Figure 3. Magnified views into the active sites of the ABL kinase domain in complex with imatinib (A) and dasatinib (B).

The two compounds have very different modes of binding to the kinase, with dasatinib more confined to the ATP-binding pocket than imatinib. In addition, imatinib binds the inactive and dasatinib the active conformations, with opposite orientations of the catalytic Glu-Phe-Gly amino acid residues (shown in light blue stick format). In the dasatinib structure, the glutamic acid of the Glu-Phe-Gly motif that coordinates a Mg²⁺ ion during catalysis is oriented properly for catalysis, whereas in the imatinib structure this residue points away from the active site. Both inhibitors reside in close proximity to the T315 residue. The side chain atoms of the residues susceptible to resistant mutations for each inhibitor are shown in green and inhibitor atoms shown in yellow stick format (nitrogen, dark blue; oxygen, red; sulfur, orange; chlorine, hot pink). The P-loop (residues 244–255) is shown in magenta and the activation loop (residues 381–402) is shown in light blue. (A) PDB entry 1IEP (24). (B) PDB entry 2GQG (78). The figure was created using PyMol (http://pymol.sourceforge.net/).