Abstract
The control of endogenous protein activity with light inside live cells is helpful for the high spatiotemporal probing of their dynamic roles. Herein, we report the first small-molecule-ligand-directed caging approach to control the endogenous human O6 -alkylguanine-DNA alkyltransferase (AGT) activity with light, and the caged AGT is constructed from the native intracellular AGT. The photo-responsive O6 -benzylguanine derivative O6 -NBG3 is developed to site-specifically cage the AGT's catalytic cysteine residue, and the light irradiation on-demand restores AGT's activity in vitro, in bacteria, and in mammalian cells. With O6 -NBG3, the alkylated AGT is dealkylated for the first time to recover the DNA repair activity in breast cancer MCF-7 cells by the dose-dependent light irradiation. This decaging strategy enables the localized modulation of endogenous AGT activity with high temporal precision without genetic engineering, which holds great potential for therapeutic applications.
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