Tsai, Y.-H. et al. Nat. Chem. doi:10.1038/nchem.2253 (18 May 2015).

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.