AI Article Synopsis
- The study introduces a novel method called genetically directed bioorthogonal ligand tethering (BOLT) for the selective regulation of target proteins in cells that have similar family members.
- The method involves creating pairs of inhibitor-conjugates and target proteins using unnatural amino acids and bioorthogonal groups for precise inhibition of protein function, demonstrated with MEK isozymes and lymphocyte-specific kinase.
- BOLT not only allows for rapid and specific inhibition but also enables reversible control through light activation (photo-BOLT), offering potential for broader applications in protein regulation where specific small-molecule ligands are unavailable.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673907 | PMC |
| http://dx.doi.org/10.1038/nchem.2253 | DOI Listing |
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