School of Chemistry and Molecular Biosciences, The University of Queensland , Brisbane, QLD 4072, Australia.
Biochemistry. 2014 Apr 29;53(16):2710-21. doi: 10.1021/bi401632z. Epub 2014 Apr 17.
The cell surface epidermal growth factor receptor (EGFR) plays a critical role in cell development and oncogenesis. The binding of growth factors to the EGFR results in a mechanical signal being transmitted through the plasma membrane. In this study, atomistic molecular dynamics simulations have been used to investigate the conformational changes associated with the binding of the epidermal growth factor (EGF) and transforming growth factor α (TGFα) to the EGFR. In the simulations, the removal of the EGF and TGFα from the extracellular domain of the EGFR homodimer led to a relative rotation of the protomers of 16-35° about the dimerization axis. The three N-terminal domains that make up the extracellular region of the receptor undergo essentially rigid-body motion. The dimerization interface itself was found to be largely unaffected by the removal of the ligand. In most simulations, the rotation within the dimer was associated with an opening of the cytokine-binding sites. On the basis of these simulations, a simple mechanical model that explains the coupling between the binding of ligand and the motions in the extracellular domains is proposed.
细胞表面表皮生长因子受体（EGFR）在细胞发育和癌变中起着关键作用。生长因子与 EGFR 的结合导致机械信号通过质膜传递。在这项研究中，使用原子分子动力学模拟来研究与表皮生长因子（EGF）和转化生长因子α（TGFα）与 EGFR 结合相关的构象变化。在模拟中，从 EGFR 同源二聚体的细胞外结构域中去除 EGF 和 TGFα 导致二聚体轴周围的原聚体相对旋转 16-35°。组成受体细胞外区域的三个 N 端结构域经历基本的刚体运动。发现二聚化界面本身基本上不受配体去除的影响。在大多数模拟中，二聚体内的旋转与细胞因子结合位点的打开有关。基于这些模拟，提出了一个简单的机械模型，该模型解释了配体结合和细胞外结构域运动之间的耦合。
