and (3). using a peptidomimetic 5,6,7-tricyclic system or a pyrazinone at P2-P3. In addition, we have found that two nicotinic acid aldehydes induce a significant conformational change in the S2 and S3 subsites of caspase-3, revealing an unexpected binding mode. These results advance the search for caspase-directed drugs by revealing how unacceptable molecular features can be removed without loss of potency.


  • Organizational Affiliation

    Departments of Medicinal Chemistry and Metabolic Disorders, Merck Research Laboratory, PO Box 2000, Rahway, New Jersey 07065, USA. joseph_becker@merck.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Caspase-3147Homo sapiensMutation(s): 0 
Gene Names: CASP3CPP32
EC: 3.4.22
UniProt & NIH Common Fund Data Resources
Find proteins for P42574 (Homo sapiens)
Explore P42574 
Go to UniProtKB:  P42574
PHAROS:  P42574
GTEx:  ENSG00000164305 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP42574
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Caspase-3102Homo sapiensMutation(s): 1 
Gene Names: CASP3CPP32
EC: 3.4.22
UniProt & NIH Common Fund Data Resources
Find proteins for P42574 (Homo sapiens)
Explore P42574 
Go to UniProtKB:  P42574
PHAROS:  P42574
GTEx:  ENSG00000164305 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP42574
Sequence Annotations
Expand
  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
acetyl-asp-glu-val-fpr5N/AMutation(s): 0 
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.190 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 69.94α = 90
b = 84.66β = 90
c = 96.82γ = 90
Software Package:
Software NamePurpose
CNXrefinement
X-GENdata reduction
SAINTdata scaling
X-PLORphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-05-11
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2011-07-27
    Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Structure summary
  • Version 1.4: 2012-12-12
    Changes: Other
  • Version 1.5: 2017-10-11
    Changes: Refinement description
  • Version 1.6: 2022-12-21
    Changes: Database references, Derived calculations
  • Version 1.7: 2023-09-20
    Changes: Data collection, Refinement description