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Structural basis of human kinesin-8 function and inhibition

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. Green open access

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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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