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

  • J Am Chem Soc. 2018 Feb 7;140(5):1863-1869. doi: 10.1021/jacs.7b12430.
Rajesh Sonti  1 ,  Ines Hertel-Hering  1 ,  Allan Joaquim Lamontanara  2 ,  Oliver Hantschel  2 ,  Stephan Grzesiek  1
Affiliations
  • 1. Focal Area Structural Biology and Biophysics, Biozentrum, University of Basel , CH-4056 Basel, Switzerland.
  • 2. Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL) , 1015 Lausanne, Switzerland.
PMID: 29319304 DOI: 10.1021/jacs.7b12430
Abstract

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.

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