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Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
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Imatinib binding to human c-Src is coupled to inter-domain allostery and suggests a novel kinase inhibition strategy

Yuko Tsutsui1, Daniel Deredge2, Patrick L Wintrode2

  • 1Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.

Scientific Reports
|August 3, 2016
PubMed

Insights

Imatinib resistance is a growing problem. This study reveals how imatinib binding affects c-Src protein dynamics, uncovering new drug targets for overcoming resistance.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Imatinib (Gleevec) is a successful non-receptor tyrosine kinase inhibitor (nRTKI) for cancer treatment.
  • Increasing imatinib-resistant mutations necessitate the development of novel analogs.
  • Understanding c-Src dynamics is crucial for developing next-generation TKIs.

Purpose of the Study:

  • To investigate the conformational dynamics of full-length human c-Src in the presence and absence of imatinib.
  • To identify allosteric sites affected by imatinib binding and their relation to kinase activation.
  • To pinpoint imatinib-sensitive and resistant mutation sites within c-Src.

Main Methods:

  • Utilized hydrogen-deuterium exchange mass spectrometry (HDX-MS).
  • Analyzed dynamics of full-length human c-Src.
  • Compared dynamics with and without bound imatinib.

Main Results:

  • Imatinib binding to the kinase domain alters dynamics in distal SH3 and SH2 domains.
  • These dynamic changes resemble structural transitions involved in kinase activation.
  • Identified specific sites associated with imatinib sensitivity and resistance.

Conclusions:

  • Imatinib binding induces allosteric conformational changes in c-Src.
  • These findings reveal novel allosteric sites linked to imatinib binding and kinase activation.
  • Provides a basis for developing modulators of TKI binding to overcome resistance.

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