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CDK1 structures reveal conserved and unique features of the essential cell cycle CDK

Author

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  • Nicholas R. Brown

    (University of Oxford
    Present address: MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK)

  • Svitlana Korolchuk

    (Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University)

  • Mathew P. Martin

    (Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University)

  • Will A. Stanley

    (Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University)

  • Rouslan Moukhametzianov

    (Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University)

  • Martin E. M. Noble

    (University of Oxford
    Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University)

  • Jane A. Endicott

    (University of Oxford
    Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University)

Abstract

CDK1 is the only essential cell cycle CDK in human cells and is required for successful completion of M-phase. It is the founding member of the CDK family and is conserved across all eukaryotes. Here we report the crystal structures of complexes of CDK1–Cks1 and CDK1–cyclin B–Cks2. These structures confirm the conserved nature of the inactive monomeric CDK fold and its ability to be remodelled by cyclin binding. Relative to CDK2–cyclin A, CDK1–cyclin B is less thermally stable, has a smaller interfacial surface, is more susceptible to activation segment dephosphorylation and shows differences in the substrate sequence features that determine activity. Both CDK1 and CDK2 are potential cancer targets for which selective compounds are required. We also describe the first structure of CDK1 bound to a potent ATP-competitive inhibitor and identify aspects of CDK1 structure and plasticity that might be exploited to develop CDK1-selective inhibitors.

Suggested Citation

  • Nicholas R. Brown & Svitlana Korolchuk & Mathew P. Martin & Will A. Stanley & Rouslan Moukhametzianov & Martin E. M. Noble & Jane A. Endicott, 2015. "CDK1 structures reveal conserved and unique features of the essential cell cycle CDK," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7769
    DOI: 10.1038/ncomms7769
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    Cited by:

    1. Rhianna J. Rowland & Svitlana Korolchuk & Marco Salamina & Natalie J. Tatum & James R. Ault & Sam Hart & Johan P. Turkenburg & James N. Blaza & Martin E. M. Noble & Jane A. Endicott, 2024. "Cryo-EM structure of the CDK2-cyclin A-CDC25A complex," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Jiawei Zhang & Yichao Gan & Hongzhi Li & Jie Yin & Xin He & Liming Lin & Senlin Xu & Zhipeng Fang & Byung-wook Kim & Lina Gao & Lili Ding & Eryun Zhang & Xiaoxiao Ma & Junfeng Li & Ling Li & Yang Xu &, 2022. "Inhibition of the CDK2 and Cyclin A complex leads to autophagic degradation of CDK2 in cancer cells," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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