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The different flexibility of c-Src and c-Abl kinases regulates the accessibility of a druggable inactive conformation

Silvia Lovera1, Ludovico Sutto, Ralitza Boubeva

  • 1Structural Biology and Biocomputing Programme, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, E-28029 Madrid, Spain.

Journal of the American Chemical Society
|January 28, 2012
PubMed

Insights

The anticancer drug imatinib targets protein kinases c-Src and c-Abl. Differences in kinase flexibility explain imatinib

Area of Science:

  • Biochemistry and Molecular Biology
  • Structural Biology
  • Pharmacology

Background:

  • c-Src and c-Abl are closely related protein kinases and significant anticancer targets.
  • These kinases exhibit differential sensitivity to the anticancer drug imatinib.
  • Imatinib selectively binds to an inactive kinase conformation (DFG-out).

Purpose of the Study:

  • To investigate the DFG conformational transition in c-Src and c-Abl.
  • To elucidate the molecular basis for imatinib's differential selectivity between c-Src and c-Abl.

Main Methods:

  • Extensive molecular dynamics simulations.
  • Free energy calculations.
  • Isothermal titration calorimetry.

Main Results:

  • Reconstructed free energy surfaces for DFG-in to DFG-out transitions in c-Src and c-Abl.
  • Identified distinct flexibility profiles between c-Src and c-Abl.
  • Demonstrated varying stability of the DFG-out conformation for each kinase.

Conclusions:

  • Differential flexibility of c-Src and c-Abl influences DFG-out conformation stability.
  • Kinase flexibility is a key determinant of imatinib selectivity.
  • Understanding these dynamics can inform the design of more selective kinase inhibitors.

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