Crystal structure of a procaspase-7 zymogen: mechanisms of activation and substrate binding.
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Chai J, Wu Q, Shiozaki E, Srinivasula SM, Alnemri ES, Shi Y
Crystal structure of a procaspase-7 zymogen: mechanisms of activation and substrate binding.
Cell. 2001 Nov 2;107(3):399-407.
- PubMed ID
- 11701129 [ View in PubMed]
- Abstract
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.