Li Shiqing, Schmitz Karl R, Jeffrey Philip D, Wiltzius Jed J W, Kussie Paul, Ferguson Kathryn M
Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Cancer Cell. 2005 Apr;7(4):301-11. doi: 10.1016/j.ccr.2005.03.003.
Recent structural studies of epidermal growth factor receptor (EGFR) family extracellular regions have identified an unexpected mechanism for ligand-induced receptor dimerization that has important implications for activation and inhibition of these receptors. Here we describe the 2.8 angstroms resolution X-ray crystal structure of the antigen binding (Fab) fragment from cetuximab (Erbitux), an inhibitory anti-EGFR antibody, in complex with the soluble extracellular region of EGFR (sEGFR). The sEGFR is in the characteristic "autoinhibited" or "tethered" inactive configuration. Cetuximab interacts exclusively with domain III of sEGFR, partially occluding the ligand binding region on this domain and sterically preventing the receptor from adopting the extended conformation required for dimerization. We suggest that both these effects contribute to potent inhibition of EGFR activation.
最近对表皮生长因子受体（EGFR）家族细胞外区域的结构研究发现了一种意想不到的配体诱导受体二聚化机制，这对这些受体的激活和抑制具有重要意义。在此，我们描述了西妥昔单抗（爱必妥）（一种抑制性抗EGFR抗体）的抗原结合（Fab）片段与EGFR可溶性细胞外区域（sEGFR）复合物的2.8埃分辨率X射线晶体结构。sEGFR处于特征性的“自抑制”或“束缚”非活性构象。西妥昔单抗仅与sEGFR的结构域III相互作用，部分封闭该结构域上的配体结合区域，并在空间上阻止受体采取二聚化所需的伸展构象。我们认为这两种作用都有助于有效抑制EGFR激活。
