Crystal structure of baculovirus P35: Role of a novel reactive site loop in apoptotic caspase inhibition

Andrew J Fisher, Wilfred Dela Cruz, Stephen J. Zoog, Christine L. Schneider, Paul D. Friesen

Research output: Contribution to journalArticlepeer-review

97 Scopus citations


The aspartate-specific caspases are critical protease effecters of programmed cell death and consequently represent important targets for apoptotic intervention. Baculovirus P35 is a potent substrate inhibitor of metazoan caspases, a property that accounts for its unique effectiveness in preventing apoptosis in phylogenetically diverse organisms. Here we report the 2.2 Å resolution crystal structure of P35, the first structure of a protein inhibitor of the death caspases. The P35 monomer possesses a solvent-exposed Loop that projects from the protein's main P-sheet core and positions the requisite aspartate cleavage site at the loop's apex. Distortion or destabilization of this reactive site loop by site-directed mutagenesis converted P35 to an efficient substrate which, unlike wild-type P35, failed to interact stably with the target caspase or block protease activity. Thus, cleavage alone is insufficient for caspase inhibition. These data are consistent with a new model wherein the P35 reactive site loop participates in a unique multi-step mechanism in which the spatial orientation of the loop with respect to the P35 core determines post-cleavage association and stoichiometric caspases.

Original languageEnglish (US)
Pages (from-to)2031-2039
Number of pages9
JournalEMBO Journal
Issue number8
StatePublished - Apr 15 1999


  • Apoptosis
  • Baculovirus
  • Caspase inhibitor
  • Crystallography
  • P35

ASJC Scopus subject areas

  • Genetics
  • Cell Biology


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