Vacca Santiago, Gragera Marcos, Buschiazzo Alejandro, Herreros David, Krieger James M, Bonn-Garcia Santiago, Melero Roberto, Sorzano Carlos Os, Carazo Jose M, Medalia Ohad, Plückthun Andreas
Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Centro Nacional de Biotecnología (CNB), CSIC, 28049, Madrid, Spain.
Sci Adv. 2025 Jul 25;11(30):eadu9945. doi: 10.1126/sciadv.adu9945.
Human epidermal growth factor receptor-2 (HER2) is a receptor tyrosine kinase, associated with a variety of malignant tumors, usually through overexpression, resulting in aberrant signaling. Trastuzumab (TZB), one of the monoclonal antibodies (mAbs) used in combination with chemotherapy, has become a major therapeutic for HER2-overexpressing cancers. Current structural understanding of HER2 and its interactions with other receptors and with different affinity agents has relied on numerous structures of individual domains of HER2. Here, we subjected purified near full-length HER2 to single-particle cryo-electron microscopy (cryo-EM) analysis. Besides the canonical conformation described in previous structural studies, we report a previously unreported conformation of the HER2 extracellular domain that is stabilized upon TZB binding, which might hamper association with HER3, a receptor with which HER2 forms an oncogenic unit. Together, our findings provide insights into the conformational dynamics of the HER2 receptor and the mechanism of action of TZB.
人表皮生长因子受体2（HER2）是一种受体酪氨酸激酶，通常通过过表达与多种恶性肿瘤相关，导致信号异常。曲妥珠单抗（TZB）是与化疗联合使用的单克隆抗体（mAb）之一，已成为HER2过表达癌症的主要治疗方法。目前对HER2及其与其他受体以及不同亲和力试剂相互作用的结构理解依赖于HER2各个结构域的众多结构。在这里，我们对纯化的近全长HER2进行了单颗粒冷冻电子显微镜（cryo-EM）分析。除了先前结构研究中描述的典型构象外，我们还报告了HER2细胞外结构域一种以前未报道的构象，该构象在TZB结合后稳定，这可能会阻碍与HER3的结合，HER2与HER3形成致癌单元。总之，我们的研究结果为HER2受体的构象动力学和TZB的作用机制提供了见解。
