Mechanism of activation and inhibition of the HER4/ErbB4 kinase
Mechanism of activation and inhibition of the HER4/ErbB4 kinase
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DOI：
10.1016/j.str.2007.12.016
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发表时间：
2008-03-01
期刊：
影响因子：
5.7
通讯作者：
Leahy, Daniel J.
中科院分区：
文献类型：
--
作者：
Qiu, Chen;Tarrant, Mary K.;Leahy, Daniel J.
HER4/ErbB4 是 EGF/ErbB 受体酪氨酸激酶家族中普遍表达的成员，对于心脏、神经系统和乳腺的正常发育至关重要。我们在此报告了活性形式和拉帕替尼抑制形式的 ErbB4 激酶结构域的晶体结构。活性 ErbB4 激酶采用不对称二聚体构象，与观察到的对 EGF 受体/ErbB1 激酶的激活很重要的构象基本相同。 Ba/F3 细胞中完整 ErbB4 的诱变研究证实了这种不对称二聚体对于激活完整 ErbB4 的重要性。拉帕替尼与 ErbB4 激酶的非活性形式结合，其方式相当于其与 EGF 受体的相互作用。拉帕替尼接触的所有 ErbB4 残基在 EGF 受体和 HER2/ErbB2 中都是保守的，拉帕替尼也是靶向的。这些结果表明激酶激活和抑制的关键元件在 ErbB 家族成员中是保守的。
HER4/ErbB4 is a ubiquitously expressed member of the EGF/ErbB family of receptor tyrosine kinases that is essential for normal development of the heart, nervous system, and mammary gland. We report here crystal structures of the ErbB4 kinase domain in active and lapatinib-inhibited forms. Active ErbB4 kinase adopts an asymmetric dimer conformation essentially identical to that observed to be important for activation of the EGF receptor/ErbB1 kinase. Mutagenesis studies of intact ErbB4 in Ba/F3 cells confirm the importance of this asymmetric dimer for activation of intact ErbB4. Lapatinib binds to an inactive form of the ErbB4 kinase in a mode equivalent to its interaction with the EGF receptor. All ErbB4 residues contacted by lapatinib are conserved in the EGF receptor and HER2/ErbB2, which lapatinib also targets. These results demonstrate that key elements of kinase activation and inhibition are conserved among ErbB family members.