2FQQ

Crystal structure of human caspase-1 (Cys285->Ala, Cys362->Ala, Cys364->Ala, Cys397->Ala) in complex with 1-methyl-3-trifluoromethyl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (2-mercapto-ethyl)-amide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.30 Å
  • R-Value Free: 0.280 
  • R-Value Work: 0.244 
  • R-Value Observed: 0.245 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

A common allosteric site and mechanism in caspases

Scheer, J.M.Romanowski, M.J.Wells, J.A.

(2006) Proc Natl Acad Sci U S A 103: 7595-7600

  • DOI: https://doi.org/10.1073/pnas.0602571103
  • Primary Citation of Related Structures:  
    2FQQ, 2H48, 2HBQ, 2HBR, 2HBY, 2HBZ

  • PubMed Abstract: 

    We present a common allosteric mechanism for control of inflammatory and apoptotic caspases. Highly specific thiol-containing inhibitors of the human inflammatory caspase-1 were identified by using disulfide trapping, a method for site-directed small-molecule discovery. These compounds became trapped by forming a disulfide bond with a cysteine residue in the cavity at the dimer interface approximately 15 A away from the active site. Mutational and structural analysis uncovered a linear circuit of functional residues that runs from one active site through the allosteric cavity and into the second active site. Kinetic analysis revealed robust positive cooperativity not seen in other endopeptidases. Recently, disulfide trapping identified a similar small-molecule site and allosteric transition in the apoptotic caspase-7 that shares only a 23% sequence identity with caspase-1. Together, these studies show a general small-molecule-binding site for functionally reversing the zymogen activation of caspases and suggest a common regulatory site for the allosteric control of inflammation and apoptosis.


  • Organizational Affiliation

    Department of Pharmaceutical Chemistry, University of California, 1700 4th Street, San Francisco, CA 94143, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Caspase-1178Homo sapiensMutation(s): 1 
Gene Names: CASP1IL1BCIL1BCE
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
Caspase-188Homo sapiensMutation(s): 3 
Gene Names: CASP1IL1BCIL1BCE
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
F1G
Query on F1G

Download Ideal Coordinates CCD File 
C [auth B]1-METHYL-3-TRIFLUOROMETHYL-1H-THIENO[2,3-C]PYRAZOLE-5-CARBOXYLIC ACID (2-MERCAPTO-ETHYL)-AMIDE
C10 H10 F3 N3 O S2
HDKGQVZBBSICLG-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.30 Å
  • R-Value Free: 0.280 
  • R-Value Work: 0.244 
  • R-Value Observed: 0.245 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 71.044α = 90
b = 71.044β = 90
c = 117.761γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
CrystalCleardata reduction
d*TREKdata scaling
AMoREphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-05-16
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Advisory, Derived calculations, Version format compliance
  • Version 1.3: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.4: 2023-08-30
    Changes: Data collection, Refinement description