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PDBsum entry 2qoh
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References listed in PDB file
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Key reference
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Title
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Crystal structure of the t315I mutant of abi kinase.
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Authors
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T.Zhou,
L.Parillon,
F.Li,
Y.Wang,
J.Keats,
S.Lamore,
Q.Xu,
W.Shakespeare,
D.Dalgarno,
X.Zhu.
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Ref.
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Chem Biol Drug Des, 2007,
70,
171-181.
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PubMed id
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Abstract
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Imatinib (Gleevec) is currently the frontline therapy for chronic myeloid
leukemia (CML), a disease characterized by the presence of a constitutively
activated chimeric tyrosine kinase protein Bcr-AbI. However, drug resistance
often occurs at later stages of the disease, principally because of the
occurrence of mutations in the kinase domain. Second generation Bcr-AbI
inhibitors, such as dasatinib and nilotinib are capable of inhibiting many
imatinib-resistant forms of the kinase but not the form in which threonine is
mutated to isoleucine at the gatekeeper position (T315I). In this study, we
present the crystal structure of the kinase domain of the c-AbI T315I mutant, as
well as the wild-type form, in complex with a pyrrolopyridine inhibitor, PPY-A.
The side chain of Ile315 is accommodated in the AbI T315I mutant structure
without large conformational changes proximal to the site of mutation. In
contrast to other inhibitors, such as imatinib and dasatinib, PPY-A does not
occupy the hydrophobic pocket behind the gatekeeper residue. This binding mode,
coupled with augmented contacts with the glycine-rich loop, appears to be
critical for its ability to override the T315I mutation. The data presented here
may provide structural guidance for the design of clinically useful inhibitors
of Bcr-AbI T315I.
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