5XDK

Crystal structure of EGFR 696-1022 T790M in complex with CO-1686

5XDK の概要

• エントリーDOI: 10.2210/pdb5xdk/pdb
• 関連するPDBエントリー: 5XDL
• 分子名称: Epidermal growth factor receptor, N-[3-[[2-[[4-(4-ethanoylpiperazin-1-yl)-2-methoxy-phenyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide (3 entities in total)
• 機能のキーワード: egfr, t790m, inhibitor, 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: 1
• 化学式量合計: 38206.15

構造登録者

Yan, X.E.,Yun, C.H. (登録日: 2017-03-28, 公開日: 2017-12-13, 最終更新日: 2024-10-23)

主引用文献

Yan, X.E.,Zhu, S.J.,Liang, L.,Zhao, P.,Choi, H.G.,Yun, C.H.
Structural basis of mutant-selectivity and drug-resistance related to CO-1686.
Oncotarget, 8:53508-53517, 2017

PubMed Abstract: Non-small-cell lung cancers (NSCLCs) caused by activating mutations in the kinase domain of epidermal growth factor receptor (EGFR) initially respond to first-generation reversible drugs gefitinib and erlotinib. However, clinical efficacy is limited due to the development of drug-resistance that in more than half of the cases are driven by the secondary T790M mutation. CO-1686 is one of the third generation irreversible inhibitors that inhibits EGFR activating mutants, including those with concurrent T790M, while avoiding the off-target toxicity owing to inhibition of wild-type EGFR in treating EGFR mutation-positive NSCLCs. Despite the remarkable success, the experimentally determined structure of this agent in complex with EGFR T790M remains unknown. In this study, we determined crystal structures of EGFR T790M or L858R mutants covalently bound by CO-1686. Based on these structural data, we can explain why CO-1686 irreversibly inhibits EGFR and selectively prefers T790M, which may help improving this or similar compounds, and explain why EGFR L718Q and L844V mutations incur resistance to this agent.

PubMed: 28881827
DOI: 10.18632/oncotarget.18588

実験手法

X-RAY DIFFRACTION (2.346 Å)