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PDBsum entry 2f4j
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References listed in PDB file
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Key reference
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Title
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Structure of the kinase domain of an imatinib-Resistant abl mutant in complex with the aurora kinase inhibitor vx-680.
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Authors
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M.A.Young,
N.P.Shah,
L.H.Chao,
M.Seeliger,
Z.V.Milanov,
W.H.Biggs,
D.K.Treiber,
H.K.Patel,
P.P.Zarrinkar,
D.J.Lockhart,
C.L.Sawyers,
J.Kuriyan.
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Ref.
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Cancer Res, 2006,
66,
1007-1014.
[DOI no: ]
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PubMed id
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Abstract
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We present a high-resolution (2.0 A) crystal structure of the catalytic domain
of a mutant form of the Abl tyrosine kinase (H396P; Abl-1a numbering) that is
resistant to the Abl inhibitor imatinib. The structure is determined in complex
with the small-molecule inhibitor VX-680 (Vertex Pharmaceuticals, Cambridge,
MA), which blocks the activity of various imatinib-resistant mutant forms of
Abl, including one (T315I) that is resistant to both imatinib and BMS-354825
(dasatinib), a dual Src/Abl inhibitor that seems to be clinically effective
against all other imatinib-resistant forms of BCR-Abl. VX-680 is shown to have
significant inhibitory activity against BCR-Abl bearing the T315I mutation in
patient-derived samples. The Abl kinase domain bound to VX-680 is not
phosphorylated on the activation loop in the crystal structure but is
nevertheless in an active conformation, previously unobserved for Abl and
inconsistent with the binding of imatinib. The adoption of an active
conformation is most likely the result of synergy between the His(396)Pro
mutation, which destabilizes the inactive conformation required for imatinib
binding, and the binding of VX-680, which favors the active conformation through
hydrogen bonding and steric effects. VX-680 is bound to Abl in a mode that
accommodates the substitution of isoleucine for threonine at residue 315 (the
"gatekeeper" position). The avoidance of the innermost cavity of the Abl kinase
domain by VX-680 and the specific recognition of the active conformation explain
the effectiveness of this compound against mutant forms of BCR-Abl, including
those with mutations at the gatekeeper position.
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