Matuzumab binding to EGFR prevents the conformational rearrangement required for dimerization
Matuzumab binding to EGFR prevents the conformational rearrangement required for dimerization
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DOI：
10.1016/j.ccr.2008.02.019
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发表时间：
2008-04-01
期刊：
影响因子：
50.3
通讯作者：
Ferguson, Kathryn M.
中科院分区：
文献类型：
--
作者：
Schmiedel, Judith;Blaukat, Andree;Ferguson, Kathryn M.
越来越多的靶向表达表皮生长因子受体（EGFR）的肿瘤的治疗性抗体正处于临床使用或临床开发的后期阶段。在这里，我们研究了治疗性抗体马妥珠单抗（EMD 72000）抑制EGFR活化的分子基础。我们描述的X-射线晶体结构的Fab片段的马妥珠单抗（Fab 72000）在复杂的分离结构域III从细胞外区域的EGFR。Fab 72000与EGFR上的表位相互作用，该表位不同于结构域III上的配体结合区和西妥昔单抗/爱必妥表位。马妥珠单抗通过在空间上阻止高亲和力配体结合和受体二聚化必须发生的结构域重排和局部构象变化，间接阻断配体诱导的受体活化。
An increasing number of therapeutic antibodies targeting tumors that express the epidermal growth factor receptor (EGFR) are in clinical use or late stages of clinical development. Here we investigate the molecular basis for inhibition of EGFR activation by the therapeutic antibody matuzumab (EMD72000). We describe the X-ray crystal structure of the Fab fragment of matuzumab (Fab72000) in complex with isolated domain III from the extracellular region of EGFR. Fab72000 interacts with an epitope on EGFR that is distinct from the ligand-binding region on domain III and from the cetuximab/Erbitux epitope. Matuzumab blocks ligand-induced receptor activation indirectly by sterically preventing the domain rearrangement and local conformational changes that must occur for high-affinity ligand binding and receptor dimerization.