2ITU

Crystal structure of EGFR kinase domain L858R mutation in complex with AFN941

Summary for 2ITU

• Entry DOI: 10.2210/pdb2itu/pdb
• Related: 1DNQ 1DNR 1IVO 1M14 1M17 1MOX 1NQL 1XKK 1YY9 1Z9I 2ITN 2ITO 2ITP 2ITQ 2ITT 2ITV 2ITW 2ITX 2ITY 2ITZ
• Descriptor: EPIDERMAL GROWTH FACTOR RECEPTOR, 1,2,3,4-Tetrahydrogen Staurosporine (3 entities in total)
• Functional Keywords: receptor, cell cycle, atp-binding, transferase, transmembrane, phosphorylation, disease mutation, polymorphism, glycoprotein, anti-oncogene, nucleotide-binding, alternative splicing, afn941, egfr, l858r, staurosporine, membrane tyrosine-protein kinase, epidermal growth factor
• Biological source: HOMO SAPIENS
• Cellular location: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
• Total number of polymer chains: 1
• Total formula weight: 37816.71

Authors

Yun, C.-H.,Boggon, T.J.,Li, Y.,Woo, S.,Greulich, H.,Meyerson, M.,Eck, M.J. (deposition date: 2006-05-25, release date: 2007-04-03, Last modification date: 2023-12-13)

Primary citation

Yun, C.-H.,Boggon, T.J.,Li, Y.,Woo, S.,Greulich, H.,Meyerson, M.,Eck, M.J.
Structures of Lung Cancer-Derived Egfr Mutants and Inhibitor Complexes: Mechanism of Activation and Insights Into Differential Inhibitor Sensitivity
Cancer Cell, 11:217-, 2007

PubMed 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.

PubMed: 17349580
DOI: 10.1016/J.CCR.2006.12.017

Experimental method

X-RAY DIFFRACTION (2.8 Å)