Jorissen Robert N, Treutlein Herbert R, Epa V Chandana, Burgess Antony W
The Ludwig Institute for Cancer Research, Post Office Box 2008, Royal Melbourne Hospital, Parkville, Victoria, 3050, Australia.
J Biomol Struct Dyn. 2002 Jun;19(6):961-72. doi: 10.1080/07391102.2002.10506800.
Signaling from the epidermal growth factor (EGF) receptor is triggered by the binding of ligands such as EGF or transforming growth factor alpha (TGF-alpha) and subsequent receptor dimerization. An understanding of these processes has been hindered by the lack of structural information about the ligand-bound, dimerized EGF receptor. Using an NMR-derived structure of EGF and a homology model of the major ligand binding domain of the EGF receptor and experimental data, we modeled the binding of EGF to this EGF receptor fragment. In this low resolution model of the complex, EGF sits across the second face of the EGF receptor L2 domain and EGF residues 10-16, 36-37, 40-47 bind to this face. The structural model is largely consistent with previously published NMR data describing the residues of TGF-alpha which interact strongly with the EGF receptor. Other EGF residues implicated in receptor binding are accounted by our proposal that the ligand binding is a two-step process with the EGF binding to at least one other site of the receptor. This three-dimensional model is expected to be useful in the design of ligand-based antagonists of the receptor.
表皮生长因子（EGF）受体的信号传导是由诸如EGF或转化生长因子α（TGF-α）等配体的结合以及随后的受体二聚化所触发的。由于缺乏关于配体结合的二聚化EGF受体的结构信息，对这些过程的理解受到了阻碍。利用通过核磁共振（NMR）获得的EGF结构、EGF受体主要配体结合结构域的同源模型以及实验数据，我们对EGF与该EGF受体片段的结合进行了建模。在这个低分辨率的复合物模型中，EGF位于EGF受体L2结构域的第二个面上，EGF的10 - 16、36 - 37、40 - 47位残基与该面结合。该结构模型在很大程度上与先前发表的描述与EGF受体强烈相互作用的TGF-α残基的NMR数据一致。我们提出配体结合是一个两步过程，其中EGF与受体的至少一个其他位点结合，这就解释了其他与受体结合有关的EGF残基。这个三维模型预计将有助于基于配体的受体拮抗剂的设计。
