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Functional Disruption of Gli1-DNA Recognition via a Cobalt(III) Complex
Christopher R Brue1, Meghan W Dukes1, Meghan Masotti1
1Departments of Chemistry, Molecular Biosciences, Neurobiology, and Radiology, Northwestern University, Evanston, IL, 60208-3113, USA.
Abstract:
The aberrant activation of the Gli family of zinc finger transcription factors (ZFTFs) is associated with several types of human cancer, including medulloblastoma and basal cell carcinoma. We have reported the use of cobalt(III) Schiff-base complexes (Co(III)-sb) as potent inhibitors of ZFTFs in vivo. These complexes inhibit transcription by displacing the zinc finger domain's structural Zn(II) ion, destabilizing the alpha helix necessary for DNA recognition. Here, we describe the use of Co(III)-sb complexes for the selective inhibition of Gli1. Spectroscopic and computational studies of the Gli1 DNA binding domain found that Co(III)-sb displaced Zn(II) through direct coordination with the His residues of the Cys2 His2 Zn(II) binding site. As a result, there is a dose-dependent degradation of the alpha-helix content in the DNA binding domain of Gli1 and corresponding inhibition of consensus sequence recognition. We conclude that this strategy is well suited for the development of new and potent inhibitors of Gli1.
Insights
Cobalt(III) Schiff-base complexes selectively inhibit Gli1 by displacing zinc ions, destabilizing its DNA-binding alpha-helix. This targeted approach offers a promising strategy for developing novel Gli1 inhibitors for cancer therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Aberrant activation of Gli transcription factors (ZFTFs) is linked to human cancers like medulloblastoma and basal cell carcinoma.
- Cobalt(III) Schiff-base complexes (Co(III)-sb) have shown potential as in vivo inhibitors of ZFTFs.
- These complexes function by displacing structural Zn(II) ions, destabilizing the alpha-helix crucial for DNA recognition.
Purpose of the Study:
- To investigate the selective inhibition of Gli1 using Co(III)-sb complexes.
- To elucidate the molecular mechanism by which Co(III)-sb complexes interact with Gli1.
Main Methods:
- Spectroscopic studies of the Gli1 DNA binding domain.
- Computational studies of Gli1-DNA interactions.
- Assessing the impact of Co(III)-sb on Gli1's alpha-helix content and DNA binding affinity.
Main Results:
- Co(III)-sb complexes were found to selectively inhibit Gli1.
- Spectroscopic and computational data revealed that Co(III)-sb displaces Zn(II) via direct coordination with histidine residues in the Zn(II) binding site.
- A dose-dependent degradation of Gli1's DNA binding domain alpha-helix content was observed, leading to inhibited consensus sequence recognition.
Conclusions:
- The Co(III)-sb complex strategy effectively targets Gli1.
- This mechanism of Zn(II) displacement and alpha-helix destabilization provides a basis for developing potent Gli1 inhibitors.
- This approach holds promise for the development of novel cancer therapeutics targeting Gli1.
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