In eukaryotic cells, the peak of protein phosphorylation occurs during mitosis, switching the activities of a significant proportion of proteins and orchestrating a wholesale reorganization of cell shape and internal architecture. Most mitotic protein phosphorylation events are catalysed by a small subset of serine/threonine protein kinases. These include members of the Cdk (cyclin-dependent kinase), Plk (Polo-like kinase), Aurora, Nek (NimA-related kinase) and Bub families, as well as Haspin, Greatwall and Mps1/TTK. There has been steady progress in resolving the structural mechanisms that regulate the catalytic activities of these mitotic kinases. From structural and biochemical perspectives, kinase activation appears not as a binary process (from inactive to active), but as a series of states that exhibit varying degrees of activity. In its lowest activity state, a mitotic kinase may exhibit diverse autoinhibited or inactive conformations. Kinase activation proceeds via phosphorylation and/or association with a binding partner. These remodel the structure into an active conformation that is common to almost all protein kinases. However, all mitotic kinases of known structure have divergent features, many of which are key to understanding their specific regulatory mechanisms. Finally, mitotic kinases are an important class of drug target, and their structural characterization has facilitated the rational design of chemical inhibitors.
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Conference Article|
July 18 2013
The structural mechanisms that underpin mitotic kinase activation
Charlotte A. Dodson;
Charlotte A. Dodson
*Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, U.K.
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Tamanna Haq;
Tamanna Haq
†Department of Biochemistry, Henry Wellcome Laboratories for Structural Biology, University of Leicester, Lancaster Road, Leicester LE1 9HN, U.K.
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Sharon Yeoh;
Sharon Yeoh
‡Centre for Translational Therapeutics, Henry Wellcome Laboratories for Structural Biology, University of Leicester, Lancaster Road, Leicester LE1 9HN, U.K.
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Andrew M. Fry;
Andrew M. Fry
†Department of Biochemistry, Henry Wellcome Laboratories for Structural Biology, University of Leicester, Lancaster Road, Leicester LE1 9HN, U.K.
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Richard Bayliss
Richard Bayliss
1
†Department of Biochemistry, Henry Wellcome Laboratories for Structural Biology, University of Leicester, Lancaster Road, Leicester LE1 9HN, U.K.
1To whom correspondence should be addressed (emailrichard.bayliss@le.ac.uk).
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Publisher: Portland Press Ltd
Received:
April 26 2013
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem Soc Trans (2013) 41 (4): 1037–1041.
Article history
Received:
April 26 2013
Citation
Charlotte A. Dodson, Tamanna Haq, Sharon Yeoh, Andrew M. Fry, Richard Bayliss; The structural mechanisms that underpin mitotic kinase activation. Biochem Soc Trans 1 August 2013; 41 (4): 1037–1041. doi: https://doi.org/10.1042/BST20130066
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