A Src-like inactive conformation in the abl tyrosine kinase domain.

Nicholas M. Levinson, Olga Kuchment, Kui Shen, Matthew A. Young, Michael Koldobskiy, Martin Karplus, Philip A. Cole, John Kuriyan

Research output: Contribution to journalArticle

Abstract

The improper activation of the Abl tyrosine kinase results in chronic myeloid leukemia (CML). The recognition of an inactive conformation of Abl, in which a catalytically important Asp-Phe-Gly (DFG) motif is flipped by approximately 180 degrees with respect to the active conformation, underlies the specificity of the cancer drug imatinib, which is used to treat CML. The DFG motif is not flipped in crystal structures of inactive forms of the closely related Src kinases, and imatinib does not inhibit c-Src. We present a structure of the kinase domain of Abl, determined in complex with an ATP-peptide conjugate, in which the protein adopts an inactive conformation that resembles closely that of the Src kinases. An interesting aspect of the Src-like inactive structure, suggested by molecular dynamics simulations and additional crystal structures, is the presence of features that might facilitate the flip of the DFG motif by providing room for the phenylalanine to move and by coordinating the aspartate side chain as it leaves the active site. One class of mutations in BCR-Abl that confers resistance to imatinib appears more likely to destabilize the inactive Src-like conformation than the active or imatinib-bound conformations. Our results suggest that interconversion between distinctly different inactive conformations is a characteristic feature of the Abl kinase domain.

Original languageEnglish (US)
JournalPLoS Biology
Volume4
Issue number5
DOIs
StatePublished - May 2006

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Protein-Tyrosine Kinases
tyrosine
Conformations
phosphotransferases (kinases)
src-Family Kinases
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
myeloid leukemia
DFG peptide
crystal structure
Phosphotransferases
Molecular Dynamics Simulation
Crystal structure
Phenylalanine
Aspartic Acid
molecular dynamics
aspartic acid
Catalytic Domain
phenylalanine
active sites
Adenosine Triphosphate

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)

Cite this

Levinson, N. M., Kuchment, O., Shen, K., Young, M. A., Koldobskiy, M., Karplus, M., ... Kuriyan, J. (2006). A Src-like inactive conformation in the abl tyrosine kinase domain. PLoS Biology, 4(5). https://doi.org/10.1371/journal.pbio.0040144

A Src-like inactive conformation in the abl tyrosine kinase domain. / Levinson, Nicholas M.; Kuchment, Olga; Shen, Kui; Young, Matthew A.; Koldobskiy, Michael; Karplus, Martin; Cole, Philip A.; Kuriyan, John.

In: PLoS Biology, Vol. 4, No. 5, 05.2006.

Research output: Contribution to journalArticle

Levinson, NM, Kuchment, O, Shen, K, Young, MA, Koldobskiy, M, Karplus, M, Cole, PA & Kuriyan, J 2006, 'A Src-like inactive conformation in the abl tyrosine kinase domain.', PLoS Biology, vol. 4, no. 5. https://doi.org/10.1371/journal.pbio.0040144
Levinson, Nicholas M. ; Kuchment, Olga ; Shen, Kui ; Young, Matthew A. ; Koldobskiy, Michael ; Karplus, Martin ; Cole, Philip A. ; Kuriyan, John. / A Src-like inactive conformation in the abl tyrosine kinase domain. In: PLoS Biology. 2006 ; Vol. 4, No. 5.
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