Hierarchical Modeling of Activation Mechanisms in the ABL and EGFR Kinase Domains: Thermodynamic and Mechanistic Catalysts of Kinase Activation by Cancer Mutations
Figure 13
A mechanistic analysis of the TMD activation pathways for the ABL- T315I and EGFR-T790M gatekeeper mutations.
A dynamic assembly of the hydrophobic spine interactions during the activation process is shown for the ABL-T315I mutant (upper panel) and the EGFR-T790M mutant (lower panel). The hydrophobic spine of the ABL kinase domain is formed through assembly of the gate-keeper residue with the Met290, Leu301, His361, and Phe382 residues. The hydrophobic spine of the EGFR kinase domain is similarly formed by linking the gate-keeper residue with Met766, Leu777, His835, and Phe856 residues respectively. (A) The initial model of ABL-T315I in the inactive form. (B) The characteristic TMD intermediate of ABL-T315I. (C) The final structure of ABL-T315I in the active form. (D) The initial model of EGFR-T790M in the inactive form. (B) The characteristic TMD intermediate of EGFR-T790M. (C) The final structure of EGFR-T790M in the active form. The assembled hydrophobic spine is present in all TMD intermediates. The determined meta-stable ABL intermediate closely resembles the Src-like inactive crystal structure.