4HVA

Mechanistic and Structural Understanding of Uncompetitive Inhibitors of Caspase-6


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.07 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.174 

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Ligand Structure Quality Assessment 


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Literature

Mechanistic and structural understanding of uncompetitive inhibitors of caspase-6.

Heise, C.E.Murray, J.Augustyn, K.E.Bravo, B.Chugha, P.Cohen, F.Giannetti, A.M.Gibbons, P.Hannoush, R.N.Hearn, B.R.Jaishankar, P.Ly, C.Q.Shah, K.Stanger, K.Steffek, M.Tang, Y.Zhao, X.Lewcock, J.W.Renslo, A.R.Flygare, J.Arkin, M.R.

(2012) PLoS One 7: e50864-e50864

  • DOI: https://doi.org/10.1371/journal.pone.0050864
  • Primary Citation of Related Structures:  
    4HVA

  • PubMed Abstract: 

    Inhibition of caspase-6 is a potential therapeutic strategy for some neurodegenerative diseases, but it has been difficult to develop selective inhibitors against caspases. We report the discovery and characterization of a potent inhibitor of caspase-6 that acts by an uncompetitive binding mode that is an unprecedented mechanism of inhibition against this target class. Biochemical assays demonstrate that, while exquisitely selective for caspase-6 over caspase-3 and -7, the compound's inhibitory activity is also dependent on the amino acid sequence and P1' character of the peptide substrate. The crystal structure of the ternary complex of caspase-6, substrate-mimetic and an 11 nM inhibitor reveals the molecular basis of inhibition. The general strategy to develop uncompetitive inhibitors together with the unique mechanism described herein provides a rationale for engineering caspase selectivity.


  • Organizational Affiliation

    Department of Biochemical and Cellular Pharmacology, Genentech, Inc, South San Francisco, California, United States of America. heise.christopher@gene.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Caspase-6
A, B
265Homo sapiensMutation(s): 0 
Gene Names: CASP6MCH2
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

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
VEID Inhibitor
C, D
5N/AMutation(s): 0 
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4HV
Query on 4HV

Download Ideal Coordinates CCD File 
E [auth A],
F [auth B]
N-[(2R)-1-(3-cyanophenyl)-3-hydroxypropan-2-yl]-5-(3,4-dimethoxyphenyl)furan-3-carboxamide
C23 H22 N2 O5
WYLRQKDQMNFNCH-LJQANCHMSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
4HV Binding MOAD:  4HVA Kd: 1300 (nM) from 1 assay(s)
PDBBind:  4HVA Kd: 1300 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.07 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.174 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 55.988α = 90
b = 62.647β = 104.79
c = 76.298γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data 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: 2013-03-20
    Type: Initial release