蛋白激酶结构域
化学
激酶
变构调节
T790米
突变体
埃罗替尼
细胞周期蛋白依赖激酶4
细胞生物学
细胞周期蛋白依赖激酶2
癌症研究
生物化学
蛋白激酶A
表皮生长因子受体
酶
吉非替尼
受体
生物
基因
作者
Melissa A. Lowder,Amy Doerner,Alanna Schepartz
摘要
Mutations in the EGFR kinase domain are implicated in non-small-cell lung cancer. Of particular interest is the drug-resistant double mutant (L858R/T790M, DM EGFR), which is not inhibited selectively by any approved kinase inhibitor. Here we apply bipartite tetracysteine display to demonstrate that DM and WT EGFR differ in structure outside the kinase domain. The structural difference is located within the cytoplasmic juxtamembrane segment (JM) that links the kinase domain with the extracellular and transmembrane regions and is essential for EGFR activation. We show further that third-generation DM EGFR-selective TKIs alter JM structure via allostery to restore the conformation found when WT EGFR is activated by the growth factors EGF and HB-EGF. This work suggests that the oncogenic activity of DM EGFR may extend beyond kinase activity per se to include kinase-independent activities. As JM structure may provide a biomarker for these kinase-independent functions, these insights could guide the development of allosteric, DM-selective inhibitors.
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