Inhibition of caspase-2 by a designed ankyrin repeat protein: specificity, structure, and inhibition mechanism

Structure. 2007 May;15(5):625-36. doi: 10.1016/j.str.2007.03.014.


Specific and potent caspase inhibitors are indispensable for the dissection of the intricate pathways leading to apoptosis. We selected a designed ankyrin repeat protein (DARPin) from a combinatorial library that inhibits caspase-2 in vitro with a subnanomolar inhibition constant and, in contrast to the peptidic caspase inhibitors, with very high specificity for this particular caspase. The crystal structure of this inhibitor (AR_F8) in complex with caspase-2 reveals the molecular basis for the specificity and, together with kinetic analyses, the allosteric mechanism of inhibition. The structure also shows a conformation of the active site that can be exploited for the design of inhibitory compounds. AR_F8 is a specific inhibitor of an initiator caspase and has the potential to help identify the function of caspase-2 in the complex biological apoptotic signaling network.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Ankyrin Repeat / physiology*
  • Caspase 2 / chemistry*
  • Caspase Inhibitors*
  • Cysteine Endopeptidases / chemistry*
  • Humans
  • Molecular Sequence Data
  • Protein Engineering*


  • Caspase Inhibitors
  • CASP2 protein, human
  • Caspase 2
  • Cysteine Endopeptidases

Associated data

  • PDB/2P2C