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    The ATP state of a mitotic Kinesin-5 bound to microtubules

    Bodey, Andrew J. and Kikkawa, M. and Moores, Carolyn A. (2009) The ATP state of a mitotic Kinesin-5 bound to microtubules. Biophysical Journal 96 (3(S1)), 215a-215a. ISSN 0006-3495.

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    The mitotic spindle is essential for faithful cell division. It is built from microtubules and is orchestrated by many proteins, including members of the kinesin superfamily. Kinesin-5 motors are essential for mitosis in many organisms and are involved in formation and maintenance of spindle bipolarity. Kinesin-5s share some properties with other kinesins including the ability to move - albeit slowly - towards the plus ends of microtubules. However, kinesin-5s have a number of unique properties, and are also of interest for cancer treatment because kinesin-5-specific small molecule inhibitors have been identified and are in clinical trials. Outstanding mechanistic questions about kinesin-5 motors relate to their interaction with microtubules. We set out to understand this interaction using cryo-electron microscopy and image processing. Cryo-electron microscopy is uniquely suited to this goal since microtubules are too large and heterogeneous to be studied by other structural techniques. Using the motor domain from Klp61f (the Drosophila kinesin-5), we imaged microtubules bound by the motor in an ATP-like state and calculated the structure of the complex at 10Å resolution. At this resolution, we are able to see the density associated with most α-helices in both the motor and the microtubule and visualise the motor in a tight-binding, AMPPNP conformation. The docked tubulin structure shows an excellent fit to our map, but available kinesin-5 crystal structures do not match the conformation of the motor in our maps, indicating that microtubule binding induces a conformational change in the kinesin-5 motor. Thus, calculation of kinesin-microtubule structures are essential for revealing the precise mechanism by which motors use energy from ATP and microtubule binding to generate force. Our structure also provides insight into the mechanisms by which anti-cancer drugs elicit their therapeutic effect.


    Item Type: Article
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Research Centres and Institutes: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 04 Aug 2010 14:09
    Last Modified: 02 Aug 2023 16:49


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