Structural basis of human kinesin-8 function and inhibition

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LOCKE, Julia, Agnel Praveen JOSEPH, Alejandro PEÑA, Martin M. MÖCKEL, Thomas U. MAYER, Maya TOPF, Carolyn A MOORES, 2017. Structural basis of human kinesin-8 function and inhibition. In: Proceedings of the National Academy of Sciences of the United States of America. 114(45), pp. E9539-E9548. ISSN 0027-8424. eISSN 1091-6490. Available under: doi: 10.1073/pnas.1712169114

@article{Locke2017Struc-40980, title={Structural basis of human kinesin-8 function and inhibition}, year={2017}, doi={10.1073/pnas.1712169114}, number={45}, volume={114}, issn={0027-8424}, journal={Proceedings of the National Academy of Sciences of the United States of America}, pages={E9539--E9548}, author={Locke, Julia and Joseph, Agnel Praveen and Peña, Alejandro and Möckel, Martin M. and Mayer, Thomas U. and Topf, Maya and Moores, Carolyn A} }

<rdf:RDF xmlns:dcterms="" xmlns:dc="" xmlns:rdf="" xmlns:bibo="" xmlns:dspace="" xmlns:foaf="" xmlns:void="" xmlns:xsd="" > <rdf:Description rdf:about=""> <dc:contributor>Joseph, Agnel Praveen</dc:contributor> <dc:creator>Mayer, Thomas U.</dc:creator> <dc:contributor>Mayer, Thomas U.</dc:contributor> <dspace:hasBitstream rdf:resource=""/> <dcterms:abstract xml:lang="eng">Kinesin motors play diverse roles in mitosis and are targets for antimitotic drugs. The clinical significance of these motors emphasizes the importance of understanding the molecular basis of their function. Equally important, investigations into the modes of inhibition of these motors provide crucial information about their molecular mechanisms. Kif18A regulates spindle microtubules through its dual functionality, with microtubule-based stepping and regulation of microtubule dynamics. We investigated the mechanism of Kif18A and its inhibition by the small molecule BTB-1. The Kif18A motor domain drives ATP-dependent plus-end microtubule gliding, and undergoes conformational changes consistent with canonical mechanisms of plus-end-directed motility. The Kif18A motor domain also depolymerizes microtubule plus and minus ends. BTB-1 inhibits both of these microtubule-based Kif18A activities. A reconstruction of BTB-1-bound, microtubule-bound Kif18A, in combination with computational modeling, identified an allosteric BTB-1-binding site near loop5, where it blocks the ATP-dependent conformational changes that we characterized. Strikingly, BTB-1 binding is close to that of well-characterized Kif11 inhibitors that block tight microtubule binding, whereas BTB-1 traps Kif18A on the microtubule. Our work highlights a general mechanism of kinesin inhibition in which small-molecule binding near loop5 prevents a range of conformational changes, blocking motor function.</dcterms:abstract> <dcterms:available rdf:datatype="">2017-12-20T10:42:23Z</dcterms:available> <dcterms:isPartOf rdf:resource=""/> <dc:creator>Topf, Maya</dc:creator> <dc:language>eng</dc:language> <dc:rights>terms-of-use</dc:rights> <foaf:homepage rdf:resource="http://localhost:8080/jspui"/> <dc:contributor>Möckel, Martin M.</dc:contributor> <dcterms:hasPart rdf:resource=""/> <dc:creator>Möckel, Martin M.</dc:creator> <dc:contributor>Moores, Carolyn A</dc:contributor> <dc:creator>Moores, Carolyn A</dc:creator> <dspace:isPartOfCollection rdf:resource=""/> <dcterms:issued>2017</dcterms:issued> <dc:contributor>Topf, Maya</dc:contributor> <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/> <dc:contributor>Locke, Julia</dc:contributor> <dc:creator>Peña, Alejandro</dc:creator> <bibo:uri rdf:resource=""/> <dcterms:rights rdf:resource=""/> <dc:creator>Joseph, Agnel Praveen</dc:creator> <dc:contributor>Peña, Alejandro</dc:contributor> <dc:date rdf:datatype="">2017-12-20T10:42:23Z</dc:date> <dc:creator>Locke, Julia</dc:creator> <dcterms:title>Structural basis of human kinesin-8 function and inhibition</dcterms:title> </rdf:Description> </rdf:RDF>

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