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08:47
Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation
Published on: March 5, 2018
Self-assembling small molecules form nanofibrils that bind procaspase-3 to promote activation
Julie A Zorn1, Holger Wille, Dennis W Wolan
1Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA.
Journal of the American Chemical Society
|November 10, 2011
Summary
Small molecule 1541 self-assembles into nanofibrils, acting as a novel biocatalytic material. These fibrils activate procaspase-3 (an enzyme precursor) through induced proximity, offering new drug discovery avenues.
Area of Science:
- Biochemistry
- Biophysics
- Drug Discovery
Background:
- Small molecules can modulate enzyme function, offering alternatives to inhibitors for drug discovery and allosteric regulation.
- A previously identified compound, 1541, was found to stimulate the activation of procaspase-3 to mature caspase-3 via high-throughput screening (HTS).
Purpose of the Study:
- To investigate the mechanism by which compound 1541 activates procaspase-3.
- To characterize the self-assembly properties of compound 1541 and its function as a biocatalytic material.
Main Methods:
- High-throughput screening (HTS) to identify compound 1541.
- Characterization of 1541 self-assembly into nanofibrils.
- Assays to determine the mechanism of procaspase-3 activation by 1541 nanofibrils.
Main Results:
- Compound 1541 self-assembles into nanofibrils longer than 1 micrometer.
- These nanofibrils exhibit distinct properties compared to typical globular protein aggregators.
- 1541 nanofibrils activate procaspase-3 through an induced proximity mechanism, functioning as a biocatalytic material.
Conclusions:
- Small molecule self-assembly into nanofibrils provides a novel platform for proenzyme activation.
- This fibril-mediated activation mechanism may mimic natural procaspase processing on protein scaffolds.
- The findings open new avenues for developing activators for drug discovery and allosteric regulation.
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