ATP Site Ligands Determine the Assembly State of the Abelson Kinase Regulatory Core via the Activation Loop Conformation

The constituent SH3, SH2, and kinase
domains of the Abl kinase
regulatory core can adopt an assembled (inactive) or a disassembled
(active) conformation. We show that this assembly state strictly correlates
with the conformation of the kinase activation loop induced by a total
of 14 ATP site ligands, comprising all FDA-approved Bcr-Abl inhibiting
drugs. The disassembly of the core by certain (type II) ligands can
be explained by an induced push on the kinase N-lobe via A- and P-loop
toward the SH3 domain. A similar sized P-loop motion is expected during
nucleotide binding and release, which would be impeded in the assembled
state, in agreement with its strongly reduced kinase activity.