Structural basis for the inhibition of Polo-like kinase 1

Nat Struct Mol Biol. 2013 Sep;20(9):1047-53. doi: 10.1038/nsmb.2623. Epub 2013 Jul 28.

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 (Map205(PBM)). 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Catalytic Domain
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / chemistry*
  • Cell Cycle Proteins / genetics
  • Crystallography, X-Ray
  • Drosophila Proteins / chemistry*
  • Drosophila Proteins / genetics
  • Humans
  • Microtubule-Associated Proteins / chemistry*
  • Microtubule-Associated Proteins / genetics
  • Models, Biological
  • Models, Molecular
  • Molecular Sequence Data
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / genetics
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / chemistry*
  • Protein-Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / chemistry*
  • Proto-Oncogene Proteins / genetics
  • Sequence Homology, Amino Acid
  • Zebrafish Proteins / antagonists & inhibitors*
  • Zebrafish Proteins / chemistry*
  • Zebrafish Proteins / genetics

Substances

  • Cell Cycle Proteins
  • Drosophila Proteins
  • Map205 protein, Drosophila
  • Microtubule-Associated Proteins
  • Multiprotein Complexes
  • Proto-Oncogene Proteins
  • Zebrafish Proteins
  • polo protein, Drosophila
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1

Associated data

  • PDB/4J7B