A conformationally constrained peptidomimetic binds to the extracellular region of HER2 protein.
A conformationally constrained peptidomimetic binds to the extracellular region of HER2 protein.
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DOI：
10.1080/07391102.2010.10507360
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发表时间：
2010-12
影响因子：
4.4
通讯作者：
Satyanarayanajois SD
中科院分区：
文献类型：
--
作者：
Banappagari S;Ronald S;Satyanarayanajois SD
人表皮生长因子受体2（HER 2）是人表皮生长因子受体激酶（其他成员包括EGFR或HER 1、HER 3和HER 4）的成员，参与细胞生长和分化的信号级联。已经确定HER 2介导的异源二聚化在癌症中具有重要意义。已知在癌细胞中发生信号通路的失调和HER 2的过表达，表明HER 2在肿瘤发生中的作用。因此，阻断HER 2介导的信号传导具有潜在的治疗价值。我们已经设计了几种肽模拟物来抑制HER 2介导的细胞生长信号传导。其中一种化合物（HERP 5，Arg-βNaph-Phe）在乳腺癌细胞系中表现出抗增殖活性，IC 50值在微摩尔至纳摩尔范围内。荧光标记的HERP 5与HER 2蛋白的结合通过荧光测定、显微镜和圆二色光谱进行评价。结果表明，HERP 5与HER 2蛋白的胞外区结合。通过NMR和分子动力学模拟研究了肽模拟物HERP 5的结构。基于这些结果，使用蛋白质-蛋白质对接方法，提出了HER 2-EGFR二聚化和可能被HERP 5肽模拟物阻断的模型。
Human epidermal growth factor receptor 2 (HER2) is a member of the human epidermal growth factor receptor kinases (other members include EGFR or HER1, HER3, and HER4) that are involved in signaling cascades for cell growth and differentiation. It is well established that HER2-mediated heterodimerization has important implications in cancer. Deregulation of signaling pathways and overexpression of HER2 is known to occur in cancer cells, indicating a role of HER2 in tumorigenesis. Therefore, blocking HER2-mediated signaling has potential therapeutic value. We have designed several peptidomimetics to inhibit HER2-mediated signaling for cell growth. One of the compounds (HERP5, Arg-βNaph-Phe) exhibited antiproliferative activity with IC50 values in the micromolar-to-nanomolar range in breast cancer cell lines. Binding of fluorescently labeled HERP5 to HER2 protein was evaluated by fluorescence assay, microscopy, and circular dichroism spectroscopy. Results indicated that HERP5 binds to the extracellular region of the HER2 protein. Structure of the peptidomimetic HERP5 was studied by NMR and molecular dynamics simulations. Based on these results a model was proposed for HER2-EGFR dimerization and possible blocking by HERP5 peptidomimetic using a protein-protein docking method.
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DOI：
10.1080/07391102.2009.10507315
发表时间：
2009-12-01
影响因子：
4.4
作者：
Chen, Calvin Yu-Chian
通讯作者：
Chen, Calvin Yu-Chian
影响因子：
45.3
作者：
Cobleigh, MA;Vogel, CL;Slamon, DJ
通讯作者：
Slamon, DJ
影响因子：
50.3
作者：
Agus, DB;Akita, RW;Sliwkowski, MX
通讯作者：
Sliwkowski, MX
影响因子：
64.8
作者：
Cho, HS;Mason, K;Leahy, DJ
通讯作者：
Leahy, DJ
DOI：
10.1080/07391102.2008.10507223
发表时间：
2008-08-01
影响因子：
4.4
作者：
Chen, Calvin Yu-Chian;Chen, Yuh-Fung;Tsai, Huei-Yann
通讯作者：
Tsai, Huei-Yann