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HER2-HER3-NRG1β复合体的结构显示出一个动态二聚体接口

Devan Diwanji^1,2, Raphael Trenker¹, Tarjani M Thaker^1,3

¹Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.

|November 11, 2021

概括

研究人员发现了HER2-HER3复合体的结构动态, 这对癌症生长至关重要. 了解这些相互作用揭示了突变和特斯图祖马布等疗法如何影响HER2-HER3二元体.

科学领域:

结构生物学
分子瘤学
生物化学

背景情况:

人体表皮生长因子受体2 (HER2) 和HER3受体在神经调节素-1β (NRG1β) 结合时形成关键的亲瘤复合体.
由于缺乏结构数据,HER2- HER3相互作用的确切机制及其结构基础仍然难以捉摸.

研究的目的:

在NRG1β结合时阐明HER2-HER3异构的结构机制.
研究瘤突变和治疗抗体对HER2-HER3复合体结构和动态的影响.

主要方法:

使用冷电子显微镜 (cryo-EM) 来确定近全长NRG1β结合HER2-HER3二元体的结构.
对瘤突变HER2 (S310F) 的结构分析及其与HER3,NRG1β以及治疗抗体 (特拉斯图祖马布,珀图祖马布) 的相互作用.

主要成果:

这项研究揭示了HER2- HER3二元化界面的意想不到的动态,HER3二元化臂在apo HER2的存在下未解决.
在HER2 (S310F) 突变体中观察到一种补偿相互作用,稳定了二聚体接口.
虽然HER2-HER3和HER2(S310F) -HER3都与特鲁祖马布结合,但突变复合体对特鲁祖马布失去亲和力,这表明药物结合机制不同.

结论:

这些发现突显了HER2-HER3异构体的内在动态,以及在二元化界面上如何对联体占用感知.
治疗药物,如trastuzumab,利用这些受体动态,类似于瘤突变.
这些结构见解为了解HER2-HER3复合体的形成及其通过突变和向治疗的调节提供了基础.

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