Structures of lung cancer-derived EGFR mutants and inhibitor complexes: Mechanism of activation and insights into differential inhibitor sensitivity
Structures of lung cancer-derived EGFR mutants and inhibitor complexes: Mechanism of activation and insights into differential inhibitor sensitivity
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DOI：
10.1016/j.ccr.2006.12.017
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发表时间：
2007-03-01
期刊：
影响因子：
50.3
通讯作者：
Eck, Michael J.
中科院分区：
文献类型：
--
作者：
Yun, Cai-Hong;Boggon, Titus J.;Eck, Michael J.
EGFR激酶的突变是非小细胞肺癌的一个原因。为了了解它们的激活机制和对药物结合的影响，我们研究了L858R和G719S突变体的动力学，并用包括吉非替尼、AEE 788和星形孢菌素的抑制剂测定了它们的晶体结构。我们发现突变通过破坏自身抑制相互作用来激活激酶，并且它们在体外加速催化多达50倍。与野生型和突变型激酶复合的抑制剂的结构揭示了吉非替尼和AEE 788的类似结合模式，但在G719S突变体中星形孢菌素的显著旋转。引人注目的是，直接结合测量显示吉非替尼与L858R突变体的结合比与野生型酶的结合紧密20倍。
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.