Crystal structure of a procaspase-7 zymogen: mechanisms of activation and substrate binding

Cell. 2001 Nov 2;107(3):399-407. doi: 10.1016/s0092-8674(01)00544-x.


Apoptosis is primarily executed by active caspases, which are derived from the inactive procaspase zymogens through proteolytic cleavage. Here we report the crystal structures of a caspase zymogen, procaspase-7, and an active caspase-7 without any bound inhibitors. Compared to the inhibitor-bound caspase-7, procaspase-7 zymogen exhibits significant structural differences surrounding the catalytic cleft, which precludes the formation of a productive conformation. Proteolytic cleavage between the large and small subunits allows rearrangement of essential loops in the active site, priming active caspase-7 for inhibitor/substrate binding. Strikingly, binding by inhibitors causes a 180 degrees flipping of the N terminus in the small subunit, which interacts with and stabilizes the catalytic cleft. These analyses reveal the structural mechanisms of caspase activation and demonstrate that the inhibitor/substrate binding is a process of induced fit.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Caspase 7
  • Caspases / chemistry*
  • Caspases / genetics
  • Caspases / metabolism
  • Crystallography, X-Ray
  • Enzyme Activation
  • Enzyme Precursors / chemistry*
  • Enzyme Precursors / genetics
  • Enzyme Precursors / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Processing, Post-Translational
  • Protein Structure, Tertiary
  • Substrate Specificity


  • Enzyme Precursors
  • Caspase 7
  • Caspases

Associated data

  • PDB/1K86
  • PDB/1K88