Modeling of FLT3-ponatinib interactions. (A) Docking model of FLT3 bound to ponatinib: gatekeeper residue F691 (cyan), I691 (brown), and L691 (green). Although F691 and I691 are compatible with ponatinib binding, L691 appears to be more intruding into the inhibitor binding pocket. (B) Space-filling model of F691I (gray) FLT3 bound with ponatinib (green). Hydrogen atoms are shown in white. (C) Space-filling model of F691L FLT3 bound with ponatinib. The minor steric clash between L691, particularly the hydrogen atom of the side chain, and ponatinib is highlighted with a red circle. (D) Model of ponatinib bound to FLT3/D835. D835 is located on the AL as shown in the purple segment. D835 makes hydrogen bond interactions with the side chain of S838 and main chain of M837, as represented by the black dashed line. (E) Model of ponatinib bound to FLT3/Y842. Y842 is located in the AL shown in purple. It makes hydrogen bonds with the side chains of D811 and R815. (F) Model of ponatinib bound to FLT3/D839. D839 forms part of the hydrogen bond network involving D839, N841, and N887, as represented by the black dashed lines. (G) AL amino-acid sequence alignment of FLT3, KIT, and PDGFR-α and -β, showing homology of FLT3/D835, KIT/D816, and PDGFR-α/D842, -β/D850.