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Biological Chemistry

New technique turns on specific kinases in mice

Genetic engineering, amino acid mutagenesis, and bioorthogonal chemistry combine to target kinase of choice

by Stu Borman
May 6, 2016 | A version of this story appeared in Volume 94, Issue 19

Off-on switch
Scheme shows how trans-cyclooctene derivative of kinase’s catalytic lysine prevents enzyme from interacting with adenosine triphosphate and phosphorylating substrate and how reaction removes trans-cyclooctene and rescues native kinase activity.
Credit: Adapted from ACS Cent. Sci.
A trans-cyclooctene (red) derivative of lysine blocks kinase activity by preventing interactions with adenosine triphosphate (ATP). A bioorthogonal reaction can then remove trans-cyclooctene and rescue activity.

A simple new technique turns on the ­enzymatic activity of specific native kinases in living cells and animals. The strategy could help elucidate the roles kinases play in cell signaling and diseases such as cancer.

Human cells make and use more than 500 types of kinases. Because of the structural similarities among them, it is hard to deactivate specific kinases with small molecules. Methods exist to turn on kinases selectively, but they produce kinases with modified structures, which may not function in the same way as the native enzymes.

Lysine is present in all kinase active sites. Peng Chen of Peking University and coworkers engineer cells in culture and in animals to incorporate a trans-cyclooctene-derivatized version of lysine in the active sites of specific kinases. This blocks the enzymes’ activity. They then inject a bioorthogonal cleavage reagent to remove the trans-cyclooctene group, restoring native kinase activity. They demonstrated the technique in cell culture and in mice on the kinase Src, which has been associated with certain cancers (ACS Cent. Sci. 2016, DOI: 10.1021/acscentsci.6b00024).

“This elegant new method shows great promise for controlling kinase action in complex environments,” comments signal transduction specialist Philip A. Cole of Johns Hopkins University.


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