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PDBsum entry 2g2h
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References listed in PDB file
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Key reference
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Title
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A src-Like inactive conformation in the abl tyrosine kinase domain.
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Authors
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N.M.Levinson,
O.Kuchment,
K.Shen,
M.A.Young,
M.Koldobskiy,
M.Karplus,
P.A.Cole,
J.Kuriyan.
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Ref.
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Plos Biol, 2006,
4,
e144-767.
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PubMed id
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Abstract
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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.
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