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对HER2-trastuzumab复合物的结构分析揭示了受体构造性适应

Santiago Vacca¹, Marcos Gragera², Alejandro Buschiazzo^3,4

¹Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.

Science advances

|July 25, 2025

概括

特拉斯图祖马布结合稳定了一个新的人体表皮生长因子受体-2 (HER2) 构造. 这种结构变化可能会阻止HER2与HER3的相互作用,影响癌症信号通路和TZBB.

科学领域:

结构生物学是结构生物学.
分子瘤学分子瘤学
生物化学生物化学

背景情况:

人体表皮生长因子受体-2 (HER2) 是一种受体氨酸激酶,通过过度表达和异常信号传递与各种癌症有关.
特拉斯图祖马布 (TZB) 是一种单克隆抗体,是HER2过度表达癌症的关键治疗药物,通常与化疗一起使用.
之前对HER2的结构洞察力依赖于分析单个域,限制了对整个受体动态的理解.

研究的目的:

用单粒子冷电子显微镜 (cryo-EM) 阐明近乎全长的人体表皮生长因子受体-2 (HER2) 结构.
为了确定HER2的新型构造,特别是在对Trastuzumab (TZB) 结合的反应中.
了解特拉斯图祖马布 (TZB) 的作用机制及其对HER2-HER3相互作用的影响.

主要方法:

净化几乎全长的人类表皮生长因子受体-2 (HER2).
单粒子冷电子显微镜 (cryo-EM) 分析HER2.
在正规和Trastuzumab (TZB) 结合状态下对HER2的结构比较.

主要成果:

通过Trastuzumab (TZB) 结合稳定HER2细胞外域的以前未报告的构造的识别.
这种TZB诱导的形状可能会阻碍HER2与HER3的关联,这是瘤信号的关键相互作用.
这项研究提供了详细的结构见解HER2的结构动态和TZB的治疗机制.

结论:

特拉斯图祖马布 (TZB) 的结合诱导了人类表皮生长因子受体-2 (HER2) 的显著构造变化.
新发现的HER2形状可能是TZB通过破坏瘤性HER2-HER3信号传递来发挥治疗作用的关键机制.
这些发现增强了我们对HER2受体动态和Trastuzumab (TZB) 作用的理解,并可能为未来的治疗策略提供信息.

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