Publikation: Chemical Genetics Approach to Engineer Kinesins with Sensitivity towards a Small-Molecule Inhibitor of Eg5
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ChemBioChem. 2016, 17(21), pp. 2042-2045. ISSN 1439-4227. eISSN 1439-7633. Available under: doi: 10.1002/cbic.201600451
Zusammenfassung
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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570 Biowissenschaften, Biologie
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MÖCKEL, Martin M., Corinna HUND, Thomas U. MAYER, 2016. Chemical Genetics Approach to Engineer Kinesins with Sensitivity towards a Small-Molecule Inhibitor of Eg5. In: ChemBioChem. 2016, 17(21), pp. 2042-2045. ISSN 1439-4227. eISSN 1439-7633. Available under: doi: 10.1002/cbic.201600451BibTex
@article{Mockel2016-11-03Chemi-36992,
year={2016},
doi={10.1002/cbic.201600451},
title={Chemical Genetics Approach to Engineer Kinesins with Sensitivity towards a Small-Molecule Inhibitor of Eg5},
number={21},
volume={17},
issn={1439-4227},
journal={ChemBioChem},
pages={2042--2045},
author={Möckel, Martin M. and Hund, Corinna and Mayer, Thomas U.}
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<dcterms:abstract xml:lang="eng">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.</dcterms:abstract>
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