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NMR reveals the allosteric opening and closing of Abelson tyrosine kinase by ATP-site and myristoyl pocket inhibitors.

  • 2013-11-06
Published in:
  • Proceedings of the National Academy of Sciences of the United States of America. - 2013
CML
heteronuclear NMR
protein dynamics
Allosteric Regulation
Benzamides
Carbon Isotopes
Escherichia coli
Fusion Proteins, bcr-abl
Humans
Imatinib Mesylate
Models, Molecular
Molecular Structure
Multiprotein Complexes
Nitrogen Isotopes
Nuclear Magnetic Resonance, Biomolecular
Piperazines
Protein Conformation
Proto-Oncogene Proteins c-abl
Pyrimidines
Scattering, Small Angle
English Successful treatment of chronic myelogenous leukemia is based on inhibitors binding to the ATP site of the deregulated breakpoint cluster region (Bcr)-Abelson tyrosine kinase (Abl) fusion protein. Recently, a new type of allosteric inhibitors targeting the Abl myristoyl pocket was shown in preclinical studies to overcome ATP-site inhibitor resistance arising in some patients. Using NMR and small-angle X-ray scattering, we have analyzed the solution conformations of apo Abelson tyrosine kinase (c-Abl) and c-Abl complexes with ATP-site and allosteric inhibitors. Binding of the ATP-site inhibitor imatinib leads to an unexpected open conformation of the multidomain SH3-SH2-kinase c-Abl core, whose relevance is confirmed by cellular assays on Bcr-Abl. The combination of imatinib with the allosteric inhibitor GNF-5 restores the closed, inactivated state. Our data provide detailed insights on the poorly understood combined effect of the two inhibitor types, which is able to overcome drug resistance.
Language
  • English
Open access status
bronze
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Persistent URL
https://sonar.ch/global/documents/232189
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