Title |
A Small Molecule-Regulated Guanine Nucleotide Exchange Factor
|
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Published in |
Journal of the American Chemical Society, December 2009
|
DOI | 10.1021/ja907886v |
Pubmed ID | |
Authors |
Inna Goreshnik, Dustin J. Maly |
Abstract |
Selective, pharmacological agents are attractive tools for studying signal transduction because they allow rapid, reversible, and dose-dependent control over intracellular protein function. However, for many targets the identification of potent and selective small molecule agonists and antagonists is a formidable challenge. An attractive strategy for circumventing this problem is to engineer a protein of interest to be sensitive to a pharmacological agent of choice. Here, we report a chemical genetic method for regulating the catalytic activity of signaling enzymes with a small molecule. This approach uses the interaction of the antiapoptotic protein Bcl-xL and a BH3 peptide as an autoinhibitory switch that can be controlled with a small molecule. We applied this strategy to the guanine nucleotide exchange factor Intersectin, which is a selective activator of the GTPase Cdc42. Replacing Intersectin's regulatory domains with the BH3 peptide/Bcl-xL binding module generated a panel of synthetic GEF constructs that can be activated with a competitive ligand. Importantly, the nucleotide exchange activities of these synthetic Intersectin constructs can be controlled in a rapid and dose-dependent manner. The modular nature of this strategy should make it useful for engineering other enzymes involved in signal transduction. |
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Unknown | 26 | 87% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 10 | 33% |
Student > Ph. D. Student | 4 | 13% |
Student > Doctoral Student | 3 | 10% |
Student > Bachelor | 3 | 10% |
Professor | 2 | 7% |
Other | 7 | 23% |
Unknown | 1 | 3% |
Readers by discipline | Count | As % |
---|---|---|
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Physics and Astronomy | 1 | 3% |
Arts and Humanities | 1 | 3% |
Other | 2 | 7% |
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