Format

Send to:

Choose Destination
See comment in PubMed Commons below
Cancer Cell. 2007 Mar;11(3):217-27.

Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity.

Author information

  • 1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, MA 02115, USA.

Abstract

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.

Comment in

  • The EGF receptor Hokey-Cokey. [Cancer Cell. 2007]
PMID:
17349580
[PubMed - indexed for MEDLINE]
PMCID:
PMC1939942
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for PubMed Central
    Loading ...
    Write to the Help Desk