Locke, Julia and Joseph, Agnel Praveen and Pena, Alejandro and Mockel, M. and Mayer, T. and Topf, Maya and Moores, Carolyn A. (2017) Structural basis of human kinesin-8 function and inhibition. Proceedings of the National Academy of Sciences of the United States of America 114 (45), E9539-E9548. ISSN 0027-8424.
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Abstract
Kinesin motors play diverse roles in mitosis and are targets for anti-mitotic drugs. The clinical significance of these motors emphasizes the importance of understanding the molecular basis of their function. Equally, investigations into the modes of inhibition of these motors provide crucial information about their molecular mechanisms. Kif18A regulates spindle microtubules through its dual functionality – 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 depolymerises microtubule plus and minus ends. BTB-1 inhibits both microtubule-based Kif18A activities. A reconstruction of BTB-1-bound, microtubule-bound Kif18A, in combination with computational modelling, identified an allosteric BTB-1 binding site near loop5, where it blocks the ATP-dependent conformational changes we characterised. Strikingly, BTB-1 binding is close to that of well-characterised 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.
Metadata
| Item Type: | Article |
|---|---|
| Keyword(s) / Subject(s): | kinesin, cryo-electron microscopy, inhibition, microtubule dynamics, mitosis |
| School: | Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences |
| Depositing User: | Carolyn Moores |
| Date Deposited: | 24 Oct 2017 10:05 |
| Last Modified: | 02 Aug 2023 17:35 |
| URI: | https://eprints.bbk.ac.uk/id/eprint/19862 |
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