Co-crystal structures of the protein kinase haspin with bisubstrate inhibitors

Acta Crystallogr F Struct Biol Commun. 2016 May;72(Pt 5):339-45. doi: 10.1107/S2053230X16004611. Epub 2016 Apr 22.

Abstract

Haspin is a mitotic protein kinase that is responsible for the phosphorylation of Thr3 of histone H3, thereby creating a recognition motif for docking of the chromosomal passenger complex that is crucial for the progression of cell division. Here, two high-resolution models of haspin with previously reported inhibitors consisting of an ATP analogue and a histone H3(1-7) peptide analogue are presented. The structures of the complexes confirm the bisubstrate character of the inhibitors by revealing the signature binding modes of the moieties targeting the ATP-binding site and the protein substrate-binding site of the kinase. This is the first structural model of a bisubstrate inhibitor targeting haspin. The presented structural data represent a model for the future development of more specific haspin inhibitors.

Keywords: bisubstrate; haspin; histone; inhibitor; linker; protein kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / chemistry*
  • Protein Conformation
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / chemistry*
  • Substrate Specificity

Substances

  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • HASPIN protein, human
  • Protein-Serine-Threonine Kinases