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Biophys Chem. 2011 Nov;159(1):100-9. doi: 10.1016/j.bpc.2011.05.013. Epub 2011 May 25.

A bifunctional allosteric site in the dimer interface of procaspase-3.

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1
Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC 27695, USA.

Abstract

The dimer interface of caspase-3 contains a bifunctional allosteric site in which the enzyme can be activated or inactivated, depending on the context of the protein. In the mature caspase-3, the binding of allosteric inhibitors to the interface results in an order-to-disorder transition in the active site loops. In procaspase-3, by contrast, the binding of allosteric activators to the interface results in a disorder-to-order transition in the active site. We have utilized the allosteric site to identify a small molecule activator of procaspase and to characterize its binding to the protease. The data suggest that an efficient activator must stabilize the active conformer of the zymogen by expelling the intersubunit linker from the interface, and it must interact with active site residues found in the allosteric site. Small molecule activators that fulfill the two requirements should provide scaffolds for drug candidates as a therapeutic strategy for directly promoting procaspase-3 activation in cancer cells.

PMID:
21645959
PMCID:
PMC3166964
DOI:
10.1016/j.bpc.2011.05.013
[Indexed for MEDLINE]
Free PMC Article
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