HER2-trastuzumab-pertuzumab复合体的结构和形状变异性
Rémi Ruedas1, Rémi Vuillemot2, Thibault Tubiana3
1Université Paris-Saclay, CEA, CNRS - Institute for Integrative Biology of the Cell (I2BC), 91198, Gif-sur-Yvette, France; Sanofi, Integrated Drug Discovery, 13, quai Jules Guesde 94403, Vitry-sur-Seine, France.
Journal of structural biology
|May 9, 2024
概括
冷EM揭示了HER2和两个抗体之间的复合物的结构,揭示了HER2域IV中的一个循环,可能与二分化和抗体结合有关,解释了它们的协同效应.
科学领域:
- 结构生物学 结构生物学
- 低温电子显微镜 (Cryo-EM) 是一种电子显微镜.
- 癌症治疗方法 癌症治疗方法
背景情况:
- 抗体-抗原复合体对结构预测具有挑战性.
- 人类表皮生长因子受体2 (HER2) 是癌症治疗的关键标.
- 了解抗体与HER2结合的结构基础对于药物开发至关重要.
研究的目的:
- 确定HER2与两种治疗抗体 - - 珀图祖马布和特拉斯图祖马布 (HTP) 之间的复合物的详细结构.
- 调查在冷EM数据处理中持续形状异质性的作用.
- 确定有助于抗体协同抗癌作用的结构特征.
主要方法:
- 使用低温传输电子显微镜 (cryo-EM) 进行单颗粒分析.
- 使用超薄的连续碳网格进行最佳的数据收集.
- 分析数据处理软件用于处理形状异质性.
主要成果:
- 获得了HTP三元复合体的详细结构,提供了比以前更全面的视图.
- 在HER2域IV中确定了一个以前被忽视的循环,可能涉及到trastuzumab的结合和HER2二重化.
- 使用先进技术证明了对小蛋白质复合体 (162 kDa) 进行冷EM的可行性.
结论:
- 已识别的HER2循环可能解释了百图祖马布和特拉斯图祖马布的协同抗癌效应.
- HTP复合体的灵活性反映了HER2信号调节和抗体抑制.
- 该研究为开发冷EM软件提供了有价值的数据集,以解决构造异质性的问题.
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