THE use of small molecules in genetics:
Normally functional analysis of a gene requires that the gene be mutated or altered in some way which, in turn, will alter the protein produced by that gene. These alterations can result in a protein that is not functional or they can result in the protein not being made at all. Using these types of experiments, one is able to determine the role a gene within the cell by assessing the phenotypes observed when the gene is mutated. The problem with this approach is that it can be difficult to use in mammals, which is why some are turning to using small molecules when studying the function of a gene’s protein product. Small molecules are organic compounds of low molecular weight that alter a protein’s function by binding to a specific site on the protein. The use of these molecules is advantageous because they can be engineered to target a certain aspect of the protein, allowing researchers to study a certain role of that protein. Additionally, some molecules bind reversible to proteins, which allows for experiments that study the temporal effect of altering a protein of interest [1]. Furthermore, these molecules can be used to develop drugs that can be used to combat diseases with known genetic origin.
Ku-55933 and Ataxia-Telangiectasia Mutated:
To better understand ATM and its role in the cell, a molecule was developed to interfere with the kinase activity of the protein. This molecule, which was termed Ku-55933 (figure 1), interferes with the activity of ATM by binding to the ATP binding site of the protein which, in turn, prevented the phosphorylation of its downstream targets [2].
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Figure 1: The molecular structure of KU-55933 which is used to inhibit the kinase activity
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discussion:
By using this molecule, researchers are able to study how the inhibition of ATM affects the cell’s response to DNA damage. Seeing as this protein sits toward the apex of the DNA damage response pathway, its disruption could be used to study how its inhibition affects the other proteins of this pathway. It could also be used to study alternative DNA repair pathways used when ATM is not functioning properly. The details regarding KU-55933 can be found here, and some of the research that includes the use of this molecule is located towards the bottom of the page under the heading-Literature. This molecule was found by searching for small molecules that interact with ATM in PubChem.
References:
1. Stockwell, B. R. (2004). Exploring biology with small organic molecules. Nature, 432(7019), 846-854. doi:10.1038/nature03196
2. Identification and Characterization of a Novel and Specific Inhibitor of the Ataxia-Telangiectasia Mutated Kinase ATM. (2004). Cancer Research, 64, 9152-9159. doi:10.1158/0008- 5472.CAN-04-2727
2. Identification and Characterization of a Novel and Specific Inhibitor of the Ataxia-Telangiectasia Mutated Kinase ATM. (2004). Cancer Research, 64, 9152-9159. doi:10.1158/0008- 5472.CAN-04-2727
This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison