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PDBsum entry 2hz0
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References listed in PDB file
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Key reference
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Title
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Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia.
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Authors
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S.W.Cowan-Jacob,
G.Fendrich,
A.Floersheimer,
P.Furet,
J.Liebetanz,
G.Rummel,
P.Rheinberger,
M.Centeleghe,
D.Fabbro,
P.W.Manley.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2007,
63,
80-93.
[DOI no: ]
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PubMed id
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Abstract
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Chronic myelogenous leukaemia (CML) results from the Bcr-Abl oncoprotein, which
has a constitutively activated Abl tyrosine kinase domain. Although most chronic
phase CML patients treated with imatinib as first-line therapy maintain
excellent durable responses, patients who have progressed to advanced-stage CML
frequently fail to respond or lose their response to therapy owing to the
emergence of drug-resistant mutants of the protein. More than 40 such point
mutations have been observed in imatinib-resistant patients. The crystal
structures of wild-type and mutant Abl kinase in complex with imatinib and other
small-molecule Abl inhibitors were determined, with the aim of understanding the
molecular basis of resistance and to aid in the design and optimization of
inhibitors active against the resistance mutants. These results are presented in
a way which illustrates the approaches used to generate multiple structures, the
type of information that can be gained and the way that this information is used
to support drug discovery.
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Figure 4.
Figure 4 (a) Superposition of the four main DFG conformations
observed in Abl kinase structures, with the active conformation
in cyan, the DFG-out conformation in yellow, the DFG-flip
conformation in grey and the Src-like inactive conformation in
green. (b) Superposition of all structures reported here plus
PDB entry 2g1t . The P-loop is shown in red, the C-helix is
cyan, the A-loop is blue and all the ligands are shown in green.
The superposition is based on an alignment of the C-terminal
lobes to emphasize the relative differences in angles between
the N- and C-terminal lobes of the kinase. (c) A stereoview of
all the ligands superimposed (imatinib, magenta C atoms;
NVP-AFN941, cyan C atoms; NVP-AFG210, yellow C atoms;
NVP-AEG082, green C atoms; PD180970, grey C atoms).
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Figure 6.
Figure 6 Comparison of the surfaces for all five structures
reported here. The inhibitor is shown with solid sticks (C,
yellow; N, blue; O, red; Cl, green; F, cyan) and the
solvent-accessible surface is coloured according to the atom
type that forms it (C, white; N, blue; O, red; S, orange). The
surface is transparent to show the buried parts of the binding
site, which are darker for the same reason. The C^  trace
of the protein is shown with white lines. (a) Imatinib, (b)
NVP-AFN941, (c) PD180970, (d) NVP-AEG082, (e) NVP-AFG210.
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The above figures are
reprinted
from an Open Access publication published by the IUCr:
Acta Crystallogr D Biol Crystallogr
(2007,
63,
80-93)
copyright 2007.
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