The Different Flexibility
of c-Src and c-Abl Kinases
Regulates the Accessibility of a Druggable Inactive Conformation
- Publication date
- Publisher
Abstract
c-Src and c-Abl are two closely related protein kinases
that constitute
important anticancer targets. Despite their high sequence identity,
they show different sensitivities to the anticancer drug imatinib,
which binds specifically to a particular inactive conformation in
which the Asp of the conserved DFG motif points outward (DFG-out).
We have analyzed the DFG conformational transition of the two kinases
using massive molecular dynamics simulations, free energy calculations,
and isothermal titration calorimetry. On the basis of the reconstruction
of the free energy surfaces for the DFG-in to DFG-out conformational
changes of c-Src and c-Abl, we propose that the different flexibility
of the two kinases results in a different stability of the DFG-out
conformation and might be the main determinant of imatinib selectivity