Mechanism of Aurora B activation by INCENP and inhibition by hesperadin

Mol Cell. 2005 Apr 29;18(3):379-91. doi: 10.1016/j.molcel.2005.03.031.

Abstract

Aurora family serine/threonine kinases control mitotic progression, and their deregulation is implicated in tumorigenesis. Aurora A and Aurora B, the best-characterized members of mammalian Aurora kinases, are approximately 60% identical but bind to unrelated activating subunits. The structure of the complex of Aurora A with the TPX2 activator has been reported previously. Here, we report the crystal structure of Aurora B in complex with the IN-box segment of the inner centromere protein (INCENP) activator and with the small molecule inhibitor Hesperadin. The Aurora B:INCENP complex is remarkably different from the Aurora A:TPX2 complex. INCENP forms a crown around the small lobe of Aurora B and induces the active conformation of the T loop allosterically. The structure represents an intermediate state of activation of Aurora B in which the Aurora B C-terminal segment stabilizes an open conformation of the catalytic cleft, and a critical ion pair in the kinase active site is impaired. Phosphorylation of two serines in the carboxyl terminus of INCENP generates the fully active kinase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Aurora Kinase B
  • Aurora Kinases
  • Binding Sites
  • Chromosomal Proteins, Non-Histone / chemistry
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Crystallography, X-Ray
  • Enzyme Activation
  • Humans
  • Indoles / chemistry
  • Indoles / metabolism*
  • Models, Molecular
  • Molecular Sequence Data
  • Multiprotein Complexes
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / chemistry*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Sequence Alignment
  • Sulfonamides / chemistry
  • Sulfonamides / metabolism*
  • Xenopus laevis

Substances

  • Chromosomal Proteins, Non-Histone
  • INCENP protein, human
  • Indoles
  • Multiprotein Complexes
  • Sulfonamides
  • AURKB protein, human
  • Aurora Kinase B
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • hesperadin

Associated data

  • PDB/2BFX
  • PDB/2BFY