3H11

Zymogen caspase-8:c-FLIPL protease domain complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.212 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Mechanism of procaspase-8 activation by c-FLIPL.

Yu, J.W.Jeffrey, P.D.Shi, Y.

(2009) Proc Natl Acad Sci U S A 106: 8169-8174

  • DOI: https://doi.org/10.1073/pnas.0812453106
  • Primary Citation of Related Structures:  
    3H11, 3H13

  • PubMed Abstract: 

    Cellular FLICE-inhibitory protein (c-FLIP(L)) is a key regulator of the extrinsic cell death pathway. Although widely regarded as an inhibitor of initiator caspase activation and cell death, c-FLIP(L) is also capable of enhancing procaspase-8 activation through heterodimerization of their respective protease domains. However, the underlying mechanism of this activation process remains enigmatic. Here, we demonstrate that cleavage of the intersubunit linker of c-FLIP(L) by procaspase-8 potentiates the activation process by enhancing heterodimerization between the two proteins and vastly improving the proteolytic activity of unprocessed caspase-(C)8. The crystal structures of the protease-like domain of c-FLIP(L) alone and in complex with zymogen C8 identify the unique determinants that favor heterodimerization over procaspase-8 homodimerization, and induce the latent active site of zymogen C8 into a productive conformation. Together, these findings provide molecular insights into a key aspect of c-FLIP(L) function that modulates procaspase-8 activation to elicit diverse responses in different cellular contexts.


  • Organizational Affiliation

    Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ 08544, USA. jwyu@princeton.edu


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CASP8 and FADD-like apoptosis regulator272Homo sapiensMutation(s): 0 
Gene Names: CFLARCASHCASP8AP1CLARPMRIT
UniProt & NIH Common Fund Data Resources
Find proteins for O15519 (Homo sapiens)
Explore O15519 
Go to UniProtKB:  O15519
PHAROS:  O15519
GTEx:  ENSG00000003402 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO15519
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Caspase-8271Homo sapiensMutation(s): 2 
Gene Names: CASP8MCH5
EC: 3.4.22.61
UniProt & NIH Common Fund Data Resources
Find proteins for Q14790 (Homo sapiens)
Explore Q14790 
Go to UniProtKB:  Q14790
PHAROS:  Q14790
GTEx:  ENSG00000064012 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ14790
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
IETD aldehyde inhibitor5N/AMutation(s): 0 
Sequence Annotations
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  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
ASA
Query on ASA
C
L-PEPTIDE LINKINGC4 H7 N O3ASP
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.212 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 52.99α = 90
b = 76.68β = 90
c = 114.19γ = 90
Software Package:
Software NamePurpose
CBASSdata collection
PHASERphasing
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-04-28
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2021-10-13
    Changes: Database references, Derived calculations