4NBL

Tailoring Small Molecules for an Allosteric Site on Procaspase-6


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.76 Å
  • R-Value Free: 0.179 
  • R-Value Work: 0.155 
  • R-Value Observed: 0.156 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Tailoring small molecules for an allosteric site on procaspase-6.

Murray, J.Giannetti, A.M.Steffek, M.Gibbons, P.Hearn, B.R.Cohen, F.Tam, C.Pozniak, C.Bravo, B.Lewcock, J.Jaishankar, P.Ly, C.Q.Zhao, X.Tang, Y.Chugha, P.Arkin, M.R.Flygare, J.Renslo, A.R.

(2014) ChemMedChem 9: 73-77

  • DOI: https://doi.org/10.1002/cmdc.201300424
  • Primary Citation of Related Structures:  
    4N5D, 4N6G, 4N7J, 4N7M, 4NBK, 4NBL, 4NBN

  • PubMed Abstract: 

    Although they represent attractive therapeutic targets, caspases have so far proven recalcitrant to the development of drugs targeting the active site. Allosteric modulation of caspase activity is an alternate strategy that potentially avoids the need for anionic and electrophilic functionality present in most active-site inhibitors. Caspase-6 has been implicated in neurodegenerative disease, including Huntington's and Alzheimer's diseases. Herein we describe a fragment-based lead discovery effort focused on caspase-6 in its active and zymogen forms. Fragments were identified for procaspase-6 using surface plasmon resonance methods and subsequently shown by X-ray crystallography to bind a putative allosteric site at the dimer interface. A fragment-merging strategy was employed to produce nanomolar-affinity ligands that contact residues in the L2 loop at the dimer interface, significantly stabilizing procaspase-6. Because rearrangement of the L2 loop is required for caspase-6 activation, our results suggest a strategy for the allosteric control of caspase activation with drug-like small molecules.


  • Organizational Affiliation

    Departments of Structural Biology, Biochemical Pharmacology, Neuroscience, and Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080 (USA). murray.jeremy@gene.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Caspase-6
A, B
282Homo sapiensMutation(s): 1 
Gene Names: CASP6MCH2procaspase-6
EC: 3.4.22.59
UniProt & NIH Common Fund Data Resources
Find proteins for P55212 (Homo sapiens)
Explore P55212 
Go to UniProtKB:  P55212
PHAROS:  P55212
GTEx:  ENSG00000138794 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP55212
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.76 Å
  • R-Value Free: 0.179 
  • R-Value Work: 0.155 
  • R-Value Observed: 0.156 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 115.784α = 90
b = 115.784β = 90
c = 79.544γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
CBASSdata collection
XSCALEdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-01-01
    Type: Initial release
  • Version 1.1: 2014-01-22
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations