Journal
NATURE CHEMISTRY
Volume 7, Issue 7, Pages 554-561Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEM.2253
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Funding
- UK Medical Research Council [U105181009, UD99999908]
- European Research Council
- EMBO Long-Term Fellowship
- DFG Research Fellowship
- MRC [MC_UP_A024_1008, MC_U105181009] Funding Source: UKRI
- Medical Research Council [MC_U105181009, MC_UP_A024_1008] Funding Source: researchfish
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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.
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