Conformational Dynamics of the ABL and SRC Complexes with Type 1 Inhibitors.

<p>Conformational dynamics profiles are shown for the crystal structures of Bosutinib complexes with ABL (pdb id 3UE4, panel A) and SRC kinases (pdb id 4MXO, panel B). Conformational dynamics profiles were computed by projecting MD trajectories onto the space of three lowest frequency modes. The color gradient from blue to red indicates the decreasing structural rigidity (or increasing conformational mobility) of the protein residues and refers to an average value over the backbone atoms in each residue. The R-spine residues are annotated in spheres and colored according to their degree of structural stability. A fully assembled architecture of the R-spine is characteristic of the active kinase conformations in the crystal structures. The inhibitors are shown in sticks and atom-based color-coded. A close up of the inhibitor binding mode and interacting residues is shown for ABL kinase (C) and SRC kinase (D). The different orientation of the regulatory kinase motifs in otherwise similar complexes with Bosutinib is highlighted: DFG-out/αC-helix-in conformation in ABL kinase (C) and DFG-in/αC-helix-in conformation in SRC kinase (D).