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Selective, rapid and optically switchable regulation of protein function in live mammalian cells
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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 (7). pp. 554-561. doi:10.1038/nchem.2253
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Official URL: http://dx.doi.org/10.1038/nchem.2253
Abstract
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: | Journal Article | ||||||||
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| Divisions: | Faculty of Medicine > Warwick Medical School > Biomedical Sciences Faculty of Medicine > Warwick Medical School |
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| Journal or Publication Title: | Nature Chemistry | ||||||||
| Publisher: | Nature Publishing Group | ||||||||
| ISSN: | 1755-4330 | ||||||||
| Official Date: | July 2015 | ||||||||
| Dates: |
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| Volume: | 7 | ||||||||
| Number: | 7 | ||||||||
| Page Range: | pp. 554-561 | ||||||||
| DOI: | 10.1038/nchem.2253 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Restricted or Subscription Access |
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