Title of article :
Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity
Author/Authors :
Yun، نويسنده , , Cai-Hong and Boggon، نويسنده , , Titus J. and Li، نويسنده , , Yiqun and Woo، نويسنده , , Michele S. and Greulich، نويسنده , , Heidi and Meyerson، نويسنده , , Matthew and Eck، نويسنده , , Michael J.، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2007
Pages :
11
From page :
217
To page :
227
Abstract :
Summary ons 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.
Journal title :
Cancer Cell
Serial Year :
2007
Journal title :
Cancer Cell
Record number :
1336427
Link To Document :
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