Small-molecule probes are important tools for studying protein function in cells. Identifying potent and specific inhibitors, however, remains a tedious and challenging process. Tsai et al. present bioorthogonal ligand tethering (BOLT), a broadly applicable method to selectively and reversibly inhibit proteins. In BOLT, an unnatural amino acid functionalized with a reactive bioorthogonal group is installed on a protein; a ligand for the protein is attached to another bioorthogonal group that reacts with the unnatural amino acid to create a covalent bond. In this manner, the proximity effect allows a ligand with low selectivity for the protein of interest to rapidly bind to that protein, as the authors demonstrate by selectively inhibiting MEK1 and MEK2 in live cells. A photoswitch can also be integrated in the ligand construct, allowing protein activity to be turned on and off with light.
Rights and permissions
About this article
Cite this article
Inhibition with BOLT. Nat Methods 12, 601 (2015). https://doi.org/10.1038/nmeth.3458
Published:
Issue Date:
DOI: https://doi.org/10.1038/nmeth.3458