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Biological Chemistry

On-Off Light Switch For Enzymes

Molecular Biology: Technique switches specific enzyme inhibition on and off with light

by Stu Borman
May 25, 2015 | A version of this story appeared in Volume 93, Issue 21

A new technique could make it easier to target and inhibit specific enzymes and other proteins in cells and to turn that regulation on and off at will with light. Jason W. Chin of the Medical Research Council Laboratory of Molecular Biology, in Cambridge, England, and coworkers previously reported an approach for genetically encoding proteins in cells with unnatural amino acids bearing strained alkene and alkyne groups. They could then rapidly and specifically label the proteins with tetrazine derivatives that react with the strained chemical groups. They have now developed a technique called bioorthogonal ligand tethering (BOLT) that is based on this labeling strategy and can be used in the lab (Nat. Chem. 2015, DOI: 10.1038/nchem.2253). They used BOLT to develop specific inhibitors for each of two closely related signaling enzymes, the kinases MEK1 and MEK2, in live mammalian cells. And they synthesized tetrazine-inhibitor conjugates with a linker that changes shape with different wavelengths of light, allowing them to turn inhibitor binding, and consequently enzyme inhibition, on and off at will.

Scheme showing photoswitchable inhibition of an enzyme.
Credit: Adapted from Nat. Chem.
An unnatural amino acid reacts with a tetrazine-inhibitor complex, leading to enzyme inhibition. Light can then change the conformation of the complex’s linker, turning inhibition on or off.


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