Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab
Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab
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DOI：
10.1038/nature01392
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发表时间：
2003-02-13
期刊：
影响因子：
64.8
通讯作者：
Leahy, DJ
中科院分区：
文献类型：
--
作者：
Cho, HS;Mason, K;Leahy, DJ
HER 2（也称为Neu、ErbB 2）是受体酪氨酸激酶表皮生长因子受体（EGFR;也称为ErbB）家族的成员，在人体中包括HER 1（EGFR、ERBB 1）、HER 2、HER 3（ERBB 3）和HER 4（ERBB 4）（1）。ErbB受体是发育中的胚胎和成人组织中细胞增殖和分化的重要介质（2），其不适当的激活与许多癌症的发展和严重程度相关（3）。在20-30%的人类乳腺癌中发现了HER 2的过表达，并且与更具侵袭性的肿瘤和较差的预后相关（4）。靶向ErbB受体的抗癌疗法已显示出前景，针对HER 2的单克隆抗体赫赛汀（也称为曲妥珠单抗）目前正用于治疗乳腺癌（5）。在这里，我们报告了大鼠HER 2在2.4埃和人HER 2与赫赛汀抗原结合片段（Fab）在2.5埃复合的整个细胞外区域的晶体结构。这些结构揭示了HER 2的固定构象，类似于配体活化状态，并显示HER 2在不存在直接配体结合的情况下与其他ErbB受体相互作用。赫赛汀与HER 2的质膜区域结合，将该位点确定为抗癌治疗的靶点。
HER2 (also known as Neu, ErbB2) is a member of the epidermal growth factor receptor (EGFR; also known as ErbB) family of receptor tyrosine kinases, which in humans includes HER1 (EGFR, ERBB1), HER2, HER3 (ERBB3) and HER4 (ERBB4)(1). ErbB receptors are essential mediators of cell proliferation and differentiation in the developing embryo and in adult tissues(2), and their inappropriate activation is associated with the development and severity of many cancers(3). Overexpression of HER2 is found in 20-30% of human breast cancers, and correlates with more aggressive tumours and a poorer prognosis(4). Anticancer therapies targeting ErbB receptors have shown promise, and a monoclonal antibody against HER2, Herceptin (also known as trastuzumab), is currently in use as a treatment for breast cancer(5). Here we report crystal structures of the entire extracellular regions of rat HER2 at 2.4 Angstrom and human HER2 complexed with the Herceptin antigen-binding fragment (Fab) at 2.5 Angstrom. These structures reveal a fixed conformation for HER2 that resembles a ligand-activated state, and show HER2 poised to interact with other ErbB receptors in the absence of direct ligand binding. Herceptin binds to the juxtamembrane region of HER2, identifying this site as a target for anticancer therapies.