Crystal structure of human aurora B in complex with INCENP and VX-680

J Med Chem. 2012 Sep 13;55(17):7841-8. doi: 10.1021/jm3008954. Epub 2012 Sep 4.

Abstract

We present the structure of the human Aurora B kinase domain in complex with the C-terminal Aurora-binding region of human INCENP and the Aurora kinase inhibitor VX-680. The structure unexpectedly reveals a dimeric arrangement of the Aurora B:INCENP complex, which was confirmed to exist in solution by analytical ultracentrifugation. The dimerization involves a domain swap of the activation loop, resulting in a different conformation of the DFG motif as compared to that seen in other kinase complexes with VX-680. The binding of INCENP differs significantly from that seen in the Xenopus laevis Aurora B:INCENP complex currently used as a model for structure-based design for this important oncology target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Aurora Kinase B
  • Aurora Kinases
  • Chromosomal Proteins, Non-Histone / chemistry*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Piperazines / chemistry*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / chemistry*
  • Sequence Homology, Amino Acid

Substances

  • Chromosomal Proteins, Non-Histone
  • INCENP protein, human
  • Piperazines
  • VX680
  • AURKB protein, human
  • Aurora Kinase B
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases