Preprints
https://doi.org/10.5194/mr-2022-6
https://doi.org/10.5194/mr-2022-6
 
28 Mar 2022
28 Mar 2022
Status: a revised version of this preprint was accepted for the journal MR and is expected to appear here in due course.

Imatinib disassembles the regulatory core of Abelson kinase by binding to its ATP site and not by binding to its myristoyl pocket

Stephan Grzesiek1, Johannes Paladini1, Judith Habazettl1, and Rajesh Sonti2 Stephan Grzesiek et al.
  • 1Biozentrum, University of Basel, CH-4056 Basel, Switzerland
  • 2Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research-Hyderabad, Telangana-500037, India

Abstract. It was recently reported (Xie et al. Journal of Molecular Biology 2022, 434 (2), 167349) that the Abelson tyrosine kinase (Abl) ATP-site inhibitor imatinib also binds to Abl’s myristoyl binding pocket, which is the target of allosteric Abl inhibitors. This was based on a crystal structure of a truncated Abl kinase domain construct in complex with imatinib bound to the allosteric site as well as some further ITC, NMR, and kinase activity data. Albeit imatinib’s affinity for the allosteric site is significantly weaker (10 μM) than for the ATP site (10 nM), imatinib binding to the allosteric site may disassemble the regulatory core of Abl, thereby stimulating kinase activity, in particular for Abl mutants with reduced imatinib ATP-site affinity. It was argued that the previously observed imatinib-induced opening of the Abl regulatory core (Skora et al. PNAS 2013, 110 (47), E4437–E4445, Sonti et al. Journal of the American Chemical Society 2018, 140 (5), 1863–1869) may be caused by the binding of imatinib to the allosteric site and not to the ATP site. We show here that this is not the case, but that indeed imatinib binding to the ATP site induces the opening of the regulatory core at nanomolar concentrations. This agrees with findings that other type-II ATP site inhibitors (nilotinib, ponatinib) disassemble the regulatory core despite demonstrated negligible binding to the allosteric site.

Stephan Grzesiek et al.

Status: closed

Comment types: AC – author | RC – referee | CC – community | EC – editor | CEC – chief editor | : Report abuse
  • RC1: 'Comment on mr-2022-6', Anonymous Referee #1, 29 Mar 2022
  • RC2: 'Comment on mr-2022-6', Anonymous Referee #1, 03 Apr 2022
  • RC3: 'Comment on mr-2022-6', Paul Schanda, 04 Apr 2022
  • CC1: 'Comment on mr-2022-6', Oliver Hantschel, 21 Apr 2022
  • CEC1: 'Comment on mr-2022-6', Gottfried Otting, 22 Apr 2022
    • AC1: 'Reply on CEC1', Stephan Grzesiek, 24 Apr 2022
  • CC2: 'Comment on mr-2022-6', Dorothee Kern, 24 Apr 2022
    • RC4: 'Reply on CC2', Paul Schanda, 24 Apr 2022
    • CC3: 'Reply on CC2', Dorothee Kern, 24 Apr 2022
    • CC4: 'Reply on CC2', Dorothee Kern, 24 Apr 2022
  • RC5: 'Comment on mr-2022-6', Anonymous Referee #3, 24 Apr 2022
  • EC1: 'Comment on mr-2022-6', Geoffrey Bodenhausen, 01 May 2022

Status: closed

Comment types: AC – author | RC – referee | CC – community | EC – editor | CEC – chief editor | : Report abuse
  • RC1: 'Comment on mr-2022-6', Anonymous Referee #1, 29 Mar 2022
  • RC2: 'Comment on mr-2022-6', Anonymous Referee #1, 03 Apr 2022
  • RC3: 'Comment on mr-2022-6', Paul Schanda, 04 Apr 2022
  • CC1: 'Comment on mr-2022-6', Oliver Hantschel, 21 Apr 2022
  • CEC1: 'Comment on mr-2022-6', Gottfried Otting, 22 Apr 2022
    • AC1: 'Reply on CEC1', Stephan Grzesiek, 24 Apr 2022
  • CC2: 'Comment on mr-2022-6', Dorothee Kern, 24 Apr 2022
    • RC4: 'Reply on CC2', Paul Schanda, 24 Apr 2022
    • CC3: 'Reply on CC2', Dorothee Kern, 24 Apr 2022
    • CC4: 'Reply on CC2', Dorothee Kern, 24 Apr 2022
  • RC5: 'Comment on mr-2022-6', Anonymous Referee #3, 24 Apr 2022
  • EC1: 'Comment on mr-2022-6', Geoffrey Bodenhausen, 01 May 2022

Stephan Grzesiek et al.

Data sets

NMR data sets Grzesiek, Paladini, Habazettl, Sonti https://doi.org/10.5281/zenodo.6368036

Stephan Grzesiek et al.

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Short summary
We show here that binding of the anticancer drug imatinib to the ATP site of Abelson kinase and not binding to its allosteric site coincides with the opening of the kinase regulatory core at nanomolar concentrations. This has implications for the understanding of Abelson’s kinase regulation and activity during medication as well as for the design of new Abelson kinase inhibitors.