Insights into the Aberrant Activity of Mutant EGFR Kinase Domain and Drug Recognition
Insights into the Aberrant Activity of Mutant EGFR Kinase Domain and Drug Recognition
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DOI：
10.1016/j.str.2012.11.014
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发表时间：
2013-02-05
期刊：
影响因子：
5.7
通讯作者：
Stewart, Al
中科院分区：
文献类型：
--
作者：
Gajiwala, Ketan S.;Feng, Junli;Stewart, Al
表皮生长因子受体（EGFR）的L 858 R突变体在非小细胞肺癌中的致瘤性被认为是由于其激酶结构域的组成性激活。市售药物吉非替尼和厄洛替尼对L 858 R突变体的选择性归因于它们对活性激酶的特异性识别以及L 858 R EGFR较弱的ATP结合。我们目前的晶体结构表明，无论是L 858 R，也不是耐药L 858 R + T790 M EGFR激酶结构域是在组成型活性构象。额外的共晶体结构表明，吉非替尼和达克替尼，目前在临床开发的不可逆苯胺基喹唑啉衍生物，可能不是构象特异性的酶的活性状态。结构数据进一步揭示了激酶结构域对C-末端尾Tyr-1016中的一个自磷酸化位点的潜在识别模式。生物化学和生物物理学证据表明，致癌突变影响酶的构象动力学。
The oncogenicity of the L858R mutant form of the epidermal growth factor receptor (EGFR) in non-small-cell lung cancer is thought to be due to the constitutive activation of its kinase domain. The selectivity of the marketed drugs gefitinib and erlotinib for L858R mutant is attributed to their specific recognition of the active kinase and to weaker ATP binding by L858R EGFR. We present crystal structures showing that neither L858R nor the drug-resistant L858R+T790M EGFR kinase domain is in the constitutively active conformation. Additional co-crystal structures show that gefitinib and dacomitinib, an irreversible anilinoquinazoline derivative currently in clinical development, may not be conformation specific for the active state of the enzyme. Structural data further reveal the potential mode of recognition of one of the autophosphorylation sites in the C-terminal tail, Tyr-1016, by the kinase domain. Biochemical and biophysical evidence suggest that the oncogenic mutations impact the conformational dynamics of the enzyme.