STRUCTURAL STUDY OF DIPHTHERIA TOXIN & RECEPTOR COMPLEX

白喉毒素（DT）细胞毒性作用的第一步是 毒素分子与易感细胞表面的结合。 毒素结合的细胞受体是膜锚定的 肝素结合EGF样生长因子（HBEGF）的前体。 我们有 在2.65 E下测定了DT与HBEGF复合物的晶体结构 分辨率 HBEGF与另一种生长因子heregulin同源 EGF家族 调蛋白是HER4的活化配体， 受体，其在乳腺癌细胞中过表达。 的 DT之间原子相互作用的详细结构信息 HBEGF是设计突变的基础， 改变DT的结合特异性。 长期目标是 工程DT将识别heregulin并作为治疗药物 乳腺癌细胞生长抑制剂。

The first step in the cytotoxic action of diphtheria toxin (DT) is binding of the toxin molecule to the surface of a susceptible cell. The cellular receptor for toxin binding is the membrane-anchored precursor of heparin-binding EGF-like growth factor (HBEGF). We have determined the crystal structure of DT in complex with HBEGF at 2.65 E resolution. HBEGF is homologous to heregulin, another growth factor from the EGF family. Heregulin is the activating ligand for the HER4 receptor, which is overexpressed in breast carcinoma cells. The detailed structural information on the atomic interactions between DT and HBEGF is serving as a basis for designing mutations that will alter the binding specificity of DT. The long-term objective is an engineered DT that will recognize heregulin and serve as a therapeutic agent for inhibiting growth of breast cancer cells.