Locke, J;
Joseph, AP;
Peña, A;
Möckel, MM;
Mayer, TU;
Topf, M;
Moores, CA;
(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.
10.1073/pnas.1712169114.
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Abstract
Kinesins are a superfamily of ATP-dependent motors important for many microtubule-based functions, including multiple roles in mitosis. Small-molecule inhibitors of mitotic kinesins disrupt cell division and are being developed as antimitotic therapies. We investigated the molecular mechanism of the multitasking human mitotic kinesin Kif18A and its inhibition by the small molecule BTB-1. We used cryo-electron microscopy to visualize nucleotide-dependent conformational changes in microtubule-bound Kif18A, and the conformation of microtubule-bound, BTB-1-bound Kif18A. We calculated a putative BTB-1–binding site and validated this site experimentally to reveal the BTB-1 inhibition mechanism. Our work points to a general mechanism of kinesin inhibition, with wide implications for a targeted blockade of these motors in both dividing and interphase cells.
| Type: | Article |
|---|---|
| Title: | Structural basis of human kinesin-8 function and inhibition |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1073/pnas.1712169114 |
| Publisher version: | https://doi.org/10.1073/pnas.1712169114 |
| Language: | English |
| Additional information: | © 2017 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | kinesin, cryo-electron microscopy, inhibition, microtubule dynamics, mitosis |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10073662 |
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