3RJM

CASPASE2 IN COMPLEX WITH CHDI LIGAND 33c


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.55 Å
  • R-Value Free: 0.249 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.190 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Exploiting differences in caspase-2 and -3 S(2) subsites for selectivity: Structure-based design, solid-phase synthesis and in vitro activity of novel substrate-based caspase-2 inhibitors.

Maillard, M.C.Brookfield, F.A.Courtney, S.M.Eustache, F.M.Gemkow, M.J.Handel, R.K.Johnson, L.C.Johnson, P.D.Kerry, M.A.Krieger, F.Meniconi, M.Munoz-Sanjuan, I.Palfrey, J.J.Park, H.Schaertl, S.Taylor, M.G.Weddell, D.Dominguez, C.

(2011) Bioorg Med Chem 19: 5833-5851

  • DOI: https://doi.org/10.1016/j.bmc.2011.08.020
  • Primary Citation of Related Structures:  
    3RJM

  • PubMed Abstract: 

    Several caspases have been implicated in the pathogenesis of Huntington's disease (HD); however, existing caspase inhibitors lack the selectivity required to investigate the specific involvement of individual caspases in the neuronal cell death associated with HD. In order to explore the potential role played by caspase-2, the potent but non-selective canonical Ac-VDVAD-CHO caspase-2 inhibitor 1 was rationally modified at the P(2) residue in an attempt to decrease its activity against caspase-3. With the aid of structural information on the caspase-2, and -3 active sites and molecular modeling, a 3-(S)-substituted-l-proline along with four additional scaffold variants were selected as P(2) elements for their predicted ability to clash sterically with a residue of the caspase-3 S(2) pocket. These elements were then incorporated by solid-phase synthesis into pentapeptide aldehydes 33a-v. Proline-based compound 33h bearing a bulky 3-(S)-substituent displayed advantageous characteristics in biochemical and cellular assays with 20- to 60-fold increased selectivity for caspase-2 and ∼200-fold decreased caspase-3 potency compared to the reference inhibitor 1. Further optimization of this prototype compound may lead to the discovery of valuable pharmacological tools for the study of caspase-2 mediated cell death, particularly as it relates to HD.


  • Organizational Affiliation

    CHDI Management, Inc., 6080 Center Drive Suite 100, Los Angeles, CA 90045, USA. michel.maillard@chdifoundation.org


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Caspase-2
A, C
169Homo sapiensMutation(s): 0 
Gene Names: CASP2Caspase-2ICH1NEDD2p19
EC: 3.4.22.55
UniProt & NIH Common Fund Data Resources
Find proteins for P42575 (Homo sapiens)
Explore P42575 
Go to UniProtKB:  P42575
PHAROS:  P42575
GTEx:  ENSG00000106144 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP42575
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Caspase-2
B, D
117Homo sapiensMutation(s): 0 
Gene Names: CASP2Caspase-2ICH1NEDD2p12
EC: 3.4.22.55
UniProt & NIH Common Fund Data Resources
Find proteins for P42575 (Homo sapiens)
Explore P42575 
Go to UniProtKB:  P42575
PHAROS:  P42575
GTEx:  ENSG00000106144 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP42575
Sequence Annotations
Expand
  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Peptide inhibitor (ACE)VDV(3PX)D-CHO
E, F
6N/AMutation(s): 0 
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
3PX
Query on 3PX
E, F
L-PEPTIDE LINKINGC8 H15 N O3PRO
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.55 Å
  • R-Value Free: 0.249 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.190 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 63.77α = 90
b = 97.38β = 90
c = 97.98γ = 90
Software Package:
Software NamePurpose
StructureStudiodata collection
PHASERphasing
REFMACrefinement
XDSdata reduction
XSCALEdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-09-21
    Type: Initial release
  • Version 1.1: 2011-10-05
    Changes: Database references
  • Version 1.2: 2012-12-12
    Changes: Other
  • Version 1.3: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.4: 2023-12-06
    Changes: Data collection