A water-mediated allosteric network governs activation of Aurora kinase A

Nat Chem Biol. 2017 Apr;13(4):402-408. doi: 10.1038/nchembio.2296. Epub 2017 Feb 6.


The catalytic activity of many protein kinases is controlled by conformational changes of a conserved Asp-Phe-Gly (DFG) motif. We used an infrared probe to track the DFG motif of the mitotic kinase Aurora A (AurA) and found that allosteric activation by the spindle-associated protein Tpx2 involves an equilibrium shift toward the active DFG-in state. Förster resonance energy transfer experiments show that the activation loop undergoes a nanometer-scale movement that is tightly coupled to the DFG equilibrium. Tpx2 further activates AurA by stabilizing a water-mediated allosteric network that links the C-helix to the active site through an unusual polar residue in the regulatory spine. The polar spine residue and water network of AurA are essential for phosphorylation-driven activation, but an alternative form of the water network found in related kinases can support Tpx2-driven activation, suggesting that variations in the water-mediated hydrogen bond network mediate regulatory diversification in protein kinases.

Publication types

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

MeSH terms

  • Allosteric Regulation
  • Aurora Kinase A / metabolism*
  • Enzyme Activation
  • Humans
  • Models, Molecular
  • Water / chemistry
  • Water / metabolism*


  • Water
  • AURKA protein, human
  • Aurora Kinase A