Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor
Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor
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DOI：
10.1074/jbc.m207135200
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发表时间：
2002-11-29
影响因子：
4.8
通讯作者：
Eigenbrot, C
中科院分区：
文献类型：
--
作者：
Stamos, J;Sliwkowski, MX;Eigenbrot, C
已经确定了来自表皮生长因子受体（EGFRK）的激酶结构域的晶体结构，其包括来自羧基末端尾的40个氨基酸，分辨率为2.6埃，在有和没有目前在III期临床试验中作为抗癌剂的EGFRK特异性抑制剂厄洛替尼（OSI-774，CP-358，774，TarcevaTM）的情况下都是如此。EGFR家族成员与所有其他已知的受体酪氨酸激酶的区别在于具有组成型激酶活性，而在其激酶结构域内没有磷酸化事件。尽管缺乏磷酸化，我们发现EGFRK激活环采用与胰岛素受体激酶结构域磷酸化活性形式相似的构象。令人惊讶的是，位于EGFRK结构域和羧基末端底物对接位点之间的推定二聚化基序的关键残基被发现与激酶结构域密切接触。重要的分子间接触，涉及羧基末端尾巴相对于受体寡聚化进行了讨论。
The crystal structure of the kinase domain from the epidermal growth factor receptor (EGFRK) including forty amino acids from the carboxyl-terminal tail has been determined to 2.6-Angstrom resolution, both with and without an EGFRK-specific inhibitor currently in Phase III clinical trials as an anti-cancer agent, erlotinib (OSI-774, CP-358,774, Tarceva(TM)). The EGFR family members are distinguished from all other known receptor tyrosine kinases in possessing constitutive kinase activity without a phosphorylation event within their kinase domains. Despite its lack of phosphorylation, we find that the EGFRK activation loop adopts a conformation similar to that of the phosphorylated active form of the kinase domain from the insulin receptor., Surprisingly, key residues of a putative dimerization motif lying between the EGFRK domain and carboxyl-terminal substrate docking sites are found in close contact with the kinase domain. Significant intermolecular contacts involving the carboxyl-terminal tail are discussed with respect to receptor oligomerization.