小柯机器人

美国加州大学旧金山分校Natalia Jura、Kliment A. Verba等研究人员合作解析HER2-HER3-NRG1β复合物的结构。相关论文于2021年11月10日在线发表在《自然》杂志上。

研究人员分离了神经调节素1β（NRG1β）结合的接近全长的人类表皮生长因子受体2（HER2）-HER3二聚体，并利用冷冻电镜重建了细胞外结构模块，揭示了HER2-HER3二聚体界面上的意外动态变化。结果表明，NRG1β结合的HER3的二聚化臂是未解析的，因为apo HER2单体不会发生建立HER3二聚化臂结合口袋所需的配体诱导的构象变化。在致癌性胞外结构域突变体HER2(S310F)的结构中，研究人员观察到与HER3二聚体臂的补偿性相互作用，从而稳定了二聚体界面。HER2-HER3和HER2(S310F)-HER3都保留了与HER2导向的治疗性抗体曲妥珠单抗结合的能力，但突变体复合物不能与帕妥珠单抗结合。

研究人员对HER2(S310F)-HER3-NRG1β-曲妥珠单抗Fab复合物的结构显示，受体二聚体经历了一个构象变化以适应曲妥珠单抗。因此，与致癌突变相似，治疗药物利用了HER2-HER3异质二聚体的内在动态。单一配体的HER2-HER3异质二聚体的独特特征强调了二聚体界面对配体占用的异构感应，并解释了为什么HER2的细胞外域不通过典型的活性二聚体界面进行同源关联。

据悉，HER2和HER3在与生长因子NRG1β结合后形成一个强有力的促肿瘤发生的异源复合物。由于没有任何复合物的结构，HER2和HER3相互作用的机制仍然是未知的。

附：英文原文

Title: Structures of the HER2–HER3–NRG1β complex reveal a dynamic dimer interface

Author: Diwanji, Devan, Trenker, Raphael, Thaker, Tarjani M., Wang, Feng, Agard, David A., Verba, Kliment A., Jura, Natalia

Issue&Volume: 2021-11-10

Abstract: Human epidermal growth factor receptor 2 (HER2) and HER3 form a potent pro-oncogenic heterocomplex1,2,3 upon binding of growth factor neuregulin-1β (NRG1β). The mechanism by which HER2 and HER3 interact remains unknown in the absence of any structures of the complex. Here we isolated the NRG1β-bound near full-length HER2–HER3 dimer and, using cryo-electron microscopy, reconstructed the extracellulardomain module, revealing unexpected dynamics at the HER2–HER3 dimerization interface. We show that the dimerization arm of NRG1β-bound HER3 is unresolved because the apo HER2 monomer does not undergo a ligand-induced conformational change needed to establish a HER3 dimerization arm-binding pocket. In a structure of the oncogenic extracellular domain mutant HER2(S310F), we observe a compensatory interaction with the HER3 dimerization arm that stabilizes the dimerization interface. Both HER2–HER3 and HER2(S310F)–HER3 retain the capacity to bind to the HER2-directed therapeutic antibody trastuzumab, but the mutant complex does not bind to pertuzumab. Our structure of the HER2(S310F)–HER3–NRG1β–trastuzumab Fab complex reveals that the receptor dimer undergoes a conformational change to accommodate trastuzumab. Thus, similar to oncogenic mutations, therapeutic agents exploit the intrinsic dynamics of the HER2–HER3 heterodimer. The unique features of a singly liganded HER2–HER3 heterodimer underscore the allosteric sensing of ligand occupancy by the dimerization interface and explain why extracellular domains of HER2 do not homo-associate via a canonical active dimer interface.

DOI: 10.1038/s41586-021-04084-z

Source: https://www.nature.com/articles/s41586-021-04084-z

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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