Ribbon representation of ABL1 kinase in complex with tyrosine kinase inhibitors. (A) Ribbon representation of 3-dimensional structure of ABL1 kinase domain (blue) in complex with imatinib (orange). The ATP-binding site in the ABL1 kinase domain is located between the activation loop (A-loop; magenta) and the phosphate-binding loop (P-loop; yellow). The A-loop controls the ABL1 catalytic activity by switching between different states in a phosphorylation-dependent manner. Imatinib inserts its pyridinyl group underneath the helix αC in the NH2-terminal lobe of ABL1 kinase, displacing ATP and trapping the kinase in its inactive conformation. (B,C) The imatinib:ABL1 (blue) and the dasatinib:ABL1 (green) complexes are shown. The A-loop (yellow) adopts diverging positions in the 2 complexes. Conformational changes in the A-loop prevent imatinib binding to the active form of the enzyme. By contrast, dasatinib binds ABL1 in its active conformation and is not involved in critical interactions with most mutated residues involved in imatinib resistance. For instance, the H396 residue is involved in a hydrogen bond that stabilizes the inactive conformation of the A-loop in the imatinib:ABL1 complex (B), whereas no discernible interactions are observed between His396 and ABL1 or dasatinib (C). Thr315 makes a critical hydrogen bond with dasatinib. T315I mutation disrupts this interaction and causes steric clash, impairing the activity of dasatinib, as well as of imatinib and nilotinib, against this mutant.