Structure of human caspase-6 in complex with Z-VAD-FMK: New peptide binding mode observed for the non-canonical caspase conformation

Bioorg Med Chem Lett. 2011 Sep 15;21(18):5244-7. doi: 10.1016/j.bmcl.2011.07.041. Epub 2011 Jul 21.


Caspase-6 is a cysteine protease implicated in neuronal survival and apoptosis. Deregulation of caspase-6 activity was linked to several neurodegenerative disorders including Alzheimer's and Huntington's Diseases. Several recent studies on the structure of caspase-6 feature the caspase-6 zymogen, mature apo-caspase-6 as well as the Ac-VEID-CHO peptide complex. All structures share the same typical dimeric caspase conformation. However, mature apo-caspase-6 crystallized at low pH revealed a novel, non-canonical inactive caspase conformation speculated to represent a latent state of the enzyme suitable for the design of allosteric inhibitors. In this treatise we present the structure of caspase-6 in the non-canonical inactive enzyme conformation bound to the irreversible inhibitor Z-VAD-FMK. The complex features a unique peptide binding mode not observed previously.

MeSH terms

  • Amino Acid Chloromethyl Ketones / chemistry
  • Amino Acid Chloromethyl Ketones / pharmacology*
  • Binding Sites / drug effects
  • Caspase 6 / chemistry
  • Caspase 6 / metabolism
  • Caspase Inhibitors*
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship


  • Amino Acid Chloromethyl Ketones
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • Caspase 6