Structural basis for inhibition of the epidermal growth factor receptor by cetuximab
Structural basis for inhibition of the epidermal growth factor receptor by cetuximab
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DOI：
10.1016/j.ccr.2005.03.003
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发表时间：
2005-04-01
期刊：
影响因子：
50.3
通讯作者：
Ferguson, KM
中科院分区：
文献类型：
--
作者：
Li, SQ;Schmitz, KR;Ferguson, KM
最近的表皮生长因子受体（EGFR）家族细胞外区域的结构研究已经确定了一个意想不到的配体诱导的受体二聚化的机制，这些受体的激活和抑制具有重要意义。在这里，我们描述了2.8埃分辨率的X-射线晶体结构的抗原结合（Fab）片段从西妥昔单抗（爱必妥），抑制性抗EGFR抗体，在复合物的可溶性细胞外区域的EGFR（sEGFR）。sEGFR处于特征性的“自抑制”或“栓系”非活性构型。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，并在空间上阻止受体采用二聚化所需的延伸构象。我们认为这两种作用都有助于有效抑制EGFR活化。
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 angstrom 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.