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Issue 38, 2015
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Degradation of HaloTag-fused nuclear proteins using bestatin-HaloTag ligand hybrid molecules

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Abstract

We have developed a protein knockdown technology using hybrid small molecules designed as conjugates of a ligand for the target protein and a ligand for ubiquitin ligase cellular inhibitor of apoptosis protein 1 (cIAP1). However, this technology has several limitations. Here, we report the development of a novel protein knockdown system to address these limitations. In this system, target proteins are fused with HaloTag to provide a common binding site for a degradation inducer. We designed and synthesized small molecules consisting of alkyl chloride as the HaloTag-binding degradation inducer, which binds to HaloTag, linked to BE04 (2), which binds to cIAP1. Using this system, we successfully knocked down HaloTag-fused cAMP responsive element binding protein 1 (HaloTag-CREB1) and HaloTag-fused c-jun (HaloTag-c-jun), which are ligand-unknown nuclear proteins, in living cells. HaloTag-binding degradation inducers can be synthesized easily, and are expected to be useful as biological tools for pan-degradation of HaloTag-fused proteins.

Graphical abstract: Degradation of HaloTag-fused nuclear proteins using bestatin-HaloTag ligand hybrid molecules

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Publication details

The article was received on 09 Jul 2015, accepted on 24 Aug 2015 and first published on 24 Aug 2015


Article type: Communication
DOI: 10.1039/C5OB01395J
Org. Biomol. Chem., 2015,13, 9746-9750

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    Degradation of HaloTag-fused nuclear proteins using bestatin-HaloTag ligand hybrid molecules

    S. Tomoshige, M. Naito, Y. Hashimoto and M. Ishikawa, Org. Biomol. Chem., 2015, 13, 9746
    DOI: 10.1039/C5OB01395J

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