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Comment
. 2020 Apr;41(4):227-230.
doi: 10.1016/j.tips.2020.02.002. Epub 2020 Feb 28.

Pharmacology on Target

Agnieszka T Kawashima  1 , Alexandra C Newton  2
Affiliations
Comment

Pharmacology on Target

Agnieszka T Kawashima et al. Trends Pharmacol Sci. 2020 Apr.

Abstract

Small-molecule inhibitors are a key resource in the cell signaling toolbox. However, because of their global distribution in the cell, they cannot provide a refined understanding of signaling at distinct subcellular locations. Bucko and colleagues have designed a novel tool to localize inhibitors to specific protein scaffolds, opening a new avenue to study localized kinase activity.

Keywords: SNAP-tag; kinase inhibitors; mitosis; protein kinases.

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Conflict of interest statement

The authors declare no conflict of interest with the contents of this article.

Figures

Figure 1:
Figure 1:
The LoKI-ON/OFF system informs on centrosomal AurA signaling. The LoKI-ON platform consists of a genetically-encoded centrosome-targeting pericentrin/AKAP450/centrosomal targeting (PACT) domain connected to a SNAP-tag in which Cys144 will form a covalent thioester bond with a benzylguanine (BG) derivative conjugated to the AurA inhibitor MLN8237 (red circle). Mutation of Cys144 to Ala blocks this reaction, forming the basis of the LoKI-OFF platform. In LoKI-ON cells, the centrosome is labelled with the BG-conjugated AurA inhibitor, providing local kinase inhibition. Conversely, the inhibitor is homogenously distributed throughout the cell in LoKI-OFF cells, resulting in global AurA inhibition. This system therefore allows direct comparison of local versus global kinase inhibition. Figure created with Biorender.
See this image and copyright information in PMC

Comment on

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