Apoptosis is primarily executed by active caspases, which are derived from
the inactive procaspase zymogens through proteolytic cleavage. Here we repo
rt the crystal structures of a caspase zymogen, procaspase-7, and an active
caspase-7 without any bound inhibitors. Compared to the inhibitor-bound ca
spase-7, procaspase-7 zymogen exhibits significant structural differences s
urrounding the catalytic cleft, which precludes the formation of a producti
ve 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 inhibitor
s causes a 180 degrees flipping of the N terminus in the small subunit, whi
ch interacts with and stabilizes the catalytic cleft. These analyses reveal
the structural mechanisms of caspase activation and demonstrate that the i
nhibitor/substrate binding is a process of induced fit.