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Structural basis for the inhibition of Polo-like kinase 1

Nature Structural & Molecular Biology volume 20, pages 1047–1053 (2013)Cite this article

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Abstract

Polo-like kinase 1 (PLK1) is a master regulator of mitosis and is considered a potential drug target for cancer therapy. PLK1 is characterized by an N-terminal kinase domain (KD) and a C-terminal Polo-box domain (PBD). The KD and PBD are mutually inhibited, but the molecular mechanisms of the autoinhibition remain unclear. Here we report the 2.3-Å crystal structure of the complex of the Danio rerio KD and PBD together with a PBD-binding motif of Drosophila melanogaster microtubule-associated protein 205 (Map205PBM). The structure reveals that the PBD binds and rigidifies the hinge region of the KD in a distinct conformation from that of the phosphopeptide-bound PBD. This structure provides a framework for understanding the autoinhibitory mechanisms of PLK1 and also sheds light on the activation mechanisms of PLK1 by phosphorylation or phosphopeptide binding.

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Figure 1: Overall structure of the KD–PBD–Map205PBM complex.
Figure 2: Details of the KD-PBD interactions.
Figure 3: Details of the PBD-Map205PBM interactions.
Figure 4: Reduced flexibility of the KD by the PBD.
Figure 5: Inhibition and activation of PLK1.
Figure 6: Model of multilevel regulation of PLK1.

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Acknowledgements

This work was supported by funds from the Chinese Ministry of Science and Technology 2012CB722602 (to J.Q.), 2013CB911501 (to T.W.) and NSFC21290180 (to J.Q.), and the Shenzhen municipal Shuang Bai Project and Science and Technology innovation program CXB201005260059A (to J.Q.), ZDSY20120614144410389 and JCYJ20120614150904060 (to T.W.). We thank the staff of beamline BL17U at Shanghai Synchrotron Radiation Facility for the technical assistance during data collection.

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  1. Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China

    Jun Xu, Chen Shen, Tao Wang & Junmin Quan

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  2. Chen Shen
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Contributions

J.X. and J.Q. designed all experiments. J.X. and C.S. performed the experiments. T.W. contributed to crystallization, X-ray diffraction data collection and structural determination. All authors discussed the results and commented on the manuscript. J.Q. supervised all aspects of the project and wrote the manuscript.

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Correspondence to Tao Wang or Junmin Quan.

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Xu, J., Shen, C., Wang, T. et al. Structural basis for the inhibition of Polo-like kinase 1. Nat Struct Mol Biol 20, 1047–1053 (2013). https://doi.org/10.1038/nsmb.2623

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