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

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posted on 10.01.2018, 00:00 by Rajesh Sonti, Ines Hertel-Hering, Allan Joaquim Lamontanara, Oliver Hantschel, Stephan Grzesiek
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.