Why does Gleevec only bind to Abl but not recognize its kin Src?

In the journal Science, Biochemistry Professor Dorothee Kern at Brandeis University, who is also a researcher at Howard Hughes Medical Institute reveals the evolution tour of billions of years of Abl and Src protein and points out the exact evolutionary change which causes the condition that Gleevec binds well with one and binds poorly with the other. Such a new method for enzyme study and their binding sites are likely to have a significant impact on the development of rational anti-cancer drugs. According to the research using recombinant mouse proteins, the researchers knew that the two proteins have only a difference of 146 amino acids, but there is a huge difference between them - i.e. Abl is sensitive to anticancer drug Gleevec, while Src is not.

Developing more drugs like Gleevec which can play a role - referred to as rational drug design - may be possible to create some new therapies targeted to specific enzymes in many cancer types. Unfortunately, scientists don't know why Gleevec is so picky that it only binds to Abl but not recognize its kin Src.

In order to unlock this puzzle, Kern and her team made use of recombinant proteins like recombinant rat proteins and recombinant human proteins and started to find out the common ancestor of Abl and Src a billion years - an original protein which is known as ANC-AS in yeast. They draw a phylogenetic tree and searched for some amino acid changes and molecular mechanisms.

With the ANC-AS evolution in more complex organisms, it began to specialize and branch into a number of proteins which showed different control, roles and catalytic processes - generated Abl and Src. By tracking this process and testing the protein's affinity for Gleevec along this road, Kern and the study group narrowed the reasons which lead to specificity of Gleevec from the differences of 146 amino acids to that of 15 amino acids.

These 15 amino acids play a role in the conformational equilibrium of Abl. Conformational equilibrium refers to the conversion of a protein between two structures. For binding to Gleevec, the main difference between Abl and Src lies in the relative time of protein staying in each conformation, resulting in the great difference in their binding ability. By understanding the causes and mechanism of Gleveec acting on Abl and being ineffective on Src, the researchers obtained a starting point to design other drugs that have high affinity, specificity and can bind to them. Flarebio provides recombinant proteins such as recombinant Ext2 at good prices.