4JR0

Human procaspase-3 bound to Ac-DEVD-CMK


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.195 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.164 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Structural snapshots reveal distinct mechanisms of procaspase-3 and -7 activation.

Thomsen, N.D.Koerber, J.T.Wells, J.A.

(2013) Proc Natl Acad Sci U S A 110: 8477-8482

  • DOI: https://doi.org/10.1073/pnas.1306759110
  • Primary Citation of Related Structures:  
    4JQY, 4JQZ, 4JR0, 4JR1, 4JR2

  • PubMed Abstract: 

    Procaspase-3 (P3) and procaspase-7 (P7) are activated through proteolytic maturation to form caspase-3 (C3) and caspase-7 (C7), respectively, which serve overlapping but nonredundant roles as the executioners of apoptosis in humans. However, it is unclear if differences in P3 and P7 maturation mechanisms underlie their unique biological functions, as the structure of P3 remains unknown. Here, we report structures of P3 in a catalytically inactive conformation, structures of P3 and P7 bound to covalent peptide inhibitors that reveal the active conformation of the zymogens, and the structure of a partially matured C7:P7 heterodimer. Along with a biochemical analysis, we show that P3 is catalytically inactive and matures through a symmetric all-or-nothing process. In contrast, P7 contains latent catalytic activity and matures through an asymmetric and tiered mechanism, suggesting a lower threshold for activation. Finally, we use our structures to design a selection strategy for conformation specific antibody fragments that stimulate procaspase activity, showing that executioner procaspase conformational equilibrium can be rationally modulated. Our studies provide a structural framework that may help to explain the unique roles of these important proapoptotic enzymes, and suggest general strategies for the discovery of proenzyme activators.


  • Organizational Affiliation

    Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Procaspase-3
A, B
247Homo sapiensMutation(s): 1 
Gene Names: CASP3CPP32
EC: 3.4.22.56
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
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Ac-DEVD-CMK
C, D
6N/AMutation(s): 0 
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
AKZ
Query on AKZ
C, D
PEPTIDE-LIKEC4 H9 N O4ASP
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.195 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.164 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 65.988α = 90
b = 84.751β = 90
c = 96.641γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
ELVESrefinement

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-05-08
    Type: Initial release
  • Version 1.1: 2013-05-22
    Changes: Database references
  • Version 1.2: 2013-06-05
    Changes: Database references
  • Version 1.3: 2017-11-15
    Changes: Refinement description
  • Version 1.4: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description