2ITT

Crystal structure of EGFR kinase domain L858R mutation in complex with AEE788

2ITT の概要

• エントリーDOI: 10.2210/pdb2itt/pdb
• 関連するPDBエントリー: 1DNQ 1DNR 1IVO 1M14 1M17 1MOX 1NQL 1XKK 1YY9 1Z9I 2ITN 2ITO 2ITP 2ITQ 2ITU 2ITV 2ITW 2ITX 2ITY 2ITZ
• 分子名称: EPIDERMAL GROWTH FACTOR RECEPTOR, 6-{4-[(4-ETHYLPIPERAZIN-1-YL)METHYL]PHENYL}-N-[(1R)-1-PHENYLETHYL]-7H-PYRROLO[2,3-D]PYRIMIDIN-4-AMINE (3 entities in total)
• 機能のキーワード: receptor, cell cycle, atp-binding, transferase, transmembrane, phosphorylation, disease mutation, polymorphism, glycoprotein, anti-oncogene, nucleotide-binding, alternative splicing, aee788, egfr, l858r, kinase, membrane, tyrosine-protein kinase, epidermal growth factor
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37788.75

構造登録者

Yun, C.-H.,Boggon, T.J.,Li, Y.,Woo, S.,Greulich, H.,Meyerson, M.,Eck, M.J. (登録日: 2006-05-25, 公開日: 2007-04-03, 最終更新日: 2023-12-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.73 Å)