2ITQ: Crystal Structure Of Egfr Kinase Domain G719s Mutation In Complex With Afn941

Citation:
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.
PDB ID: 2ITQDownload
MMDB ID: 45077
PDB Deposition Date: 2006/5/25
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 2.68  Å
Source Organism:
Similar Structures:
Biological Unit for 2ITQ: monomeric; determined by author and by software (PQS)
Molecular Components in 2ITQ
Label Count Molecule
Protein (1 molecule)
1
Epidermal Growth Factor Receptor(Gene symbol: EGFR)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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