5X2F

Crystal structure of EGFR 696-1022 T790M/V948R in complex with SKLB(6)

5X2F の概要

• エントリーDOI: 10.2210/pdb5x2f/pdb
• 関連するPDBエントリー: 5X26 5X27 5X28 5X2A 5X2C 5X2K
• 分子名称: Epidermal growth factor receptor, 9-cyclohexyl-N2-[4-(4-methylpiperazin-1-yl)phenyl]-N8-phenyl-purine-2,8-diamine (3 entities in total)
• 機能のキーワード: egfr, t790m, v948r, sklb, transferase
• 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: 4
• 化学式量合計: 152828.88

構造登録者

Yun, C.H. (登録日: 2017-01-31, 公開日: 2018-02-07, 最終更新日: 2024-03-27)

主引用文献

Zhu, S.J.,Zhao, P.,Yang, J.,Ma, R.,Yan, X.E.,Yang, S.Y.,Yang, J.W.,Yun, C.H.
Structural insights into drug development strategy targeting EGFR T790M/C797S.
Oncotarget, 9:13652-13665, 2018

PubMed Abstract: Treatment of non-small-cell lung cancers (NSCLCs) harboring primary EGFR oncogenic mutations such as L858R and exon 19 deletion delE746_A750 (Del-19) using gefitinib/erlotinib ultimately fails due to the emergence of T790M mutation. Though WZ4002/CO-1686/AZD9291 are effective in overcoming EGFR T790M by targeting Cys797 via covalent bonding, their efficacy is again limited due to the emergence of C797S mutation. New agents effectively inhibiting EGFR T790M without covalent linkage through Cys 797 may solve this problem. We presented here crystal structures of EGFR activating/drug-resistant mutants in complex with a panel of reversible inhibitors along with mutagenesis and enzyme kinetic data. These data revealed a previously un-described hydrophobic clamp structure in the EGFR kinase which may be exploited to facilitate development of next generation drugs targeting EGFR T790M with or without concomitant C797S. Interestingly, mutations in the hydrophobic clamp that hinder drug binding often also weaken ATP binding and/or abolish kinase activity, thus do not readily result in resistance to the drugs.

PubMed: 29568384
DOI: 10.18632/oncotarget.24113

実験手法

X-RAY DIFFRACTION (2.2 Å)