期刊
CHEMBIOCHEM
卷 17, 期 21, 页码 2042-2045出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201600451
关键词
allosterism; chemical genetics; inhibitors; kinesin; mechanochemistry
资金
- Deutsche Forschungsgemeinschaft [CRC969]
- Konstanz Research School Chemical Biology (KoRS-CB)
Due to their fast and often reversible mode of action, small molecules are ideally suited to dissect biological processes. Yet, the validity of small-molecule studies is intimately tied to the specificity of the applied compounds, thus imposing a great challenge to screens for novel inhibitors. Here, we applied a chemical-genetics approach to render kinesin motor proteins sensitive to inhibition by the well-characterized small molecule S-Trityl-l-cysteine (STLC). STLC specifically inhibits the kinesin Eg5 through binding to a known allosteric site within the motor domain. Transfer of this allosteric binding site into the motor domain of the human kinesins Kif3A and Kif4A sensitizes them towards STLC. Single-molecule microscopy analyses confirmed that STLC inhibits the movement of chimeric but not wild-type Kif4A along microtubules. Thus, our proof-of-concept study revealed that this chemical-genetic approach provides a powerful strategy to specifically inhibit kinesins in vitro for which small-molecule inhibitors are not yet available.
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