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PDBsum entry 2itp
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References listed in PDB file
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Key reference
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Title
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Structures of lung cancer-Derived egfr mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity.
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Authors
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C.H.Yun,
T.J.Boggon,
Y.Li,
M.S.Woo,
H.Greulich,
M.Meyerson,
M.J.Eck.
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Ref.
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Cancer Cell, 2007,
11,
217-227.
[DOI no: ]
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PubMed id
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Abstract
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Mutations in the EGFR kinase are a cause of non-small-cell lung cancer. To
understand their mechanism of activation and effects on drug binding, we studied
the kinetics of the L858R and G719S mutants and determined their crystal
structures with inhibitors including gefitinib, AEE788, and a staurosporine. We
find that the mutations activate the kinase by disrupting autoinhibitory
interactions, and that they accelerate catalysis as much as 50-fold in vitro.
Structures of inhibitors in complex with both wild-type and mutant kinases
reveal similar binding modes for gefitinib and AEE788, but a marked rotation of
the staurosporine in the G719S mutant. Strikingly, direct binding measurements
show that gefitinib binds 20-fold more tightly to the L858R mutant than to the
wild-type enzyme.
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Figure 3.
Figure 3. Schematic Drawings of the EGFR Inhibitors Discussed
Here
Inhibitors are drawn in a consistent orientation
approximately reflecting their conformations when bound to the
EGFR kinase (Figure 4).
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Figure 4.
Figure 4. Drug Binding Modes in the Wild-Type and Mutant EGFR
Kinase
The binding modes of gefitinib (A, C, and E) and
AEE788 (B, D, and F) are compared in the wild-type (yellow),
L858R (green), and G719S (blue) kinases. Key side chains are
labeled, the inhibitors are shown in stick form with carbons
colored yellow, and hydrogen bonds are indicated with dashed
lines. Compare binding of different inhibitors to the same
mutant within rows and binding of the same inhibitor among
wild-type and mutants within columns. Binding modes of both
compounds are essentially the same in all three structures. Note
also the closely corresponding orientations of the
pyrrolopyrimidine scaffold in the AEE788 complexes and the
quinazoline core in the gefitinib complexes. Additionally, the
phenylethyl amine moiety in AEE788 occupies the same space as
the aniline substituent in the gefitinib and erlotinib
complexes.
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The above figures are
reprinted
by permission from Cell Press:
Cancer Cell
(2007,
11,
217-227)
copyright 2007.
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