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Selective, rapid and optically switchable regulation of protein function in live mammalian cells

Tsai, Yu-Hsuan, Essig, Sebastian, James, John R., Lang, Kathrin and Chin, Jason W. 2015. Selective, rapid and optically switchable regulation of protein function in live mammalian cells. Nature Chemistry 7 , pp. 554-561. 10.1038/nchem.2253

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The rapid and selective regulation of a target protein within living cells that contain closely related family members is an outstanding challenge. Here we introduce genetically directed bioorthogonal ligand tethering (BOLT) and demonstrate selective inhibition (iBOLT) of protein function. In iBOLT, inhibitor–conjugate/target protein pairs are created where the target protein contains a genetically encoded unnatural amino acid with bioorthogonal reactivity and the inhibitor conjugate contains a complementary bioorthogonal group. iBOLT enables the first rapid and specific inhibition of MEK isozymes, and introducing photoisomerizable linkers in the inhibitor conjugate enables reversible, optical regulation of protein activity (photo-BOLT) in live mammalian cells. We demonstrate that a pan kinase inhibitor conjugate allows selective and rapid inhibition of the lymphocyte specific kinase, indicating the modularity and scalability of BOLT. We anticipate that BOLT will enable the rapid and selective regulation of diverse proteins for which no selective small-molecule ligands exist.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Subjects: Q Science > QD Chemistry
Publisher: Nature Publishing Group
ISSN: 1755-4330
Date of Acceptance: 26 March 2015
Last Modified: 23 Sep 2020 13:45

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