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Exploring Caspase Mutations and Post-Translational Modification by Molecular Modeling Approaches
Published on: October 13, 2022
A bifunctional allosteric site in the dimer interface of procaspase-3
Joshua L Schipper1, Sarah H MacKenzie, Anil Sharma
1Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC 27695, USA.
Biophysical Chemistry
|June 8, 2011
Summary
Researchers identified a small molecule activator for procaspase-3, a key enzyme in cell death. This activator stabilizes the enzyme
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Caspase-3 exists as an inactive zymogen (procaspase-3) and a mature, active form.
- The dimer interface of caspase-3 possesses a bifunctional allosteric site that regulates enzyme activity.
- Allosteric inhibitor binding to mature caspase-3 induces order-to-disorder transitions in active site loops.
Purpose of the Study:
- To identify and characterize small molecule activators of procaspase-3 using its allosteric site.
- To understand the mechanism by which allosteric activators modulate procaspase-3 conformation.
- To explore the therapeutic potential of procaspase-3 activators in cancer treatment.
Main Methods:
- Utilized the allosteric site of procaspase-3 to screen for small molecule activators.
- Characterized the binding of identified activators to the protease.
- Analyzed conformational changes in procaspase-3 upon activator binding.
Main Results:
- Identified a small molecule activator that binds to the procaspase-3 allosteric site.
- Demonstrated that efficient activators stabilize the active zymogen conformation by displacing the intersubunit linker.
- Showed that activators must interact with active site residues within the allosteric site.
Conclusions:
- The allosteric site is crucial for regulating procaspase-3 activation.
- Small molecule activators can promote procaspase-3 activation by stabilizing its active conformation.
- These findings provide a basis for developing drug candidates to activate procaspase-3 in cancer therapy.
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